Breast Cancer

CHICAGO – Adding carboplatin to standard chemotherapy for patients with basal-like breast cancer neither increased toxicity of the regimen nor improved its efficacy, reported investigators at the annual meeting of the American Society of Clinical Oncology.

Patients who were randomized to receive epirubicin and cyclophosphamide followed by docetaxel (Taxotere) and carboplatin had a pathologically confirmed complete response (pCR) rate of 30%, compared with 35% for patients who were assigned to a similar regimen without the platinum compound (P = .6064).

Mastectomy rates were also similar between the groups, at 28% and 33%, respectively, reported Dr. Emilio Alba from Hospital Universitario Virgen de la Victoria in Malaga, Spain, and colleagues in the Spanish Breast Cancer Research Group (GEICAM).

The rationale for adding carboplatin to a standard chemotherapy regimen is that basal-like breast cancer and the genetically similar triple-negative breast cancer subtypes are known to be sensitive to DNA-damaging agents such as alkylators, anthracyclines, and – theoretically – platinum compounds. But the patients in the study had already been exposed to an anthracycline (epirubicin), which may explain the lack of efficacy of a second DNA-damaging agent, the investigators speculated.

"Do we know whether a platinum compound is necessary for the efficacy? There are many other potential agents under investigation, including a PARP [poly (ADP [adenosine diphosphate]–ribose) polymerase] inhibitor, and we don’t really know what the molecular signature is to predict the benefit of adding another toxin," said Dr. George Somlo of the City of Hope Cancer Center in Duarte, Calif., who commented on the study in a poster discussion session.

He added that there are data to suggest that paclitaxel may be a better partner than docetaxel in this population.

The GEICAM investigators enrolled women with tumors 2 cm in diameter or greater (smaller tumors were allowed if axillary nodes were positive) and basal-like disease by immunophenotype (negative for the estrogen receptor, progesterone receptor, and HER2, but positive for cytokeratin 5/6 and/or epidermal growth factor receptor).

The patients were randomly assigned to receive either epirubicin 90 mg/m² plus cyclophosphamide 600 mg/m² for four cycles, followed by either docetaxel 100 mg/m² for four cycles, or docetaxel 75 mg/m² plus carboplatin to an area-under-the-curve dose of 6 mL/min for four cycles. In all, 46 patients were assigned to standard therapy, and 47 to the carboplatin arm.

The primary end point was pCR measured by Miller and Payne criteria. Secondary end points included clinical response, toxicity, type of surgery, and axillary status at surgery.

In an intention-to-treat analysis, the overall response rate was 72% in the standard arm and 79% in the carboplatin arm. The pCRs in the breast and axilla combined were 30% in each arm.

Grade 3/4 toxicities were generally similar between the treatment groups, with neutropenia, febrile neutropenia, fatigue, infection, and vomiting more frequent in the standard therapy arm; and hemoglobinemia, leukocytopenia, nausea and syncope more frequent in the carboplatin group.

The authors recommend that "the findings from this trial should be taken into account in the future development of PARP inhibitors."

The study was supported by the GEICAM. The authors had no disclosures.

CHICAGO – Adding carboplatin to standard chemotherapy for patients with basal-like breast cancer neither increased toxicity of the regimen nor improved its efficacy, reported investigators at the annual meeting of the American Society of Clinical Oncology.

Patients who were randomized to receive epirubicin and cyclophosphamide followed by docetaxel (Taxotere) and carboplatin had a pathologically confirmed complete response (pCR) rate of 30%, compared with 35% for patients who were assigned to a similar regimen without the platinum compound (P = .6064).

Mastectomy rates were also similar between the groups, at 28% and 33%, respectively, reported Dr. Emilio Alba from Hospital Universitario Virgen de la Victoria in Malaga, Spain, and colleagues in the Spanish Breast Cancer Research Group (GEICAM).

The rationale for adding carboplatin to a standard chemotherapy regimen is that basal-like breast cancer and the genetically similar triple-negative breast cancer subtypes are known to be sensitive to DNA-damaging agents such as alkylators, anthracyclines, and – theoretically – platinum compounds. But the patients in the study had already been exposed to an anthracycline (epirubicin), which may explain the lack of efficacy of a second DNA-damaging agent, the investigators speculated.

"Do we know whether a platinum compound is necessary for the efficacy? There are many other potential agents under investigation, including a PARP [poly (ADP [adenosine diphosphate]–ribose) polymerase] inhibitor, and we don’t really know what the molecular signature is to predict the benefit of adding another toxin," said Dr. George Somlo of the City of Hope Cancer Center in Duarte, Calif., who commented on the study in a poster discussion session.

He added that there are data to suggest that paclitaxel may be a better partner than docetaxel in this population.

The GEICAM investigators enrolled women with tumors 2 cm in diameter or greater (smaller tumors were allowed if axillary nodes were positive) and basal-like disease by immunophenotype (negative for the estrogen receptor, progesterone receptor, and HER2, but positive for cytokeratin 5/6 and/or epidermal growth factor receptor).

The patients were randomly assigned to receive either epirubicin 90 mg/m² plus cyclophosphamide 600 mg/m² for four cycles, followed by either docetaxel 100 mg/m² for four cycles, or docetaxel 75 mg/m² plus carboplatin to an area-under-the-curve dose of 6 mL/min for four cycles. In all, 46 patients were assigned to standard therapy, and 47 to the carboplatin arm.

The primary end point was pCR measured by Miller and Payne criteria. Secondary end points included clinical response, toxicity, type of surgery, and axillary status at surgery.

In an intention-to-treat analysis, the overall response rate was 72% in the standard arm and 79% in the carboplatin arm. The pCRs in the breast and axilla combined were 30% in each arm.

Grade 3/4 toxicities were generally similar between the treatment groups, with neutropenia, febrile neutropenia, fatigue, infection, and vomiting more frequent in the standard therapy arm; and hemoglobinemia, leukocytopenia, nausea and syncope more frequent in the carboplatin group.

The authors recommend that "the findings from this trial should be taken into account in the future development of PARP inhibitors."

The study was supported by the GEICAM. The authors had no disclosures.

CHICAGO – Adding carboplatin to standard chemotherapy for patients with basal-like breast cancer neither increased toxicity of the regimen nor improved its efficacy, reported investigators at the annual meeting of the American Society of Clinical Oncology.

Patients who were randomized to receive epirubicin and cyclophosphamide followed by docetaxel (Taxotere) and carboplatin had a pathologically confirmed complete response (pCR) rate of 30%, compared with 35% for patients who were assigned to a similar regimen without the platinum compound (P = .6064).

Mastectomy rates were also similar between the groups, at 28% and 33%, respectively, reported Dr. Emilio Alba from Hospital Universitario Virgen de la Victoria in Malaga, Spain, and colleagues in the Spanish Breast Cancer Research Group (GEICAM).

The rationale for adding carboplatin to a standard chemotherapy regimen is that basal-like breast cancer and the genetically similar triple-negative breast cancer subtypes are known to be sensitive to DNA-damaging agents such as alkylators, anthracyclines, and – theoretically – platinum compounds. But the patients in the study had already been exposed to an anthracycline (epirubicin), which may explain the lack of efficacy of a second DNA-damaging agent, the investigators speculated.

"Do we know whether a platinum compound is necessary for the efficacy? There are many other potential agents under investigation, including a PARP [poly (ADP [adenosine diphosphate]–ribose) polymerase] inhibitor, and we don’t really know what the molecular signature is to predict the benefit of adding another toxin," said Dr. George Somlo of the City of Hope Cancer Center in Duarte, Calif., who commented on the study in a poster discussion session.

He added that there are data to suggest that paclitaxel may be a better partner than docetaxel in this population.

The GEICAM investigators enrolled women with tumors 2 cm in diameter or greater (smaller tumors were allowed if axillary nodes were positive) and basal-like disease by immunophenotype (negative for the estrogen receptor, progesterone receptor, and HER2, but positive for cytokeratin 5/6 and/or epidermal growth factor receptor).

The patients were randomly assigned to receive either epirubicin 90 mg/m² plus cyclophosphamide 600 mg/m² for four cycles, followed by either docetaxel 100 mg/m² for four cycles, or docetaxel 75 mg/m² plus carboplatin to an area-under-the-curve dose of 6 mL/min for four cycles. In all, 46 patients were assigned to standard therapy, and 47 to the carboplatin arm.

The primary end point was pCR measured by Miller and Payne criteria. Secondary end points included clinical response, toxicity, type of surgery, and axillary status at surgery.

In an intention-to-treat analysis, the overall response rate was 72% in the standard arm and 79% in the carboplatin arm. The pCRs in the breast and axilla combined were 30% in each arm.

Grade 3/4 toxicities were generally similar between the treatment groups, with neutropenia, febrile neutropenia, fatigue, infection, and vomiting more frequent in the standard therapy arm; and hemoglobinemia, leukocytopenia, nausea and syncope more frequent in the carboplatin group.

The authors recommend that "the findings from this trial should be taken into account in the future development of PARP inhibitors."

The study was supported by the GEICAM. The authors had no disclosures.

CHICAGO – Eating bars rich in flaxseed failed to reduce hot flashes for postmenopausal women in a randomized, placebo-controlled, phase III trial conducted by the North Central Cancer Treatment Group.

Mean hot flash scores fell comparably in both arms of the study, which enrolled breast cancer patients and women who never had the disease. Instead of relief from this troubling symptom, many participants reported GI distress.

"Our findings do not support the use of 410 mg of flaxseed lignans for the reduction of hot flashes. The gastrointestinal side effects seen in both groups were more likely due to the fiber content in the flaxseed and the placebo bars," said Dr. Sandhya Pruthi of the Mayo Clinic in Rochester, Minn. She presented the results at the annual meeting of the American Society of Clinical Oncology.

"Because hot flashes can negatively impact quality of life for many women, there is increasing interest in the use of complementary therapies such as flaxseed," Dr. Pruthi said, laying out the rationale for the trial.

Flaxseed is an annual plant, rich in lignans, which are a major class of phytoestrogens, she said. It is thought to have a weak estrogenlike effect, as well as estrogen antagonist effect.

In 2005, a pilot study of flaxseed was conducted in 30 women. They were given 400 mg of ground flaxseed, and investigators reported a 57% reduction in hot flash scores and a 50% reduction in hot flash frequency. This – along with a patient who claimed that flaxseed was successful in treating her hot flashes – led to the current trial, said Dr. Pruthi.

To be eligible, women with or without a history of breast cancer had to have more than 28 hot flashes per week. In all, 188 women were enrolled and 178 were randomized (88 to flaxseed bars containing 410 mg of lignans and fiber, and 90 to placebo bars containing protein and fiber, but no flaxseed, soy, or lignans). For 6 weeks, the participants were to eat one bar per day. The primary end point was a change from baseline in hot flash scores at week 6.

Of the entire group, 91 had a history of breast cancer but were without active disease. This group included women who were being treated with an aromatase inhibitor or tamoxifen.

Mean hot flash scores decreased by 4.9 units (about 33%) in the flaxseed arm, and 3.5 (about 29%) in the placebo arm (P = .29). "There was no significant difference in the reduction of hot flash scores between the two arms," said Dr. Pruthi.

No statistically significant toxicity was experienced by women in either arm, but both groups reported abdominal distention, gas, diarrhea, and nausea.

Although the results were disappointing, the trial does not leave women without remedies for hot flashes. Dr. Pruthi noted that venlafaxine and gabapentin were effective, and had been studied in randomized, placebo-controlled trials. "So we do have options for women who are not wanting to take hormonal therapies like estrogen or progesterone, especially with a history of breast cancer," she said.

"However, there are side effects with those drugs. Patients need to balance between treating their symptoms and managing their side effects, which is why we need to do more studies in other complementary therapies that we think might have [fewer side effects] and still give us the benefit of treating hot flashes," she said.

Dr. Pruthi reported having nothing to disclose. This study was funded by the National Cancer Institute.

CHICAGO – Eating bars rich in flaxseed failed to reduce hot flashes for postmenopausal women in a randomized, placebo-controlled, phase III trial conducted by the North Central Cancer Treatment Group.

Mean hot flash scores fell comparably in both arms of the study, which enrolled breast cancer patients and women who never had the disease. Instead of relief from this troubling symptom, many participants reported GI distress.

"Our findings do not support the use of 410 mg of flaxseed lignans for the reduction of hot flashes. The gastrointestinal side effects seen in both groups were more likely due to the fiber content in the flaxseed and the placebo bars," said Dr. Sandhya Pruthi of the Mayo Clinic in Rochester, Minn. She presented the results at the annual meeting of the American Society of Clinical Oncology.

"Because hot flashes can negatively impact quality of life for many women, there is increasing interest in the use of complementary therapies such as flaxseed," Dr. Pruthi said, laying out the rationale for the trial.

Flaxseed is an annual plant, rich in lignans, which are a major class of phytoestrogens, she said. It is thought to have a weak estrogenlike effect, as well as estrogen antagonist effect.

In 2005, a pilot study of flaxseed was conducted in 30 women. They were given 400 mg of ground flaxseed, and investigators reported a 57% reduction in hot flash scores and a 50% reduction in hot flash frequency. This – along with a patient who claimed that flaxseed was successful in treating her hot flashes – led to the current trial, said Dr. Pruthi.

To be eligible, women with or without a history of breast cancer had to have more than 28 hot flashes per week. In all, 188 women were enrolled and 178 were randomized (88 to flaxseed bars containing 410 mg of lignans and fiber, and 90 to placebo bars containing protein and fiber, but no flaxseed, soy, or lignans). For 6 weeks, the participants were to eat one bar per day. The primary end point was a change from baseline in hot flash scores at week 6.

Of the entire group, 91 had a history of breast cancer but were without active disease. This group included women who were being treated with an aromatase inhibitor or tamoxifen.

Mean hot flash scores decreased by 4.9 units (about 33%) in the flaxseed arm, and 3.5 (about 29%) in the placebo arm (P = .29). "There was no significant difference in the reduction of hot flash scores between the two arms," said Dr. Pruthi.

No statistically significant toxicity was experienced by women in either arm, but both groups reported abdominal distention, gas, diarrhea, and nausea.

Although the results were disappointing, the trial does not leave women without remedies for hot flashes. Dr. Pruthi noted that venlafaxine and gabapentin were effective, and had been studied in randomized, placebo-controlled trials. "So we do have options for women who are not wanting to take hormonal therapies like estrogen or progesterone, especially with a history of breast cancer," she said.

"However, there are side effects with those drugs. Patients need to balance between treating their symptoms and managing their side effects, which is why we need to do more studies in other complementary therapies that we think might have [fewer side effects] and still give us the benefit of treating hot flashes," she said.

Dr. Pruthi reported having nothing to disclose. This study was funded by the National Cancer Institute.

CHICAGO – Eating bars rich in flaxseed failed to reduce hot flashes for postmenopausal women in a randomized, placebo-controlled, phase III trial conducted by the North Central Cancer Treatment Group.

Mean hot flash scores fell comparably in both arms of the study, which enrolled breast cancer patients and women who never had the disease. Instead of relief from this troubling symptom, many participants reported GI distress.

"Our findings do not support the use of 410 mg of flaxseed lignans for the reduction of hot flashes. The gastrointestinal side effects seen in both groups were more likely due to the fiber content in the flaxseed and the placebo bars," said Dr. Sandhya Pruthi of the Mayo Clinic in Rochester, Minn. She presented the results at the annual meeting of the American Society of Clinical Oncology.

"Because hot flashes can negatively impact quality of life for many women, there is increasing interest in the use of complementary therapies such as flaxseed," Dr. Pruthi said, laying out the rationale for the trial.

Flaxseed is an annual plant, rich in lignans, which are a major class of phytoestrogens, she said. It is thought to have a weak estrogenlike effect, as well as estrogen antagonist effect.

In 2005, a pilot study of flaxseed was conducted in 30 women. They were given 400 mg of ground flaxseed, and investigators reported a 57% reduction in hot flash scores and a 50% reduction in hot flash frequency. This – along with a patient who claimed that flaxseed was successful in treating her hot flashes – led to the current trial, said Dr. Pruthi.

To be eligible, women with or without a history of breast cancer had to have more than 28 hot flashes per week. In all, 188 women were enrolled and 178 were randomized (88 to flaxseed bars containing 410 mg of lignans and fiber, and 90 to placebo bars containing protein and fiber, but no flaxseed, soy, or lignans). For 6 weeks, the participants were to eat one bar per day. The primary end point was a change from baseline in hot flash scores at week 6.

Of the entire group, 91 had a history of breast cancer but were without active disease. This group included women who were being treated with an aromatase inhibitor or tamoxifen.

Mean hot flash scores decreased by 4.9 units (about 33%) in the flaxseed arm, and 3.5 (about 29%) in the placebo arm (P = .29). "There was no significant difference in the reduction of hot flash scores between the two arms," said Dr. Pruthi.

No statistically significant toxicity was experienced by women in either arm, but both groups reported abdominal distention, gas, diarrhea, and nausea.

Although the results were disappointing, the trial does not leave women without remedies for hot flashes. Dr. Pruthi noted that venlafaxine and gabapentin were effective, and had been studied in randomized, placebo-controlled trials. "So we do have options for women who are not wanting to take hormonal therapies like estrogen or progesterone, especially with a history of breast cancer," she said.

"However, there are side effects with those drugs. Patients need to balance between treating their symptoms and managing their side effects, which is why we need to do more studies in other complementary therapies that we think might have [fewer side effects] and still give us the benefit of treating hot flashes," she said.

Dr. Pruthi reported having nothing to disclose. This study was funded by the National Cancer Institute.

CHICAGO – Adding bevacizumab to chemotherapy may prolong survival in women with newly diagnosed ovarian, primary peritoneal, or fallopian tube cancer who are at high risk for poor outcomes, suggests an interim analysis from the randomized phase III ICON7 trial.

Trials results, reported at a median follow-up of 28 months, showed that when this antiangiogenic agent was added during and after chemotherapy, the risk of death was reduced by a significant 36% among high-risk patients. There was a nonsignificant 15% risk reduction among the study population as a whole.

"Bevacizumab is the first new active agent for the front-line treatment of ovarian cancer in more than 15 years," lead investigator Dr. Gunnar Kristensen said in a press briefing.

"Based on this interim analysis ... we see there is an overall trend for improvement of overall survival with bevacizumab," he said. "The treatment effect is greater in high-risk patients, which may be of clinical relevance."

Indeed, Dr. Kristensen acknowledged, cost considerations and lack of substantial survival benefit in patients who are not at high risk may ultimately guide use of bevacizumab in this context.

"Here we present our data, and then of course it is up to the doctors how they will use the drug," he said. "Personally, I ... [agree] on restricting it to the high-risk group."

The trial differs from the OCEANS trial, also reported at the meeting, in the dose and duration of bevacizumab used, and the patient population, noted moderator Dr. Andrew Seidman, an attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, both in New York.

"However, the consistent results of these studies, in addition to a previously reported trial, the GOG-0218 trial, and the already documented efficacy of bevacizumab as a single agent in ovarian cancer, I think do all lend support to a potentially important role for bevacizumab as the first biologic agent to be used in this disease," he said.

The investigators conducted the trial among 1,528 women with newly diagnosed, high-risk early or advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. All underwent debulking surgery.

The patients were assigned in nearly equal numbers to receive six cycles of standard chemotherapy (carboplatin and paclitaxel) at 3-week intervals alone, or the same chemotherapy given concurrently with bevacizumab (Avastin, 7.5 mg/kg) followed by single-agent bevacizumab every 3 weeks for 12 additional cycles or until progression.

"This treatment was tolerated well, without a substantial increase in side effects," Dr. Kristensen reported. "The side effects were mild and manageable."

The mature progression-free survival results, previously reported at the 2010 European Society for Medical Oncology meeting, showed that the median duration of progression-free survival was 19.0 months with bevacizumab and 17.3 months without it (hazard ratio, 0.81; P = .004).

U.S. and European regulatory authorities requested an interim analysis of overall survival, in support of applications to license the drug for this indication, according to Dr. Kristensen, a senior consultant in the department for gynecologic oncology at Norwegian Radium Hospital in Oslo.

The interim analysis of overall survival, which was based on 53% of the number of events needed for the final analysis, showed that the risk of death in the entire trial population was lower with bevacizumab than without it, but not significantly so (hazard ratio, 0.85; P = .11).

However, in a preplanned subgroup analysis among the 30% of patients falling into a high-risk category – those with stage III disease whose debulking surgery was suboptimal (leaving more than 1 cm of residual tumor) and those with stage IV disease – there was a significant 36% reduction in the risk of death (hazard ratio, 0.64; P = .002). In this subgroup, the median duration of survival was 7.8 months longer with bevacizumab (36.6 vs. 28.8 months).

Final overall survival results are expected in 2013, according to Dr. Kristensen. "We have to remember that the data [are] premature. It’s an interim analysis. There are very few events in this group of patients" not at high risk, he cautioned when presenting the results in a session. "So we have to await the final analysis in 2 years before we can make conclusions about this group."

The reason for the apparent greater benefit in the high-risk group is as yet unclear, he said, while agreeing with an attendee that tumors that are more difficult to optimally debulk may be more aggressive and more susceptible to antiangiogenic therapy.

"We have just used clinical parameters here, whether they were optimally debulked or not, and we see that we have the main effect in the suboptimally debulked population. Then come all the questions about the biology," he commented. "We have an ancillary research program along with the study, but it will, of course, take time."

In the updated analysis of progression-free survival, the median duration of progression-free survival in the entire trial population continued to be better with bevacizumab, at 19.8 months, than without it, at 17.4 months (hazard ratio, 0.87; P = .039).

Dr. Kristensen reported that he is a consultant to Roche. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding bevacizumab to chemotherapy may prolong survival in women with newly diagnosed ovarian, primary peritoneal, or fallopian tube cancer who are at high risk for poor outcomes, suggests an interim analysis from the randomized phase III ICON7 trial.

Trials results, reported at a median follow-up of 28 months, showed that when this antiangiogenic agent was added during and after chemotherapy, the risk of death was reduced by a significant 36% among high-risk patients. There was a nonsignificant 15% risk reduction among the study population as a whole.

"Bevacizumab is the first new active agent for the front-line treatment of ovarian cancer in more than 15 years," lead investigator Dr. Gunnar Kristensen said in a press briefing.

"Based on this interim analysis ... we see there is an overall trend for improvement of overall survival with bevacizumab," he said. "The treatment effect is greater in high-risk patients, which may be of clinical relevance."

Indeed, Dr. Kristensen acknowledged, cost considerations and lack of substantial survival benefit in patients who are not at high risk may ultimately guide use of bevacizumab in this context.

"Here we present our data, and then of course it is up to the doctors how they will use the drug," he said. "Personally, I ... [agree] on restricting it to the high-risk group."

The trial differs from the OCEANS trial, also reported at the meeting, in the dose and duration of bevacizumab used, and the patient population, noted moderator Dr. Andrew Seidman, an attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, both in New York.

"However, the consistent results of these studies, in addition to a previously reported trial, the GOG-0218 trial, and the already documented efficacy of bevacizumab as a single agent in ovarian cancer, I think do all lend support to a potentially important role for bevacizumab as the first biologic agent to be used in this disease," he said.

The investigators conducted the trial among 1,528 women with newly diagnosed, high-risk early or advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. All underwent debulking surgery.

The patients were assigned in nearly equal numbers to receive six cycles of standard chemotherapy (carboplatin and paclitaxel) at 3-week intervals alone, or the same chemotherapy given concurrently with bevacizumab (Avastin, 7.5 mg/kg) followed by single-agent bevacizumab every 3 weeks for 12 additional cycles or until progression.

"This treatment was tolerated well, without a substantial increase in side effects," Dr. Kristensen reported. "The side effects were mild and manageable."

The mature progression-free survival results, previously reported at the 2010 European Society for Medical Oncology meeting, showed that the median duration of progression-free survival was 19.0 months with bevacizumab and 17.3 months without it (hazard ratio, 0.81; P = .004).

U.S. and European regulatory authorities requested an interim analysis of overall survival, in support of applications to license the drug for this indication, according to Dr. Kristensen, a senior consultant in the department for gynecologic oncology at Norwegian Radium Hospital in Oslo.

The interim analysis of overall survival, which was based on 53% of the number of events needed for the final analysis, showed that the risk of death in the entire trial population was lower with bevacizumab than without it, but not significantly so (hazard ratio, 0.85; P = .11).

However, in a preplanned subgroup analysis among the 30% of patients falling into a high-risk category – those with stage III disease whose debulking surgery was suboptimal (leaving more than 1 cm of residual tumor) and those with stage IV disease – there was a significant 36% reduction in the risk of death (hazard ratio, 0.64; P = .002). In this subgroup, the median duration of survival was 7.8 months longer with bevacizumab (36.6 vs. 28.8 months).

Final overall survival results are expected in 2013, according to Dr. Kristensen. "We have to remember that the data [are] premature. It’s an interim analysis. There are very few events in this group of patients" not at high risk, he cautioned when presenting the results in a session. "So we have to await the final analysis in 2 years before we can make conclusions about this group."

The reason for the apparent greater benefit in the high-risk group is as yet unclear, he said, while agreeing with an attendee that tumors that are more difficult to optimally debulk may be more aggressive and more susceptible to antiangiogenic therapy.

"We have just used clinical parameters here, whether they were optimally debulked or not, and we see that we have the main effect in the suboptimally debulked population. Then come all the questions about the biology," he commented. "We have an ancillary research program along with the study, but it will, of course, take time."

In the updated analysis of progression-free survival, the median duration of progression-free survival in the entire trial population continued to be better with bevacizumab, at 19.8 months, than without it, at 17.4 months (hazard ratio, 0.87; P = .039).

Dr. Kristensen reported that he is a consultant to Roche. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO – Adding bevacizumab to chemotherapy may prolong survival in women with newly diagnosed ovarian, primary peritoneal, or fallopian tube cancer who are at high risk for poor outcomes, suggests an interim analysis from the randomized phase III ICON7 trial.

Trials results, reported at a median follow-up of 28 months, showed that when this antiangiogenic agent was added during and after chemotherapy, the risk of death was reduced by a significant 36% among high-risk patients. There was a nonsignificant 15% risk reduction among the study population as a whole.

"Bevacizumab is the first new active agent for the front-line treatment of ovarian cancer in more than 15 years," lead investigator Dr. Gunnar Kristensen said in a press briefing.

"Based on this interim analysis ... we see there is an overall trend for improvement of overall survival with bevacizumab," he said. "The treatment effect is greater in high-risk patients, which may be of clinical relevance."

Indeed, Dr. Kristensen acknowledged, cost considerations and lack of substantial survival benefit in patients who are not at high risk may ultimately guide use of bevacizumab in this context.

"Here we present our data, and then of course it is up to the doctors how they will use the drug," he said. "Personally, I ... [agree] on restricting it to the high-risk group."

The trial differs from the OCEANS trial, also reported at the meeting, in the dose and duration of bevacizumab used, and the patient population, noted moderator Dr. Andrew Seidman, an attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, both in New York.

"However, the consistent results of these studies, in addition to a previously reported trial, the GOG-0218 trial, and the already documented efficacy of bevacizumab as a single agent in ovarian cancer, I think do all lend support to a potentially important role for bevacizumab as the first biologic agent to be used in this disease," he said.

The investigators conducted the trial among 1,528 women with newly diagnosed, high-risk early or advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. All underwent debulking surgery.

The patients were assigned in nearly equal numbers to receive six cycles of standard chemotherapy (carboplatin and paclitaxel) at 3-week intervals alone, or the same chemotherapy given concurrently with bevacizumab (Avastin, 7.5 mg/kg) followed by single-agent bevacizumab every 3 weeks for 12 additional cycles or until progression.

"This treatment was tolerated well, without a substantial increase in side effects," Dr. Kristensen reported. "The side effects were mild and manageable."

The mature progression-free survival results, previously reported at the 2010 European Society for Medical Oncology meeting, showed that the median duration of progression-free survival was 19.0 months with bevacizumab and 17.3 months without it (hazard ratio, 0.81; P = .004).

U.S. and European regulatory authorities requested an interim analysis of overall survival, in support of applications to license the drug for this indication, according to Dr. Kristensen, a senior consultant in the department for gynecologic oncology at Norwegian Radium Hospital in Oslo.

The interim analysis of overall survival, which was based on 53% of the number of events needed for the final analysis, showed that the risk of death in the entire trial population was lower with bevacizumab than without it, but not significantly so (hazard ratio, 0.85; P = .11).

However, in a preplanned subgroup analysis among the 30% of patients falling into a high-risk category – those with stage III disease whose debulking surgery was suboptimal (leaving more than 1 cm of residual tumor) and those with stage IV disease – there was a significant 36% reduction in the risk of death (hazard ratio, 0.64; P = .002). In this subgroup, the median duration of survival was 7.8 months longer with bevacizumab (36.6 vs. 28.8 months).

Final overall survival results are expected in 2013, according to Dr. Kristensen. "We have to remember that the data [are] premature. It’s an interim analysis. There are very few events in this group of patients" not at high risk, he cautioned when presenting the results in a session. "So we have to await the final analysis in 2 years before we can make conclusions about this group."

The reason for the apparent greater benefit in the high-risk group is as yet unclear, he said, while agreeing with an attendee that tumors that are more difficult to optimally debulk may be more aggressive and more susceptible to antiangiogenic therapy.

"We have just used clinical parameters here, whether they were optimally debulked or not, and we see that we have the main effect in the suboptimally debulked population. Then come all the questions about the biology," he commented. "We have an ancillary research program along with the study, but it will, of course, take time."

In the updated analysis of progression-free survival, the median duration of progression-free survival in the entire trial population continued to be better with bevacizumab, at 19.8 months, than without it, at 17.4 months (hazard ratio, 0.87; P = .039).

Dr. Kristensen reported that he is a consultant to Roche. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies. Dr. Davidson and Dr. Kensler disclosed no relevant conflicts of interest.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies. Dr. Davidson and Dr. Kensler disclosed no relevant conflicts of interest.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies. Dr. Davidson and Dr. Kensler disclosed no relevant conflicts of interest.

CHICAGO – Adding regional nodal irradiation to whole-breast irradiation significantly improved disease-free survival, but not overall survival in a randomized multi-center phase III trial of women with node-positive or high-risk node-negative disease treated with breast-conserving surgery and adjuvant therapy.

An interim analysis of 1,832 women with breast cancer found that after a median follow-up of 62 months, whole breast irradiation (WBI) plus regional nodal irradiation (RNI) significantly reduced the risk of locoregional recurrence from 5.5% to 3.2% (P = .02; hazard ratio 0.8) and distant recurrence from 13% to 7.6% (P = .002; HR 0.64), lead investigator Dr. Timothy Whelan reported at the annual meeting of the American Society of Clinical Oncology.

Overall survival in the intergroup trial was 9.3% with WBI vs. 7.7% with the combined radiation regimen, but the difference did not reach statistical significance (P = .07; HR 0.76).

In view of the positive findings, the data safety monitoring committee recommended that the results be released, Dr. Whelan told reporters at a press briefing during the meeting.

He suggested that the findings could expand the pool of women offered RNI. Currently, ASCO and the American Society for Therapeutic Radiology and Oncology (ASTRO) guidelines recommend locoregional radiation following mastectomy for tumors greater than 5 cm or with more than three positive axillary nodes.

Of the 1,832 women enrolled in the National Cancer Institute of Canada Clinical Trials Group MA.20 trial, 85% had one to three positive lymph nodes, and 10% had high-risk, node-negative breast cancer. All women were treated with breast-conserving surgery plus adjuvant chemotherapy or endocrine therapy.

"Results from MA.20 suggest that all women with node-positive disease be offered regional node irradiation provided they are made aware of the associated toxicities," said Dr. Whelan, head of radiation oncology at McMaster University and the Juravinski Cancer Centre, Hamilton, Ont.

The addition of RNI to WBI significantly increased the rates of grade 2 or higher dermatitis from 40% to 50% (P less than .001), pneumonitis from 0.2% to 1.3% (P = .01), and lymphedema from 4% to 7% (P = .004). The lymphedema was primarily grade 2, Dr. Whelen pointed out.

Reporters questioned why an earlier unpublished French study did not find a benefit with RNI, while MA.20 did. Dr. Whelan responded that regional radiation in the earlier study was limited to the internal mammary lymph nodes alone, whereas MA.20 expanded the upper radiation field to include the upper internal mammary nodes, supraclavicular nodes, and high axillary nodes. He could not explain why overall survival was not improved.

Radiation dosages for WBI were 50 Gy in 25 fractions plus a boost at the discretion of the cancer center of 10 Gy in 5 fractions. The RNI dosage was 45 Gy in 25 fractions.

WBI and RNI were delivered concurrently, so the added therapy would not require additional office visits for women, and would modestly lengthen the therapy.

The researchers will continue to monitor the patients and evaluate new techniques to reduce potential side effects, he said in an interview.

MA.20 was sponsored by the Canadian Cancer Society Research Institute, National Cancer Institute/Cancer Therapy Evaluation Program, and Canadian Breast Cancer Research Alliance. Dr. Whelan and his coauthors disclosed no conflicts of interest.

CHICAGO – Adding regional nodal irradiation to whole-breast irradiation significantly improved disease-free survival, but not overall survival in a randomized multi-center phase III trial of women with node-positive or high-risk node-negative disease treated with breast-conserving surgery and adjuvant therapy.

An interim analysis of 1,832 women with breast cancer found that after a median follow-up of 62 months, whole breast irradiation (WBI) plus regional nodal irradiation (RNI) significantly reduced the risk of locoregional recurrence from 5.5% to 3.2% (P = .02; hazard ratio 0.8) and distant recurrence from 13% to 7.6% (P = .002; HR 0.64), lead investigator Dr. Timothy Whelan reported at the annual meeting of the American Society of Clinical Oncology.

Overall survival in the intergroup trial was 9.3% with WBI vs. 7.7% with the combined radiation regimen, but the difference did not reach statistical significance (P = .07; HR 0.76).

In view of the positive findings, the data safety monitoring committee recommended that the results be released, Dr. Whelan told reporters at a press briefing during the meeting.

He suggested that the findings could expand the pool of women offered RNI. Currently, ASCO and the American Society for Therapeutic Radiology and Oncology (ASTRO) guidelines recommend locoregional radiation following mastectomy for tumors greater than 5 cm or with more than three positive axillary nodes.

Of the 1,832 women enrolled in the National Cancer Institute of Canada Clinical Trials Group MA.20 trial, 85% had one to three positive lymph nodes, and 10% had high-risk, node-negative breast cancer. All women were treated with breast-conserving surgery plus adjuvant chemotherapy or endocrine therapy.

"Results from MA.20 suggest that all women with node-positive disease be offered regional node irradiation provided they are made aware of the associated toxicities," said Dr. Whelan, head of radiation oncology at McMaster University and the Juravinski Cancer Centre, Hamilton, Ont.

The addition of RNI to WBI significantly increased the rates of grade 2 or higher dermatitis from 40% to 50% (P less than .001), pneumonitis from 0.2% to 1.3% (P = .01), and lymphedema from 4% to 7% (P = .004). The lymphedema was primarily grade 2, Dr. Whelen pointed out.

Reporters questioned why an earlier unpublished French study did not find a benefit with RNI, while MA.20 did. Dr. Whelan responded that regional radiation in the earlier study was limited to the internal mammary lymph nodes alone, whereas MA.20 expanded the upper radiation field to include the upper internal mammary nodes, supraclavicular nodes, and high axillary nodes. He could not explain why overall survival was not improved.

Radiation dosages for WBI were 50 Gy in 25 fractions plus a boost at the discretion of the cancer center of 10 Gy in 5 fractions. The RNI dosage was 45 Gy in 25 fractions.

WBI and RNI were delivered concurrently, so the added therapy would not require additional office visits for women, and would modestly lengthen the therapy.

The researchers will continue to monitor the patients and evaluate new techniques to reduce potential side effects, he said in an interview.

MA.20 was sponsored by the Canadian Cancer Society Research Institute, National Cancer Institute/Cancer Therapy Evaluation Program, and Canadian Breast Cancer Research Alliance. Dr. Whelan and his coauthors disclosed no conflicts of interest.

CHICAGO – Adding regional nodal irradiation to whole-breast irradiation significantly improved disease-free survival, but not overall survival in a randomized multi-center phase III trial of women with node-positive or high-risk node-negative disease treated with breast-conserving surgery and adjuvant therapy.

An interim analysis of 1,832 women with breast cancer found that after a median follow-up of 62 months, whole breast irradiation (WBI) plus regional nodal irradiation (RNI) significantly reduced the risk of locoregional recurrence from 5.5% to 3.2% (P = .02; hazard ratio 0.8) and distant recurrence from 13% to 7.6% (P = .002; HR 0.64), lead investigator Dr. Timothy Whelan reported at the annual meeting of the American Society of Clinical Oncology.

Overall survival in the intergroup trial was 9.3% with WBI vs. 7.7% with the combined radiation regimen, but the difference did not reach statistical significance (P = .07; HR 0.76).

In view of the positive findings, the data safety monitoring committee recommended that the results be released, Dr. Whelan told reporters at a press briefing during the meeting.

He suggested that the findings could expand the pool of women offered RNI. Currently, ASCO and the American Society for Therapeutic Radiology and Oncology (ASTRO) guidelines recommend locoregional radiation following mastectomy for tumors greater than 5 cm or with more than three positive axillary nodes.

Of the 1,832 women enrolled in the National Cancer Institute of Canada Clinical Trials Group MA.20 trial, 85% had one to three positive lymph nodes, and 10% had high-risk, node-negative breast cancer. All women were treated with breast-conserving surgery plus adjuvant chemotherapy or endocrine therapy.

"Results from MA.20 suggest that all women with node-positive disease be offered regional node irradiation provided they are made aware of the associated toxicities," said Dr. Whelan, head of radiation oncology at McMaster University and the Juravinski Cancer Centre, Hamilton, Ont.

The addition of RNI to WBI significantly increased the rates of grade 2 or higher dermatitis from 40% to 50% (P less than .001), pneumonitis from 0.2% to 1.3% (P = .01), and lymphedema from 4% to 7% (P = .004). The lymphedema was primarily grade 2, Dr. Whelen pointed out.

Reporters questioned why an earlier unpublished French study did not find a benefit with RNI, while MA.20 did. Dr. Whelan responded that regional radiation in the earlier study was limited to the internal mammary lymph nodes alone, whereas MA.20 expanded the upper radiation field to include the upper internal mammary nodes, supraclavicular nodes, and high axillary nodes. He could not explain why overall survival was not improved.

Radiation dosages for WBI were 50 Gy in 25 fractions plus a boost at the discretion of the cancer center of 10 Gy in 5 fractions. The RNI dosage was 45 Gy in 25 fractions.

WBI and RNI were delivered concurrently, so the added therapy would not require additional office visits for women, and would modestly lengthen the therapy.

The researchers will continue to monitor the patients and evaluate new techniques to reduce potential side effects, he said in an interview.

MA.20 was sponsored by the Canadian Cancer Society Research Institute, National Cancer Institute/Cancer Therapy Evaluation Program, and Canadian Breast Cancer Research Alliance. Dr. Whelan and his coauthors disclosed no conflicts of interest.

The emerging role for PARP inhibitors in BRCA-mutated cancers is reviewed by Community Oncology Editor-in-Chief Dr. Lee Schwartzberg.

Editor-in-Chief Lee S. Schwartzberg, M.D., is the research medical director at The West Clinic in Memphis, TN.

Download the PARP Inhibitors Powerpoint Slideshow

The emerging role for PARP inhibitors in BRCA-mutated cancers is reviewed by Community Oncology Editor-in-Chief Dr. Lee Schwartzberg.

Editor-in-Chief Lee S. Schwartzberg, M.D., is the research medical director at The West Clinic in Memphis, TN.

Download the PARP Inhibitors Powerpoint Slideshow

The emerging role for PARP inhibitors in BRCA-mutated cancers is reviewed by Community Oncology Editor-in-Chief Dr. Lee Schwartzberg.

Editor-in-Chief Lee S. Schwartzberg, M.D., is the research medical director at The West Clinic in Memphis, TN.

Download the PARP Inhibitors Powerpoint Slideshow

Beta-blockers – safe and inexpensive drugs used for 4 decades in the management of cardiovascular disease – have shown surprising promise in inhibiting breast cancer progression and metastasis.

Two retrospective observational studies, published May 31 in Journal of Clinical Oncology, offer the latest evidence that the drugs, which have a role in neuroendocrine signaling pathways, lower the risk of recurrence, metastasis, and cancer-specific mortality.

In an editorial comment (doi:10.1200/JCO.2011.35.8820) accompanying the articles, Dr. Patricia A. Ganz and Steven W. Cole, Ph.D., both of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, wrote that the findings raised "the intriguing possibility" that these and other agents targeted to other diseases might provide "previously unappreciated opportunities for therapeutic control of disease progression, metastasis, and disease recurrence."

Because of this, they argued, future clinical treatment trials should "endeavor to collect prospective data on relevant medication exposures, weight and weight gain, comorbid conditions, and behaviors that have the potential to influence the microenvironment of the tumor, as these may be potent mediators of prognosis and survival, and may or may not be effectively accounted for in randomization."

In both studies, women with breast cancer prescribed beta-blockers for hypertension and other cardiovascular conditions were compared with women not taking the drugs.

For the first study (doi:10.1200/JCO.2010.33.5422), Thomas I. Barron, Ph.D., of Trinity College Dublin and his colleagues used linked data from an Irish national tumor registry and a pharmacy database to set up a case-control comparison of women prescribed the beta-blockers propranolol (n = 70) or atenolol (n = 525) in the year before and after their breast cancer diagnoses. These women were matched 1:2 to 4,738 women not prescribed beta-blockers, with matching inclusive of age, socioeconomic status, tumor grade and stage, and comorbidities.

After a median follow-up period of 3.5 years for the propranolol group and controls and slightly less than 3 years for the atenolol group and controls, the investigators found significant reductions in tumor size and nodal or metastatic distribution for the propranolol users, but not for the atenolol users. The cumulative probability of breast cancer–specific mortality was significantly lower among propranolol users (HR, 0.19). Propranolol users were also significantly less likely to present with a T4 (OR, 0.24) or N2/N3/M1 (OR, 0.20) tumor compared with matched controls. However, the atenolol group saw neither a significant reduction in breast-cancer specific mortality nor a difference in T4 or N2/N3/M1 tumor incidence from the matched controls.

In the second study (doi:10.1200/JCO.2010.33.4441), Dr. Amal Melhem-Bertrandt of the M.D. Anderson Cancer Center at the University of Texas, Houston, and colleagues identified 1,413 patients treated for breast cancer in a 12-year period, comparing those with (n = 102) and without (n = 1,311) concurrent beta-blocker exposure for a pathologic complete response, relapse-free survival, and overall survival. Mean follow-up was 55 months in the beta-blocker group and 63 months in the nonuser group.

The investigators saw no difference in pathologic response for those taking beta-blockers; however, after adjustment for variables including age, race, and tumor grade, women on beta-blockers showed significantly greater relapse-free survival (HR, 0.52; P = .015) and a trend toward greater overall survival that did not reach statistical significance (HR, 0.64; P = .09).

In a triple-negative subgroup (n = 377), the investigators found significant effects for beta-blocker use on relapse-free (HR, 0.30; P = .03) but not overall survival (HR, 0.35; P = .05) after adjustment.

In their editorial, Dr. Ganz and Dr. Cole noted that the findings from the second study, in which most of the beta-blockers were the beta-1–selective agents metoprolol (42% of patients) followed by atenolol (37%), would seem to contradict Dr. Barron and his colleagues’ findings, in which only propranolol, which inhibits both beta 1 and beta 2, had a significant effect. However, they wrote, "Neither metoprolol or atenolol is totally beta-1 specific; both partially inhibit beta-2–adrenergic receptors as well."

The editorialists noted that the new findings build on recent animal work indicating that beta-adrenergic receptors affect breast tumor growth and metastasis, and also on a 2010 U.K. retrospective study (n = 466) that was the first to look at a variety of antihypertensive agents in women with breast cancer. It found that women treated simultaneously with beta-blockers had a 57% reduced risk of metastasis compared with breast cancer patients receiving either other types of antihypertensive drugs or no antihypertensive drugs. Women on beta-blockers also saw 71% less cancer-specific mortality after 10 years (Oncotarget 2010; 1: 628-38).

"Beta-adrenergic signaling appears to have little effect on the biologic processes involved in breast cancer initiation, but more strongly affects the biologic processes involved in the subsequent progression and metastasis of incipient tumors. Given these results from the laboratory, and the clinical results from three recent retrospective reports suggesting the potential to limit recurrence of incident tumors, perhaps it is time to consider proof-of-concept trials testing the value of [beta-blockers] in the setting of breast cancer," Dr. Ganz and Dr. Cole wrote.

Dr. Barron and his colleagues declared that they had no financial disclosures relevant to their study, which was funded by the Irish government. Dr. Melhem-Bertrandt and colleagues said they had no financial disclosures relevant to their study, which was supported by a grant from the National Institutes of Health. Dr. Ganz and Dr. Cole, who were supported by the Breast Cancer Research Foundation, the Jonsson Comprehensive Cancer Center Foundation, Susan G. Komen for the Cure, and the National Cancer Institute, also declared that they had no relevant financial disclosures.

Beta-blockers – safe and inexpensive drugs used for 4 decades in the management of cardiovascular disease – have shown surprising promise in inhibiting breast cancer progression and metastasis.

Two retrospective observational studies, published May 31 in Journal of Clinical Oncology, offer the latest evidence that the drugs, which have a role in neuroendocrine signaling pathways, lower the risk of recurrence, metastasis, and cancer-specific mortality.

In an editorial comment (doi:10.1200/JCO.2011.35.8820) accompanying the articles, Dr. Patricia A. Ganz and Steven W. Cole, Ph.D., both of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, wrote that the findings raised "the intriguing possibility" that these and other agents targeted to other diseases might provide "previously unappreciated opportunities for therapeutic control of disease progression, metastasis, and disease recurrence."

Because of this, they argued, future clinical treatment trials should "endeavor to collect prospective data on relevant medication exposures, weight and weight gain, comorbid conditions, and behaviors that have the potential to influence the microenvironment of the tumor, as these may be potent mediators of prognosis and survival, and may or may not be effectively accounted for in randomization."

In both studies, women with breast cancer prescribed beta-blockers for hypertension and other cardiovascular conditions were compared with women not taking the drugs.

For the first study (doi:10.1200/JCO.2010.33.5422), Thomas I. Barron, Ph.D., of Trinity College Dublin and his colleagues used linked data from an Irish national tumor registry and a pharmacy database to set up a case-control comparison of women prescribed the beta-blockers propranolol (n = 70) or atenolol (n = 525) in the year before and after their breast cancer diagnoses. These women were matched 1:2 to 4,738 women not prescribed beta-blockers, with matching inclusive of age, socioeconomic status, tumor grade and stage, and comorbidities.

After a median follow-up period of 3.5 years for the propranolol group and controls and slightly less than 3 years for the atenolol group and controls, the investigators found significant reductions in tumor size and nodal or metastatic distribution for the propranolol users, but not for the atenolol users. The cumulative probability of breast cancer–specific mortality was significantly lower among propranolol users (HR, 0.19). Propranolol users were also significantly less likely to present with a T4 (OR, 0.24) or N2/N3/M1 (OR, 0.20) tumor compared with matched controls. However, the atenolol group saw neither a significant reduction in breast-cancer specific mortality nor a difference in T4 or N2/N3/M1 tumor incidence from the matched controls.

In the second study (doi:10.1200/JCO.2010.33.4441), Dr. Amal Melhem-Bertrandt of the M.D. Anderson Cancer Center at the University of Texas, Houston, and colleagues identified 1,413 patients treated for breast cancer in a 12-year period, comparing those with (n = 102) and without (n = 1,311) concurrent beta-blocker exposure for a pathologic complete response, relapse-free survival, and overall survival. Mean follow-up was 55 months in the beta-blocker group and 63 months in the nonuser group.

The investigators saw no difference in pathologic response for those taking beta-blockers; however, after adjustment for variables including age, race, and tumor grade, women on beta-blockers showed significantly greater relapse-free survival (HR, 0.52; P = .015) and a trend toward greater overall survival that did not reach statistical significance (HR, 0.64; P = .09).

In a triple-negative subgroup (n = 377), the investigators found significant effects for beta-blocker use on relapse-free (HR, 0.30; P = .03) but not overall survival (HR, 0.35; P = .05) after adjustment.

In their editorial, Dr. Ganz and Dr. Cole noted that the findings from the second study, in which most of the beta-blockers were the beta-1–selective agents metoprolol (42% of patients) followed by atenolol (37%), would seem to contradict Dr. Barron and his colleagues’ findings, in which only propranolol, which inhibits both beta 1 and beta 2, had a significant effect. However, they wrote, "Neither metoprolol or atenolol is totally beta-1 specific; both partially inhibit beta-2–adrenergic receptors as well."

The editorialists noted that the new findings build on recent animal work indicating that beta-adrenergic receptors affect breast tumor growth and metastasis, and also on a 2010 U.K. retrospective study (n = 466) that was the first to look at a variety of antihypertensive agents in women with breast cancer. It found that women treated simultaneously with beta-blockers had a 57% reduced risk of metastasis compared with breast cancer patients receiving either other types of antihypertensive drugs or no antihypertensive drugs. Women on beta-blockers also saw 71% less cancer-specific mortality after 10 years (Oncotarget 2010; 1: 628-38).

"Beta-adrenergic signaling appears to have little effect on the biologic processes involved in breast cancer initiation, but more strongly affects the biologic processes involved in the subsequent progression and metastasis of incipient tumors. Given these results from the laboratory, and the clinical results from three recent retrospective reports suggesting the potential to limit recurrence of incident tumors, perhaps it is time to consider proof-of-concept trials testing the value of [beta-blockers] in the setting of breast cancer," Dr. Ganz and Dr. Cole wrote.

Dr. Barron and his colleagues declared that they had no financial disclosures relevant to their study, which was funded by the Irish government. Dr. Melhem-Bertrandt and colleagues said they had no financial disclosures relevant to their study, which was supported by a grant from the National Institutes of Health. Dr. Ganz and Dr. Cole, who were supported by the Breast Cancer Research Foundation, the Jonsson Comprehensive Cancer Center Foundation, Susan G. Komen for the Cure, and the National Cancer Institute, also declared that they had no relevant financial disclosures.

Beta-blockers – safe and inexpensive drugs used for 4 decades in the management of cardiovascular disease – have shown surprising promise in inhibiting breast cancer progression and metastasis.

Two retrospective observational studies, published May 31 in Journal of Clinical Oncology, offer the latest evidence that the drugs, which have a role in neuroendocrine signaling pathways, lower the risk of recurrence, metastasis, and cancer-specific mortality.

In an editorial comment (doi:10.1200/JCO.2011.35.8820) accompanying the articles, Dr. Patricia A. Ganz and Steven W. Cole, Ph.D., both of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, wrote that the findings raised "the intriguing possibility" that these and other agents targeted to other diseases might provide "previously unappreciated opportunities for therapeutic control of disease progression, metastasis, and disease recurrence."

Because of this, they argued, future clinical treatment trials should "endeavor to collect prospective data on relevant medication exposures, weight and weight gain, comorbid conditions, and behaviors that have the potential to influence the microenvironment of the tumor, as these may be potent mediators of prognosis and survival, and may or may not be effectively accounted for in randomization."

In both studies, women with breast cancer prescribed beta-blockers for hypertension and other cardiovascular conditions were compared with women not taking the drugs.

For the first study (doi:10.1200/JCO.2010.33.5422), Thomas I. Barron, Ph.D., of Trinity College Dublin and his colleagues used linked data from an Irish national tumor registry and a pharmacy database to set up a case-control comparison of women prescribed the beta-blockers propranolol (n = 70) or atenolol (n = 525) in the year before and after their breast cancer diagnoses. These women were matched 1:2 to 4,738 women not prescribed beta-blockers, with matching inclusive of age, socioeconomic status, tumor grade and stage, and comorbidities.

After a median follow-up period of 3.5 years for the propranolol group and controls and slightly less than 3 years for the atenolol group and controls, the investigators found significant reductions in tumor size and nodal or metastatic distribution for the propranolol users, but not for the atenolol users. The cumulative probability of breast cancer–specific mortality was significantly lower among propranolol users (HR, 0.19). Propranolol users were also significantly less likely to present with a T4 (OR, 0.24) or N2/N3/M1 (OR, 0.20) tumor compared with matched controls. However, the atenolol group saw neither a significant reduction in breast-cancer specific mortality nor a difference in T4 or N2/N3/M1 tumor incidence from the matched controls.

In the second study (doi:10.1200/JCO.2010.33.4441), Dr. Amal Melhem-Bertrandt of the M.D. Anderson Cancer Center at the University of Texas, Houston, and colleagues identified 1,413 patients treated for breast cancer in a 12-year period, comparing those with (n = 102) and without (n = 1,311) concurrent beta-blocker exposure for a pathologic complete response, relapse-free survival, and overall survival. Mean follow-up was 55 months in the beta-blocker group and 63 months in the nonuser group.

The investigators saw no difference in pathologic response for those taking beta-blockers; however, after adjustment for variables including age, race, and tumor grade, women on beta-blockers showed significantly greater relapse-free survival (HR, 0.52; P = .015) and a trend toward greater overall survival that did not reach statistical significance (HR, 0.64; P = .09).

In a triple-negative subgroup (n = 377), the investigators found significant effects for beta-blocker use on relapse-free (HR, 0.30; P = .03) but not overall survival (HR, 0.35; P = .05) after adjustment.

In their editorial, Dr. Ganz and Dr. Cole noted that the findings from the second study, in which most of the beta-blockers were the beta-1–selective agents metoprolol (42% of patients) followed by atenolol (37%), would seem to contradict Dr. Barron and his colleagues’ findings, in which only propranolol, which inhibits both beta 1 and beta 2, had a significant effect. However, they wrote, "Neither metoprolol or atenolol is totally beta-1 specific; both partially inhibit beta-2–adrenergic receptors as well."

The editorialists noted that the new findings build on recent animal work indicating that beta-adrenergic receptors affect breast tumor growth and metastasis, and also on a 2010 U.K. retrospective study (n = 466) that was the first to look at a variety of antihypertensive agents in women with breast cancer. It found that women treated simultaneously with beta-blockers had a 57% reduced risk of metastasis compared with breast cancer patients receiving either other types of antihypertensive drugs or no antihypertensive drugs. Women on beta-blockers also saw 71% less cancer-specific mortality after 10 years (Oncotarget 2010; 1: 628-38).

"Beta-adrenergic signaling appears to have little effect on the biologic processes involved in breast cancer initiation, but more strongly affects the biologic processes involved in the subsequent progression and metastasis of incipient tumors. Given these results from the laboratory, and the clinical results from three recent retrospective reports suggesting the potential to limit recurrence of incident tumors, perhaps it is time to consider proof-of-concept trials testing the value of [beta-blockers] in the setting of breast cancer," Dr. Ganz and Dr. Cole wrote.

Dr. Barron and his colleagues declared that they had no financial disclosures relevant to their study, which was funded by the Irish government. Dr. Melhem-Bertrandt and colleagues said they had no financial disclosures relevant to their study, which was supported by a grant from the National Institutes of Health. Dr. Ganz and Dr. Cole, who were supported by the Breast Cancer Research Foundation, the Jonsson Comprehensive Cancer Center Foundation, Susan G. Komen for the Cure, and the National Cancer Institute, also declared that they had no relevant financial disclosures.

Yes – It Is Time to Consider a Paradigm Shift.

In stage IV breast cancer, local therapy is not considered important except for controlling symptoms. But recent large-scale retrospective studies tell us that, if you follow enough women long enough, you see a difference in survival related to control of local disease. These emerging data tell us it’s time to consider a paradigm shift in the treatment of stage IV breast cancer.

Researchers are finding that primary site treatment regimens are important because an intact primary tumor can serve as a continued source of new metastatic lesions. There is reason, therefore, to believe that treating these can prolong life.

First explored by Dr. Larry Norton and Joan Massagué, Ph.D., (Nature Med. 2006;12:875-8), the concept of cancer self-seeding holds that cells from the primary tumor not only travel unidirectionally to seed metastases but also return to the primary tumor, self-seeding it and helping it to grow even more.

This view incorporates the microenvironment of the primary tumor. Here, fibroblasts and other cells – particularly mesenchymal stem cells derived from bone marrow – may play a very important role, creating a reactive stroma that seems to release growth-promoting substances that increase the metastatic efficiency of the circulating cells.

Robert A. Weinberg, Ph.D., published data showing that these mesenchymal stem cells are pluripotent progenitor cells. When weakly metastatic human breast cancer cells were mixed with these stem cells, the cancer cells’ metastatic potential greatly increased. The breast cancer cells then stimulated the stem cells to secrete a chemokine which – in turn – enhanced the cancer cells’ motility and their ability to invade and metastasize (Nature 2007;449:557-63). In effect, the primary tumor acts like a filling station, giving these tumor cells more energy to go out and metastasize in different sites.

Although such studies remain animal models, I think we can say there is a basis for primary tumor therapy in the metastatic setting. A dozen or more retrospective studies of large institutional series, cancer databases, and population-based studies have examined outcomes in women treated with and without surgical resection. Data on about 30,000 women have been published, with about 50% receiving some form of primary tumor therapy. The survival benefit across them is quite consistent, with the hazard ratio of death over a given time period reduced from 30% to 50%.

These studies do demonstrate selection bias: Women treated with surgical removal were more likely to be young, white, married, with smaller tumors and a lower burden of disease, and it is possible that they would have done better anyway. Studies have also shown that better survival, even in stage IV cancer, occurs in women who have a therapeutic target (that is, hormone receptors or HER2). But there was still a significant survival benefit for surgery.

Surgical resection may also confer benefit by preventing the primary tumor in the breast from becoming a quality of-life problem. At Northwestern Memorial Hospital, Chicago, we conducted a study that showed the odds of symptomatic chest wall disease were far lower in the surgical group, compared with the nonsurgical group. In this 2008 study, we found that women with good local control– surgical or systemic - did better. Time to first progression was prolonged by 50% in the surgical group, while chest wall control was associated with a 60% improvement in overall survival, regardless of whether surgical resection was performed (Cancer 2008;113:2011-9).

So the question is, do we need a randomized trial? My unbiased answer is that we do – and I am the principal investigator of such a trial open to all U.S. and Canadian institutions (NCT01242800). The end points are survival, local control, and quality of life. In addition, the trial will provide an opportunity to answer biological questions regarding the relationship between the primary tumor and metastatic site. Only when we have samples of primary and metastatic tumors can we settle this continuing debate.

Dr. Khan is the Bluhm Family Professor of Cancer Research at the Lurie Comprehensive Cancer Center, Chicago.

No – Case Selection Bias Is Behind the Survival Advantage.

It’s true that some studies show an increase in stage IV breast cancer survival after primary site resection – but this more likely reflects a bias of case selection than a true benefit of local therapy.

Any findings of positive benefit other than case selection must be biologically plausible. The suggestion that the primary tumor releases some sort of growth-promoting substance that is gone when you remove the tumor, inhibiting metastatic disease has not yet been proven in humans; nor has the proposition that continued cell shedding might further metastasis.

Decreased tumor burden has sometimes been shown to increase the usefulness of systemic therapy, but I think that, all in all, case selection simply promotes breast surgery in patients with a better prognosis.

To show improved survival, we must find causality and not simply coincidence. Findings from large case series or cancer databases are unable to provide the answer. Although registry interpretations can provide basic data, they often break down when you attempt to extract detailed data.

Sometimes a stage IV cancer is registered initially on the basis of a pulmonary or liver shadow on imaging, which later is proven not to have been metastatic disease – and the case is never amended in the registry. There are also registry misinterpretations of the type of surgery that’s been done.

We performed a matched pair analysis of stage IV breast cancer patients with and without resection of the primary tumor. This was based on the Partners Health Care Consortium cancer database, which included information on 19,464 invasive breast cancers treated between 1970 and 2002; 808 of these (4%) were recorded as stage IV. Of these, 622 were analyzed by case matching that considered age, diagnostic date, metastatic disease location, estrogen-receptor status, and systemic therapy (Ann. Surg. Oncol. 2008; 15:3384-95).

It’s absolutely true that there was a statistically significant difference in survival in the overall comparison of surgery vs. no surgery. With bone metastases only, it was still statistically significant, but with a substantially lower difference in survival. In visceral metastases, the difference became nonsignificant.

Looking at therapy sequence in those who had the same type of systemic therapy, but with chemotherapy before or after surgery, you see a suggestion that giving systemic therapy first with a clinical response, which is a favorable prognostic indication, leads to a selection bias in choosing patients for surgery.

I reviewed the 86 cases who survived 5 years with records available. In those records, 22 were actually not stage IV disease, leaving 64 with confirmed stage IV (M1) – an overall 10% 5-year survival rate. Patients who survived were significantly younger than those who did not survive, significantly more likely to have estrogen receptor-positive tumors, and significantly more likely to have bone rather than visceral metastases or oligometastatic disease – all of which are good prognostic factors.

Among the 64 5-year survivors, 25 had therapeutic breast surgery. Of these, 8 had an excellent chemotherapy response followed by breast surgery; 8 had delayed surgery following a failure of systemic therapy; 7 had an initial therapeutic and curative surgery, but staging revealed metastases because of unexpected positive nodes; and 2 had initial surgery with oligometastatic resection.

Thirty-nine patients had no therapeutic breast surgery, and, of these, 16 had an excellent response to systemic therapy; 15 had slowly progressive disease; and 8 had oligometastatic disease – a positive prognostic factor. Thus, favorable prognostic factors led to a selection of primary-site surgery, whereas poor prognostic factors mean that primary-site surgery was avoided, contradicting the assumption of its therapeutic benefit.

There were also surgical discrepancies among the 5-year survivors. The registry listed 11 as having had breast surgery, while a chart review showed that surgery was not therapeutic. Five were listed as having no breast surgery, while they had indeed undergone a therapeutic operation.

Cancer registry data are not reliable for defining stage IV disease, discriminating advanced local disease with bone involvement from true distant, imaging-confirmed metastasis, or assessing surgical procedures. Case selection bias accounts for most, if not all, of the apparent survival advantage.

Dr. Blake Cady is professor of surgery (emeritus) at Harvard Medical School, Boston, and at Brown University, Providence, R.I.

Yes – It Is Time to Consider a Paradigm Shift.

In stage IV breast cancer, local therapy is not considered important except for controlling symptoms. But recent large-scale retrospective studies tell us that, if you follow enough women long enough, you see a difference in survival related to control of local disease. These emerging data tell us it’s time to consider a paradigm shift in the treatment of stage IV breast cancer.

Researchers are finding that primary site treatment regimens are important because an intact primary tumor can serve as a continued source of new metastatic lesions. There is reason, therefore, to believe that treating these can prolong life.

First explored by Dr. Larry Norton and Joan Massagué, Ph.D., (Nature Med. 2006;12:875-8), the concept of cancer self-seeding holds that cells from the primary tumor not only travel unidirectionally to seed metastases but also return to the primary tumor, self-seeding it and helping it to grow even more.

This view incorporates the microenvironment of the primary tumor. Here, fibroblasts and other cells – particularly mesenchymal stem cells derived from bone marrow – may play a very important role, creating a reactive stroma that seems to release growth-promoting substances that increase the metastatic efficiency of the circulating cells.

Robert A. Weinberg, Ph.D., published data showing that these mesenchymal stem cells are pluripotent progenitor cells. When weakly metastatic human breast cancer cells were mixed with these stem cells, the cancer cells’ metastatic potential greatly increased. The breast cancer cells then stimulated the stem cells to secrete a chemokine which – in turn – enhanced the cancer cells’ motility and their ability to invade and metastasize (Nature 2007;449:557-63). In effect, the primary tumor acts like a filling station, giving these tumor cells more energy to go out and metastasize in different sites.

Although such studies remain animal models, I think we can say there is a basis for primary tumor therapy in the metastatic setting. A dozen or more retrospective studies of large institutional series, cancer databases, and population-based studies have examined outcomes in women treated with and without surgical resection. Data on about 30,000 women have been published, with about 50% receiving some form of primary tumor therapy. The survival benefit across them is quite consistent, with the hazard ratio of death over a given time period reduced from 30% to 50%.

These studies do demonstrate selection bias: Women treated with surgical removal were more likely to be young, white, married, with smaller tumors and a lower burden of disease, and it is possible that they would have done better anyway. Studies have also shown that better survival, even in stage IV cancer, occurs in women who have a therapeutic target (that is, hormone receptors or HER2). But there was still a significant survival benefit for surgery.

Surgical resection may also confer benefit by preventing the primary tumor in the breast from becoming a quality of-life problem. At Northwestern Memorial Hospital, Chicago, we conducted a study that showed the odds of symptomatic chest wall disease were far lower in the surgical group, compared with the nonsurgical group. In this 2008 study, we found that women with good local control– surgical or systemic - did better. Time to first progression was prolonged by 50% in the surgical group, while chest wall control was associated with a 60% improvement in overall survival, regardless of whether surgical resection was performed (Cancer 2008;113:2011-9).

So the question is, do we need a randomized trial? My unbiased answer is that we do – and I am the principal investigator of such a trial open to all U.S. and Canadian institutions (NCT01242800). The end points are survival, local control, and quality of life. In addition, the trial will provide an opportunity to answer biological questions regarding the relationship between the primary tumor and metastatic site. Only when we have samples of primary and metastatic tumors can we settle this continuing debate.

Dr. Khan is the Bluhm Family Professor of Cancer Research at the Lurie Comprehensive Cancer Center, Chicago.

No – Case Selection Bias Is Behind the Survival Advantage.

It’s true that some studies show an increase in stage IV breast cancer survival after primary site resection – but this more likely reflects a bias of case selection than a true benefit of local therapy.

Any findings of positive benefit other than case selection must be biologically plausible. The suggestion that the primary tumor releases some sort of growth-promoting substance that is gone when you remove the tumor, inhibiting metastatic disease has not yet been proven in humans; nor has the proposition that continued cell shedding might further metastasis.

Decreased tumor burden has sometimes been shown to increase the usefulness of systemic therapy, but I think that, all in all, case selection simply promotes breast surgery in patients with a better prognosis.

To show improved survival, we must find causality and not simply coincidence. Findings from large case series or cancer databases are unable to provide the answer. Although registry interpretations can provide basic data, they often break down when you attempt to extract detailed data.

Sometimes a stage IV cancer is registered initially on the basis of a pulmonary or liver shadow on imaging, which later is proven not to have been metastatic disease – and the case is never amended in the registry. There are also registry misinterpretations of the type of surgery that’s been done.

We performed a matched pair analysis of stage IV breast cancer patients with and without resection of the primary tumor. This was based on the Partners Health Care Consortium cancer database, which included information on 19,464 invasive breast cancers treated between 1970 and 2002; 808 of these (4%) were recorded as stage IV. Of these, 622 were analyzed by case matching that considered age, diagnostic date, metastatic disease location, estrogen-receptor status, and systemic therapy (Ann. Surg. Oncol. 2008; 15:3384-95).

It’s absolutely true that there was a statistically significant difference in survival in the overall comparison of surgery vs. no surgery. With bone metastases only, it was still statistically significant, but with a substantially lower difference in survival. In visceral metastases, the difference became nonsignificant.

Looking at therapy sequence in those who had the same type of systemic therapy, but with chemotherapy before or after surgery, you see a suggestion that giving systemic therapy first with a clinical response, which is a favorable prognostic indication, leads to a selection bias in choosing patients for surgery.

I reviewed the 86 cases who survived 5 years with records available. In those records, 22 were actually not stage IV disease, leaving 64 with confirmed stage IV (M1) – an overall 10% 5-year survival rate. Patients who survived were significantly younger than those who did not survive, significantly more likely to have estrogen receptor-positive tumors, and significantly more likely to have bone rather than visceral metastases or oligometastatic disease – all of which are good prognostic factors.

Among the 64 5-year survivors, 25 had therapeutic breast surgery. Of these, 8 had an excellent chemotherapy response followed by breast surgery; 8 had delayed surgery following a failure of systemic therapy; 7 had an initial therapeutic and curative surgery, but staging revealed metastases because of unexpected positive nodes; and 2 had initial surgery with oligometastatic resection.

Thirty-nine patients had no therapeutic breast surgery, and, of these, 16 had an excellent response to systemic therapy; 15 had slowly progressive disease; and 8 had oligometastatic disease – a positive prognostic factor. Thus, favorable prognostic factors led to a selection of primary-site surgery, whereas poor prognostic factors mean that primary-site surgery was avoided, contradicting the assumption of its therapeutic benefit.

There were also surgical discrepancies among the 5-year survivors. The registry listed 11 as having had breast surgery, while a chart review showed that surgery was not therapeutic. Five were listed as having no breast surgery, while they had indeed undergone a therapeutic operation.

Cancer registry data are not reliable for defining stage IV disease, discriminating advanced local disease with bone involvement from true distant, imaging-confirmed metastasis, or assessing surgical procedures. Case selection bias accounts for most, if not all, of the apparent survival advantage.

Dr. Blake Cady is professor of surgery (emeritus) at Harvard Medical School, Boston, and at Brown University, Providence, R.I.

Yes – It Is Time to Consider a Paradigm Shift.

In stage IV breast cancer, local therapy is not considered important except for controlling symptoms. But recent large-scale retrospective studies tell us that, if you follow enough women long enough, you see a difference in survival related to control of local disease. These emerging data tell us it’s time to consider a paradigm shift in the treatment of stage IV breast cancer.

Researchers are finding that primary site treatment regimens are important because an intact primary tumor can serve as a continued source of new metastatic lesions. There is reason, therefore, to believe that treating these can prolong life.

First explored by Dr. Larry Norton and Joan Massagué, Ph.D., (Nature Med. 2006;12:875-8), the concept of cancer self-seeding holds that cells from the primary tumor not only travel unidirectionally to seed metastases but also return to the primary tumor, self-seeding it and helping it to grow even more.

This view incorporates the microenvironment of the primary tumor. Here, fibroblasts and other cells – particularly mesenchymal stem cells derived from bone marrow – may play a very important role, creating a reactive stroma that seems to release growth-promoting substances that increase the metastatic efficiency of the circulating cells.

Robert A. Weinberg, Ph.D., published data showing that these mesenchymal stem cells are pluripotent progenitor cells. When weakly metastatic human breast cancer cells were mixed with these stem cells, the cancer cells’ metastatic potential greatly increased. The breast cancer cells then stimulated the stem cells to secrete a chemokine which – in turn – enhanced the cancer cells’ motility and their ability to invade and metastasize (Nature 2007;449:557-63). In effect, the primary tumor acts like a filling station, giving these tumor cells more energy to go out and metastasize in different sites.

Although such studies remain animal models, I think we can say there is a basis for primary tumor therapy in the metastatic setting. A dozen or more retrospective studies of large institutional series, cancer databases, and population-based studies have examined outcomes in women treated with and without surgical resection. Data on about 30,000 women have been published, with about 50% receiving some form of primary tumor therapy. The survival benefit across them is quite consistent, with the hazard ratio of death over a given time period reduced from 30% to 50%.

These studies do demonstrate selection bias: Women treated with surgical removal were more likely to be young, white, married, with smaller tumors and a lower burden of disease, and it is possible that they would have done better anyway. Studies have also shown that better survival, even in stage IV cancer, occurs in women who have a therapeutic target (that is, hormone receptors or HER2). But there was still a significant survival benefit for surgery.

Surgical resection may also confer benefit by preventing the primary tumor in the breast from becoming a quality of-life problem. At Northwestern Memorial Hospital, Chicago, we conducted a study that showed the odds of symptomatic chest wall disease were far lower in the surgical group, compared with the nonsurgical group. In this 2008 study, we found that women with good local control– surgical or systemic - did better. Time to first progression was prolonged by 50% in the surgical group, while chest wall control was associated with a 60% improvement in overall survival, regardless of whether surgical resection was performed (Cancer 2008;113:2011-9).

So the question is, do we need a randomized trial? My unbiased answer is that we do – and I am the principal investigator of such a trial open to all U.S. and Canadian institutions (NCT01242800). The end points are survival, local control, and quality of life. In addition, the trial will provide an opportunity to answer biological questions regarding the relationship between the primary tumor and metastatic site. Only when we have samples of primary and metastatic tumors can we settle this continuing debate.

Dr. Khan is the Bluhm Family Professor of Cancer Research at the Lurie Comprehensive Cancer Center, Chicago.

No – Case Selection Bias Is Behind the Survival Advantage.

It’s true that some studies show an increase in stage IV breast cancer survival after primary site resection – but this more likely reflects a bias of case selection than a true benefit of local therapy.

Any findings of positive benefit other than case selection must be biologically plausible. The suggestion that the primary tumor releases some sort of growth-promoting substance that is gone when you remove the tumor, inhibiting metastatic disease has not yet been proven in humans; nor has the proposition that continued cell shedding might further metastasis.

Decreased tumor burden has sometimes been shown to increase the usefulness of systemic therapy, but I think that, all in all, case selection simply promotes breast surgery in patients with a better prognosis.

To show improved survival, we must find causality and not simply coincidence. Findings from large case series or cancer databases are unable to provide the answer. Although registry interpretations can provide basic data, they often break down when you attempt to extract detailed data.

Sometimes a stage IV cancer is registered initially on the basis of a pulmonary or liver shadow on imaging, which later is proven not to have been metastatic disease – and the case is never amended in the registry. There are also registry misinterpretations of the type of surgery that’s been done.

We performed a matched pair analysis of stage IV breast cancer patients with and without resection of the primary tumor. This was based on the Partners Health Care Consortium cancer database, which included information on 19,464 invasive breast cancers treated between 1970 and 2002; 808 of these (4%) were recorded as stage IV. Of these, 622 were analyzed by case matching that considered age, diagnostic date, metastatic disease location, estrogen-receptor status, and systemic therapy (Ann. Surg. Oncol. 2008; 15:3384-95).

It’s absolutely true that there was a statistically significant difference in survival in the overall comparison of surgery vs. no surgery. With bone metastases only, it was still statistically significant, but with a substantially lower difference in survival. In visceral metastases, the difference became nonsignificant.

Looking at therapy sequence in those who had the same type of systemic therapy, but with chemotherapy before or after surgery, you see a suggestion that giving systemic therapy first with a clinical response, which is a favorable prognostic indication, leads to a selection bias in choosing patients for surgery.

I reviewed the 86 cases who survived 5 years with records available. In those records, 22 were actually not stage IV disease, leaving 64 with confirmed stage IV (M1) – an overall 10% 5-year survival rate. Patients who survived were significantly younger than those who did not survive, significantly more likely to have estrogen receptor-positive tumors, and significantly more likely to have bone rather than visceral metastases or oligometastatic disease – all of which are good prognostic factors.

Among the 64 5-year survivors, 25 had therapeutic breast surgery. Of these, 8 had an excellent chemotherapy response followed by breast surgery; 8 had delayed surgery following a failure of systemic therapy; 7 had an initial therapeutic and curative surgery, but staging revealed metastases because of unexpected positive nodes; and 2 had initial surgery with oligometastatic resection.

Thirty-nine patients had no therapeutic breast surgery, and, of these, 16 had an excellent response to systemic therapy; 15 had slowly progressive disease; and 8 had oligometastatic disease – a positive prognostic factor. Thus, favorable prognostic factors led to a selection of primary-site surgery, whereas poor prognostic factors mean that primary-site surgery was avoided, contradicting the assumption of its therapeutic benefit.

There were also surgical discrepancies among the 5-year survivors. The registry listed 11 as having had breast surgery, while a chart review showed that surgery was not therapeutic. Five were listed as having no breast surgery, while they had indeed undergone a therapeutic operation.

Cancer registry data are not reliable for defining stage IV disease, discriminating advanced local disease with bone involvement from true distant, imaging-confirmed metastasis, or assessing surgical procedures. Case selection bias accounts for most, if not all, of the apparent survival advantage.

Dr. Blake Cady is professor of surgery (emeritus) at Harvard Medical School, Boston, and at Brown University, Providence, R.I.

The standard of care for locally advanced breast cancer (LABC) is neoadjuvant chemotherapy,¹ with LABC including clinical stages IIA, IIB, and IIIA. The goals of preoperative chemotherapy are to downstage so as to render breast conservation feasible, to eradicate disease in the axillary nodes, and to allow in vivo testing of tumor drug sensitivity, all with the ultimate aim of improving prognosis. Clinical trials have demonstrated that the pathologic in-breast response generally correlates with pathologic response in the lymph nodes. Furthermore, nodal status at the time of surgery correlates with overall survival (OS) and disease-free survival (DFS).²,³ A combined analysis of two large prospective neoadjuvant chemotherapy trials demonstrated significantly higher 5-year OS and DFS in patients achieving in-breast pathologic complete response (pCR), compared with those who did not (OS, 89% vs 64%; DFS, 87% vs 58%, respectively).⁴

At the start of this trial, the most effective neoad- juvant regimen remained in question. Even now, National Comprehensive Cancer Center guidelines suggest that any recommended adjuvant regimen can be used in the neoadjuvant setting.¹ Numerous phase II and III trials have evaluated single-agent^5–8 and combination^{9– 32} chemotherapies, most of which are anthracycline- based, with pCR rates reported between 7% and 36%. In the NSABP-B27 study, patients treated preoperatively with four cycles of doxorubicin and cyclophosphamide (AC) followed by four cycles of docetaxel (Taxotere) had a 26% pCR rate versus a 13% pCR rate in those receiving preoperative AC and postoperative docetaxel. Despite the doubling of pCR with neoadjuvant docetaxel, there was no difference in DFS or OS.9 However, as reported by Kuerer et al, patients achieving a pCR after completion of neoadjuvant chemotherapy appeared to have superior survival.⁴

Many previous trials (including the study reported here) did not exclude patients with human epidermal growth factor receptor 2 (HER2)-positive disease. It is now well established that such patients should be treated with neoadjuvant regimens incorporating HER2-targeted therapy. In fact, an early neoadjuvant study of paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide with or without 24 weeks of concurrent trastuzumab (Herceptin) in patients with HER2-positive tumors was closed early because patients receiving trastuzumab had a pCR rate of 65%, compared with 26% in those who did not receive it.³³ Expanded clinical trials of this approach are in progress.

The selection of capecitabine (Xeloda) and docetaxel in the present trial was based on the hypothesis that the upregulation of thymidine phosphorylase by docetaxel should increase the activity of capecitabine. ^34–36 Single-agent docetaxel in the neoadjuvant setting has yielded pCR rates of 7%–20%.^6–8 Treatment with docetaxel and capecitabine together has been reported to produce pCR rates of 10%–21%.^37–39 The addition of carboplatin was based on studies by Hurley et al at the University of Miami^{39– 41} suggesting that platinum salts appeared quite active in the neoadjuvant setting, with the combination of docetaxel and cisplatin producing a pCR rate of 20%, with no residual disease in the breast or axilla.40 Other regimens incorporating cisplatin or carboplatin have pCR rates ranging from 16% to 24%.^27,42–44

Patients and methods

Study design

In this phase II multicenter study, patients were assigned to receive docetaxel (30 mg/m2 IV) and carboplatin (AUC 2 IV) on days 1, 8, and 15 of each 28-day cycle plus capecitabine (625 mg/m2 PO) twice daily on days 5–18. The capecitabine dose was based on observations that this dose was effective and relatively nontoxic in metastatic breast cancer (C.L. Vogel, empirical observations). Patients were to receive four cycles prior to surgical resection.

Given that this neoadjuvant regimen was under study, all of the patients were scheduled to receive a proven standard postoperative adjuvant chemotherapy regimen, starting 4–6 weeks postoperatively, with doxorubicin (60 mg/m2 IV) and cyclophosphamide (600 mg/m2 IV) every 21 days for 4 cycles. This sequential design was prompted by studies such as the NSABP B-27 and Aberdeen trials.^9,32

Radiation therapy after lumpectomy or mastectomy was given according to individual institution guidelines. Patients with hormone receptor–positive tumors received appropriate antihormonal therapy. Tumor measurements were assessed at baseline and on day 1 of each cycle by physical examination with calipers. No breast or other imaging was required during the period of neoadjuvant chemotherapy or immediately preoperatively. Patients were considered evaluable if they proceeded to surgery after all intended cycles of neoadjuvant chemotherapy or if they developed disease progression during neoadjuvant therapy.

Patients

Eligible patients were men and women regardless of menopausal status ≥ 18 years of age with coreneedle biopsy proven locally advanced or inflammatory breast cancer. Breast cancer characteristics such as estrogen receptor (ER), progesterone receptor (PR), or HER2 status were collected but not used for inclusion/exclusion. Eligible tumors were T2 requiring mastectomy; T3N0–2; T4; and any TN2–3 that by calipers was > 2 cm or with fixed or matted axillary or imaging-detected internal mammary nodes. Patients with prior ductal carcinoma in situ (DCIS) were included, as were those with ≤ T2N0M0 breast cancer > 5 years prior.

Other requirements were an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; life expectancy > 6 months; negative metastatic workup (bone scan and CT chest/abdomen/pelvis); adequate bone marrow, liver, and kidney function; and peripheral neuropathy ≤ grade 1. All patients of child-bearing potential were required to consent to dual methods of contraception during treatment and for 3 months afterward. A negative pregnancy test was required for these women before treatment, and any suspicion of pregnancy had to be reported to the treating physician.

Study endpoints

The primary endpoint of the study was the in-breast pCR after four cycles of platinum-based neoadjuvant chemotherapy. Pathologic complete response was defined as complete disappearance of invasive and in situ disease or invasive disease alone. During the course of this trial, it became generally acceptable to include patients with only residual DCIS as equivalent to pCR.⁴⁵

The secondary endpoints were pCR in the lymph nodes; clinical response rate; tolerability; breast conservation; time to disease progression (local, regional, and distant); and OS. Also recorded was minimal residual disease (MRD), which we arbitrarily defined as ≤ 1 cm invasive carcinoma at resection. The overall treatment plan included postoperative AC to provide a standard-of-care regimen to maximize curative potential.

Statistical analysis

Data were analyzed on an intentto- treat basis. Although pCR rates with doxorubicin plus either cyclophosphamide or docetaxel have been < 15%, the studies by Smith et al26 and Hurley et al39 with in-breast pCR rates of at least 20% served as comparators (albeit imprecise).

Applying the min/max statistical design, the procedure tests the null hypothesis H0: P ≤ 0.15 against the alternative hypothesis H1: P ≥ 0.30. The overall level of significance and power for this design are 5% and 80%, respectively. The sample size needed for the first stage was 23 evaluable patients. If three or fewer pCR responses were observed, then the study would be terminated and the treatment regimen would not be investigated further. Otherwise, an additional 25 evaluable patients would be accrued for a total of 48 study patients. If 11 or fewer responses were observed, then the study would be terminated. Otherwise, this treatment regimen would be recommended to proceed to phase III for further investigation.

Tolerability assessment

At each visit, toxicities were assessed and graded according to the National Cancer Institute Common Toxicity Criteria, version 2.46 Two dose reductions were allowed for all drugs.

Ethical considerations

The investigational nature of this study was fully disclosed to each patient. In accordance with institutional and federal guidelines, the patients were guided through and subsequently signed the informed consent approved by the appropriate site Institutional Review Board.

Literature review

The terms “neoadjuvant” and “breast” were used in a literature search on PubMed, with filters “English” and “clinical trials.” Abstracts for each of the 398 results were reviewed We used phase II or III trials with at least 30 patients, at least four cycles of chemotherapy, and clearly defined pCR for comparison to this study.

Results Patients

Between June 2003 and December 2006, 50 women with a median age of 49 years (range, 28–75 years) were enrolled. One patient was ineligible due to preceding lumpectomy. The 49 eligible patients were treated with ≥ 1 cycle of neoadjuvant chemotherapy between June 27, 2003, and April 12, 2007.

The baseline characteristics of the 49 eligible patients are summarized in Table 3. Thirty-one patients (63%) were premenopausal. Twenty patients (41%) were positive for either ER or PR and were negative for HER2. Eight patients (16%) had HER2- positive tumors, and 23 (46%) had triple-negative tumors. At baseline, 22 patients (45%) had clinical lymphadenopathy, and 1 patient (2%) had inflammatory breast cancer.

The 41 patients (83%) who completed all four cycles of therapy were evaluable for response; 8 (16%) were inevaluable due to noncompliance (1), grade 3 or 4 toxicity (5), or withdrawal of consent (2). The following efficacy assessments apply to the 41 evaluable patients, whereas the toxicity assessments include the 49 patients who received at least one full cycle of chemotherapy.

Clinical response

At study onset, of the 49 eligible patients, 38 (78%) had a palpable inbreast tumor (median size, 5.5 cm); 22 (45%) had enlarged nodes, and 34 (69%) had confirmed nodal involvement (by biopsy or imaging). A clinical complete response (cCR) rate in the breast was seen in 23 of 41 (56%) evaluable patients. Of 22 patients with baseline lymphadenopathy (by imaging or physical examination), 13 had axillary assessment by physical examination throughout treatment, with 12 (92%) exhibiting a cCR in the axilla.

Pathologic response

After four cycles of chemotherapy, an in-breast pCR (the primary endpoint) was demonstrated in 6 of 41 patients (15%). One of these six patients had residual DCIS and is listed separately. All of these patients had nodal pCR, whereas overall, 20 patients (49%) had negative nodes at resection.

The pathology reports of two patients were read as having invasive tumor within lymphatics and lymphovascular invasion (one each) with no measurable disease, with tumor thus sized as Tx. Neither of these patients had involved lymph nodes. Fourteen patients (34%) had MRD in the breast, and 8 of these 14 patients (57%) had residual nodal disease. Nine patients (22%) had T1c tumors (> 1–2 cm), with five of these nine patients (55%) having nodal disease. Seven patients (17%) had T2 tumors (> 2–5 cm) tumors, with five of these seven patients (71%) having nodal disease. These findings are summarized in Table 4. The correlation between in-breast cCR and pCR was 26%.

Biologic features of responders

Of interest, five of the six patients with a pCR had triple-negative tumors. This translates to a 22% pCR rate (5 of 23) in the triple-negative subset, and a pCR rate of 6% (1 of 18) in patients with ER-positive and/ or PR-positive tumors. The remaining patient with a pCR had ER-, PR-, and HER2-positive disease.

One patient had inflammatory breast cancer at diagnosis, and another developed this during the course of chemotherapy; the latter patient was removed from the study for progressive disease. Interestingly, the patient who presented with inflammatory breast cancer was one of the six patients with a pCR. Both of these inflammatory disease patients had triple-negative tumors.

Conversion to breast conservation

Breast conservation was offered to patients if it was deemed appropriate by the treating surgeon. Preoperative imaging was not mandated and thus was not routinely performed. Mastectomy was ultimately performed in 4 of the 6 patients (67%) with pCR and in 22 of the 35 patients (63%) with less than a pCR. Thus, the choice for breast conservation did not correlate well with response to chemotherapy.

Time to disease progression

At a median follow-up of 48 months (range, 7–63), 36 of 41 patients (88%) remained free of disease (range, 19–63 months). Two patients had progressive disease while they were on study treatment and had T3 tumors on resection. Another three patients were found to have progressive disease at 10, 41, and 50 months from study day 1.

Of the nine patients with T1c disease, only one patient (who had positive nodes at resection) had a recurrence (at 41 months). Overall, the patients who had a recurrence had MRD (one patient), T1c (one patient), T2 (one patient), and T3 (the same two patients whose disease progressed while they were on treatment and continued to progress after surgery).

Disease-free and overall survival

Three patients were lost to followup, with point of last contact at 19, 34, and 59 months. Of the 41 evaluable patients, 5 patients developed progressive disease, with 2 of these patients progressing during the study treatment. Disease-free survival at 12, 24, and 36 months was 89%, 89%, and 78%, respectively. Overall survival at these same time points was 95%, 90%, and 76%. None of the patients with a pCR is known to have recurrent disease. Of the six patients achieving pCR, two were lost to follow-up after 34 and 59 months, and four continued diseasefree at 38, 39, 55, and 62 months.

Adverse events

Five patients were removed from the study secondary to toxicities. Grade 3 and 4 toxicity events are summarized in Table 5. Grade 3 toxicities were anemia (4), diarrhea (2), epigastric pain (1), fatigue (2), hand-foot syndrome (1), infection (1), leukopenia (9), pain (5), and peripheral sensory neuropathy (1). Grade 4 toxicities were depression (1) and leukopenia (4). Toxicities (all grades) occurring in ≥ 10% of the 49 treated patients were anemia (76%), leukopenia (70%), fatigue (67%), nausea (59%), alopecia (49%), thrombocytopenia (47%), diarrhea (47%), constipation (37%), pain (35%), vomiting (31%), epigastric pain (27%), nail changes (22%), epiphora (22%), hand-foot syndrome (20%), infection (18%), edema (16%), rash (16%), anorexia (16%), and depression (10%). In the intent-to-treat population, there were nine dose reductions among nine patients, and 19 dose delays among 15 patients.

Discussion

The combination of agents tested thus far in the neoadjuvant setting consistently produce pCR rates far less than 50% in unselected populations. This study was begun prior to the widespread use of personalized medicine. Most prior published trials had utilized anthracycline-based chemotherapy, with response rates generally ranging between 7% and 36%.6,9–26,28–31,41,42

The idea of thymidine phosphorylase upregulation by the combination of capecitabine and docetaxel upon which this study was largely based^34–36 has since been disputed.⁴⁷ The primary endpoint of this trial of a novel platinum- based regimen was a pCR rate of 15%. It is significant that 83% of the pCRs were in triple-negative tumors. A secondary endpoint of MRD was calculated, as this was in the original design of the study, but ultimately was not relevant to the primary endpoint.

Ultimately, pCR is the more relevant point of discussion for the modern era. The 15% pCR rate seen in this phase II study was within range of those achieved in numerous other phase II/III neoadjuvant chemotherapy trials with ≥ 25 patients, ≥ 3 cycles of chemotherapy, and pCR defined as absence of carcinoma in the breast and axilla. To date, no patient in our study with a pCR has been noted to have recurrent disease. However, a recently published French study found a 22% recurrence rate at 11 years in patients with triple-negative breast cancer achieving pCR, highlighting the importance of longer-term follow- up.⁴⁸.

The inclusion of patients with HER2-positive disease in neoadjuvant studies without HER2-targeted therapy was standard at the time that this study was conducted, but is no longer appropriate. If we were to exclude the eight HER2-positive patients from analysis, then there would be only 34 patients evaluable for response, with a pCR rate of 18%. Buzdar et al33 demonstrated a 65% pCR rate in women with HER2-positive disease treated with neoadjuvant chemotherapy plus trastuzumab. The improvement in pCR with the addition of trastuzumab is supported by other confirmatory trials. Authors of a single-arm trial of dose-dense epirubicin and cyclophosphamide followed by dosedense docetaxel and trastuzumab in a HER2-positive population reported a pCR rate of 57%.⁴⁹ The randomized NOAH study50 achieved a pCR rate of 23% in 115 patients treated with trastuzumab-based chemotherapy.

It is interesting to note that five of six patients (83%) achieving a pCR in our study had triple-negative tumors. Investigators at the University of Miami presented a retrospective review of locally advanced triple-negative breast cancer treated with docetaxel and a platinum salt, with 61% of patients also receiving AC. The authors reported a pCR rate of 34% overall and 40% for patients receiving AC.⁵¹ A pCR rate of 60% was noted in the triplenegative subset of patients in another study evaluating docetaxel, doxorubicin, and cyclophosphamide with or without vinorelbine/capecitabine (GeparTrio Study).⁵² Further, a pCR rate of 72% was achieved with singleagent cisplatin in a group of 25 women with BRCA1 mutations, suggesting, if confirmed by others, that this largely triple- negative population may be exquisitely sensitive to platinum salts.⁴³ In contrast, in a previous study of cisplatin in BRCA mutation carriers, Garber et al44 reported a pCR rate of 22%, suggesting that further trials are needed specifically in BRCA carriers and in triple-negative tumors to see whether these specific patient subsets preferentially derive benefit from platinum salts in the neoadjuvant setting.

The results of the current study are consistent with others indicating a low likelihood of pCR in patients with ERpositive tumors. In fact, none of our ER-positive patients had a pCR. Neoadjuvant endocrine therapy in postmenopausal women with ER- and/ or PR-positive disease is a reasonable treatment option for selected patients, but endpoints other than pCR have often been used.^53,54 It is therefore difficult to directly compare these two strategies. Currently, investigators are comparing the three aromatase inhibitors head to head in the neoadjuvant setting for postmenopausal women with hormone receptor–positive tumors.⁵⁵

The historic pCR ceiling appears to be rising, albeit slowly. Where targets such as HER2 overexpression and triple- negative biology are recognized, progress is being made. Patient eligibility criteria for neoadjuvant breast cancer studies at the time of this trial were quite broad, and it is now recognized that specific subsets of breast cancer respond differently to different classes of agents. Furthermore, our knowledge about breast cancer prognostic markers continues to expand. Had this study been designed in 2011, other data points such as Ki67 would have been collected. A recently published study on neoadjuvant triplenegative breast cancer found that only patients with baseline Ki67% expression > 10% achieved pCR.⁵⁶

Given the long-term implications of not achieving pCR, optimal treatment of patients in the adjuvant setting is critical. Although neoadjuvantly treated patients with ER-positive or HER2-positive disease go on to receive adjuvant agents (antihormonal therapy for ER-positive disease and trastuzumab for HER2-positive disease), patients with triple-negative disease lack long-term therapies of proven efficacy. Perhaps, as we edge closer to defining the optimal neoadjuvant agents for each subset of patients, this will be less of a concern. Many earlyphase neoadjuvant studies have been conducted, with promising reports, yet the results of larger, randomized trials continue to frustrate both investigators and clinicians. These deficits in care can only be answered by carefully planned randomized clinical trials.

Acknowledgment: Funding for this study was provided by sanofi-aventis, U.S.

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ABOUT THE AUTHORS

Aruna Mani, MD; Sandra X. Franco, MD; Grace Wang, MD: Neil Abramson, MD; Lee S. Schwartzberg, MD: James Jakub, MD; Elizabeth Tan-Chiu, MD: Alisha Stein, RNC, BSN, OCN; Alejandra T. Perez, MD; and Charles L Vogel, MD.

Affiliations: Dr. Mani is a breast medical oncologist at Memorial Cancer Institute, Pembroke Pines, FL. Dr. Franco is now Chief of Oncology at the Oncology Center, Clinica del Country, Bogota, Colombia. Dr. Wang is an oncologist at Advanced Medical Specialties, Miami, FL. Dr. Abramson is Clinical Professor of Medicine and Emeritus Director of Education and Research at Baptist Cancer Institute, University of Florida, Jacksonville, FL. Dr. Schwartzberg is Medical Director of The West Clinic, Memphis, TN. Dr. Jakub is now Assistant Professor of Surgery, Division of Gastroenterology and General Surgery, Mayo Clinic, Rochester, MN. Dr. Tan-Chiu is Medical Director of Florida Cancer Care, Davie, FL. Dr. Schwartz is Principal Investigator at Mount Sinai Medical Center, Miami Beach, FL. Ms. Frankel is Director of Oncology Clinical Research and Development at Memorial Cancer Institute, Hollywood, FL. Dr. Krill-Jackson is an oncologist at Mount Sinai Comprehensive Cancer Center, Miami, FL. Ms. Stein is now Oncology Clinical Coordinator at Genentech Inc., Fort Lauderdale, FL. Dr. Perez is Director of the Breast Cancer Center at Memorial Cancer Institute, Hollywood, FL. Dr. Vogel is Professor of Clinical Medicine and Director of the Women’s Center, Sylvester Comprehensive Cancer Center, Deerfield Beach, FL.

Conflicts of interest: Dr. Vogel has served as an advisor and is a member of the speakers’ bureaus of sanofi-aventis U.S. and Roche, as well as many other companies whose products were not part of the current study plan. The other authors have no pertinent conflicts of interest to disclose.

The standard of care for locally advanced breast cancer (LABC) is neoadjuvant chemotherapy,¹ with LABC including clinical stages IIA, IIB, and IIIA. The goals of preoperative chemotherapy are to downstage so as to render breast conservation feasible, to eradicate disease in the axillary nodes, and to allow in vivo testing of tumor drug sensitivity, all with the ultimate aim of improving prognosis. Clinical trials have demonstrated that the pathologic in-breast response generally correlates with pathologic response in the lymph nodes. Furthermore, nodal status at the time of surgery correlates with overall survival (OS) and disease-free survival (DFS).²,³ A combined analysis of two large prospective neoadjuvant chemotherapy trials demonstrated significantly higher 5-year OS and DFS in patients achieving in-breast pathologic complete response (pCR), compared with those who did not (OS, 89% vs 64%; DFS, 87% vs 58%, respectively).⁴

At the start of this trial, the most effective neoad- juvant regimen remained in question. Even now, National Comprehensive Cancer Center guidelines suggest that any recommended adjuvant regimen can be used in the neoadjuvant setting.¹ Numerous phase II and III trials have evaluated single-agent^5–8 and combination^{9– 32} chemotherapies, most of which are anthracycline- based, with pCR rates reported between 7% and 36%. In the NSABP-B27 study, patients treated preoperatively with four cycles of doxorubicin and cyclophosphamide (AC) followed by four cycles of docetaxel (Taxotere) had a 26% pCR rate versus a 13% pCR rate in those receiving preoperative AC and postoperative docetaxel. Despite the doubling of pCR with neoadjuvant docetaxel, there was no difference in DFS or OS.9 However, as reported by Kuerer et al, patients achieving a pCR after completion of neoadjuvant chemotherapy appeared to have superior survival.⁴

Many previous trials (including the study reported here) did not exclude patients with human epidermal growth factor receptor 2 (HER2)-positive disease. It is now well established that such patients should be treated with neoadjuvant regimens incorporating HER2-targeted therapy. In fact, an early neoadjuvant study of paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide with or without 24 weeks of concurrent trastuzumab (Herceptin) in patients with HER2-positive tumors was closed early because patients receiving trastuzumab had a pCR rate of 65%, compared with 26% in those who did not receive it.³³ Expanded clinical trials of this approach are in progress.

The selection of capecitabine (Xeloda) and docetaxel in the present trial was based on the hypothesis that the upregulation of thymidine phosphorylase by docetaxel should increase the activity of capecitabine. ^34–36 Single-agent docetaxel in the neoadjuvant setting has yielded pCR rates of 7%–20%.^6–8 Treatment with docetaxel and capecitabine together has been reported to produce pCR rates of 10%–21%.^37–39 The addition of carboplatin was based on studies by Hurley et al at the University of Miami^{39– 41} suggesting that platinum salts appeared quite active in the neoadjuvant setting, with the combination of docetaxel and cisplatin producing a pCR rate of 20%, with no residual disease in the breast or axilla.40 Other regimens incorporating cisplatin or carboplatin have pCR rates ranging from 16% to 24%.^27,42–44

Patients and methods

Study design

In this phase II multicenter study, patients were assigned to receive docetaxel (30 mg/m2 IV) and carboplatin (AUC 2 IV) on days 1, 8, and 15 of each 28-day cycle plus capecitabine (625 mg/m2 PO) twice daily on days 5–18. The capecitabine dose was based on observations that this dose was effective and relatively nontoxic in metastatic breast cancer (C.L. Vogel, empirical observations). Patients were to receive four cycles prior to surgical resection.

Given that this neoadjuvant regimen was under study, all of the patients were scheduled to receive a proven standard postoperative adjuvant chemotherapy regimen, starting 4–6 weeks postoperatively, with doxorubicin (60 mg/m2 IV) and cyclophosphamide (600 mg/m2 IV) every 21 days for 4 cycles. This sequential design was prompted by studies such as the NSABP B-27 and Aberdeen trials.^9,32

Radiation therapy after lumpectomy or mastectomy was given according to individual institution guidelines. Patients with hormone receptor–positive tumors received appropriate antihormonal therapy. Tumor measurements were assessed at baseline and on day 1 of each cycle by physical examination with calipers. No breast or other imaging was required during the period of neoadjuvant chemotherapy or immediately preoperatively. Patients were considered evaluable if they proceeded to surgery after all intended cycles of neoadjuvant chemotherapy or if they developed disease progression during neoadjuvant therapy.

Patients

Eligible patients were men and women regardless of menopausal status ≥ 18 years of age with coreneedle biopsy proven locally advanced or inflammatory breast cancer. Breast cancer characteristics such as estrogen receptor (ER), progesterone receptor (PR), or HER2 status were collected but not used for inclusion/exclusion. Eligible tumors were T2 requiring mastectomy; T3N0–2; T4; and any TN2–3 that by calipers was > 2 cm or with fixed or matted axillary or imaging-detected internal mammary nodes. Patients with prior ductal carcinoma in situ (DCIS) were included, as were those with ≤ T2N0M0 breast cancer > 5 years prior.

Other requirements were an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; life expectancy > 6 months; negative metastatic workup (bone scan and CT chest/abdomen/pelvis); adequate bone marrow, liver, and kidney function; and peripheral neuropathy ≤ grade 1. All patients of child-bearing potential were required to consent to dual methods of contraception during treatment and for 3 months afterward. A negative pregnancy test was required for these women before treatment, and any suspicion of pregnancy had to be reported to the treating physician.

Study endpoints

The primary endpoint of the study was the in-breast pCR after four cycles of platinum-based neoadjuvant chemotherapy. Pathologic complete response was defined as complete disappearance of invasive and in situ disease or invasive disease alone. During the course of this trial, it became generally acceptable to include patients with only residual DCIS as equivalent to pCR.⁴⁵

The secondary endpoints were pCR in the lymph nodes; clinical response rate; tolerability; breast conservation; time to disease progression (local, regional, and distant); and OS. Also recorded was minimal residual disease (MRD), which we arbitrarily defined as ≤ 1 cm invasive carcinoma at resection. The overall treatment plan included postoperative AC to provide a standard-of-care regimen to maximize curative potential.

Statistical analysis

Data were analyzed on an intentto- treat basis. Although pCR rates with doxorubicin plus either cyclophosphamide or docetaxel have been < 15%, the studies by Smith et al26 and Hurley et al39 with in-breast pCR rates of at least 20% served as comparators (albeit imprecise).

Applying the min/max statistical design, the procedure tests the null hypothesis H0: P ≤ 0.15 against the alternative hypothesis H1: P ≥ 0.30. The overall level of significance and power for this design are 5% and 80%, respectively. The sample size needed for the first stage was 23 evaluable patients. If three or fewer pCR responses were observed, then the study would be terminated and the treatment regimen would not be investigated further. Otherwise, an additional 25 evaluable patients would be accrued for a total of 48 study patients. If 11 or fewer responses were observed, then the study would be terminated. Otherwise, this treatment regimen would be recommended to proceed to phase III for further investigation.

Tolerability assessment

At each visit, toxicities were assessed and graded according to the National Cancer Institute Common Toxicity Criteria, version 2.46 Two dose reductions were allowed for all drugs.

Ethical considerations

The investigational nature of this study was fully disclosed to each patient. In accordance with institutional and federal guidelines, the patients were guided through and subsequently signed the informed consent approved by the appropriate site Institutional Review Board.

Literature review

The terms “neoadjuvant” and “breast” were used in a literature search on PubMed, with filters “English” and “clinical trials.” Abstracts for each of the 398 results were reviewed We used phase II or III trials with at least 30 patients, at least four cycles of chemotherapy, and clearly defined pCR for comparison to this study.

Results Patients

Between June 2003 and December 2006, 50 women with a median age of 49 years (range, 28–75 years) were enrolled. One patient was ineligible due to preceding lumpectomy. The 49 eligible patients were treated with ≥ 1 cycle of neoadjuvant chemotherapy between June 27, 2003, and April 12, 2007.

The baseline characteristics of the 49 eligible patients are summarized in Table 3. Thirty-one patients (63%) were premenopausal. Twenty patients (41%) were positive for either ER or PR and were negative for HER2. Eight patients (16%) had HER2- positive tumors, and 23 (46%) had triple-negative tumors. At baseline, 22 patients (45%) had clinical lymphadenopathy, and 1 patient (2%) had inflammatory breast cancer.

The 41 patients (83%) who completed all four cycles of therapy were evaluable for response; 8 (16%) were inevaluable due to noncompliance (1), grade 3 or 4 toxicity (5), or withdrawal of consent (2). The following efficacy assessments apply to the 41 evaluable patients, whereas the toxicity assessments include the 49 patients who received at least one full cycle of chemotherapy.

Clinical response

At study onset, of the 49 eligible patients, 38 (78%) had a palpable inbreast tumor (median size, 5.5 cm); 22 (45%) had enlarged nodes, and 34 (69%) had confirmed nodal involvement (by biopsy or imaging). A clinical complete response (cCR) rate in the breast was seen in 23 of 41 (56%) evaluable patients. Of 22 patients with baseline lymphadenopathy (by imaging or physical examination), 13 had axillary assessment by physical examination throughout treatment, with 12 (92%) exhibiting a cCR in the axilla.

Pathologic response

After four cycles of chemotherapy, an in-breast pCR (the primary endpoint) was demonstrated in 6 of 41 patients (15%). One of these six patients had residual DCIS and is listed separately. All of these patients had nodal pCR, whereas overall, 20 patients (49%) had negative nodes at resection.

The pathology reports of two patients were read as having invasive tumor within lymphatics and lymphovascular invasion (one each) with no measurable disease, with tumor thus sized as Tx. Neither of these patients had involved lymph nodes. Fourteen patients (34%) had MRD in the breast, and 8 of these 14 patients (57%) had residual nodal disease. Nine patients (22%) had T1c tumors (> 1–2 cm), with five of these nine patients (55%) having nodal disease. Seven patients (17%) had T2 tumors (> 2–5 cm) tumors, with five of these seven patients (71%) having nodal disease. These findings are summarized in Table 4. The correlation between in-breast cCR and pCR was 26%.

Biologic features of responders

Of interest, five of the six patients with a pCR had triple-negative tumors. This translates to a 22% pCR rate (5 of 23) in the triple-negative subset, and a pCR rate of 6% (1 of 18) in patients with ER-positive and/ or PR-positive tumors. The remaining patient with a pCR had ER-, PR-, and HER2-positive disease.

One patient had inflammatory breast cancer at diagnosis, and another developed this during the course of chemotherapy; the latter patient was removed from the study for progressive disease. Interestingly, the patient who presented with inflammatory breast cancer was one of the six patients with a pCR. Both of these inflammatory disease patients had triple-negative tumors.

Conversion to breast conservation

Breast conservation was offered to patients if it was deemed appropriate by the treating surgeon. Preoperative imaging was not mandated and thus was not routinely performed. Mastectomy was ultimately performed in 4 of the 6 patients (67%) with pCR and in 22 of the 35 patients (63%) with less than a pCR. Thus, the choice for breast conservation did not correlate well with response to chemotherapy.

Time to disease progression

At a median follow-up of 48 months (range, 7–63), 36 of 41 patients (88%) remained free of disease (range, 19–63 months). Two patients had progressive disease while they were on study treatment and had T3 tumors on resection. Another three patients were found to have progressive disease at 10, 41, and 50 months from study day 1.

Of the nine patients with T1c disease, only one patient (who had positive nodes at resection) had a recurrence (at 41 months). Overall, the patients who had a recurrence had MRD (one patient), T1c (one patient), T2 (one patient), and T3 (the same two patients whose disease progressed while they were on treatment and continued to progress after surgery).

Disease-free and overall survival

Three patients were lost to followup, with point of last contact at 19, 34, and 59 months. Of the 41 evaluable patients, 5 patients developed progressive disease, with 2 of these patients progressing during the study treatment. Disease-free survival at 12, 24, and 36 months was 89%, 89%, and 78%, respectively. Overall survival at these same time points was 95%, 90%, and 76%. None of the patients with a pCR is known to have recurrent disease. Of the six patients achieving pCR, two were lost to follow-up after 34 and 59 months, and four continued diseasefree at 38, 39, 55, and 62 months.

Adverse events

Five patients were removed from the study secondary to toxicities. Grade 3 and 4 toxicity events are summarized in Table 5. Grade 3 toxicities were anemia (4), diarrhea (2), epigastric pain (1), fatigue (2), hand-foot syndrome (1), infection (1), leukopenia (9), pain (5), and peripheral sensory neuropathy (1). Grade 4 toxicities were depression (1) and leukopenia (4). Toxicities (all grades) occurring in ≥ 10% of the 49 treated patients were anemia (76%), leukopenia (70%), fatigue (67%), nausea (59%), alopecia (49%), thrombocytopenia (47%), diarrhea (47%), constipation (37%), pain (35%), vomiting (31%), epigastric pain (27%), nail changes (22%), epiphora (22%), hand-foot syndrome (20%), infection (18%), edema (16%), rash (16%), anorexia (16%), and depression (10%). In the intent-to-treat population, there were nine dose reductions among nine patients, and 19 dose delays among 15 patients.

Discussion

The combination of agents tested thus far in the neoadjuvant setting consistently produce pCR rates far less than 50% in unselected populations. This study was begun prior to the widespread use of personalized medicine. Most prior published trials had utilized anthracycline-based chemotherapy, with response rates generally ranging between 7% and 36%.6,9–26,28–31,41,42

The idea of thymidine phosphorylase upregulation by the combination of capecitabine and docetaxel upon which this study was largely based^34–36 has since been disputed.⁴⁷ The primary endpoint of this trial of a novel platinum- based regimen was a pCR rate of 15%. It is significant that 83% of the pCRs were in triple-negative tumors. A secondary endpoint of MRD was calculated, as this was in the original design of the study, but ultimately was not relevant to the primary endpoint.

Ultimately, pCR is the more relevant point of discussion for the modern era. The 15% pCR rate seen in this phase II study was within range of those achieved in numerous other phase II/III neoadjuvant chemotherapy trials with ≥ 25 patients, ≥ 3 cycles of chemotherapy, and pCR defined as absence of carcinoma in the breast and axilla. To date, no patient in our study with a pCR has been noted to have recurrent disease. However, a recently published French study found a 22% recurrence rate at 11 years in patients with triple-negative breast cancer achieving pCR, highlighting the importance of longer-term follow- up.⁴⁸.

The inclusion of patients with HER2-positive disease in neoadjuvant studies without HER2-targeted therapy was standard at the time that this study was conducted, but is no longer appropriate. If we were to exclude the eight HER2-positive patients from analysis, then there would be only 34 patients evaluable for response, with a pCR rate of 18%. Buzdar et al33 demonstrated a 65% pCR rate in women with HER2-positive disease treated with neoadjuvant chemotherapy plus trastuzumab. The improvement in pCR with the addition of trastuzumab is supported by other confirmatory trials. Authors of a single-arm trial of dose-dense epirubicin and cyclophosphamide followed by dosedense docetaxel and trastuzumab in a HER2-positive population reported a pCR rate of 57%.⁴⁹ The randomized NOAH study50 achieved a pCR rate of 23% in 115 patients treated with trastuzumab-based chemotherapy.

It is interesting to note that five of six patients (83%) achieving a pCR in our study had triple-negative tumors. Investigators at the University of Miami presented a retrospective review of locally advanced triple-negative breast cancer treated with docetaxel and a platinum salt, with 61% of patients also receiving AC. The authors reported a pCR rate of 34% overall and 40% for patients receiving AC.⁵¹ A pCR rate of 60% was noted in the triplenegative subset of patients in another study evaluating docetaxel, doxorubicin, and cyclophosphamide with or without vinorelbine/capecitabine (GeparTrio Study).⁵² Further, a pCR rate of 72% was achieved with singleagent cisplatin in a group of 25 women with BRCA1 mutations, suggesting, if confirmed by others, that this largely triple- negative population may be exquisitely sensitive to platinum salts.⁴³ In contrast, in a previous study of cisplatin in BRCA mutation carriers, Garber et al44 reported a pCR rate of 22%, suggesting that further trials are needed specifically in BRCA carriers and in triple-negative tumors to see whether these specific patient subsets preferentially derive benefit from platinum salts in the neoadjuvant setting.

The results of the current study are consistent with others indicating a low likelihood of pCR in patients with ERpositive tumors. In fact, none of our ER-positive patients had a pCR. Neoadjuvant endocrine therapy in postmenopausal women with ER- and/ or PR-positive disease is a reasonable treatment option for selected patients, but endpoints other than pCR have often been used.^53,54 It is therefore difficult to directly compare these two strategies. Currently, investigators are comparing the three aromatase inhibitors head to head in the neoadjuvant setting for postmenopausal women with hormone receptor–positive tumors.⁵⁵

The historic pCR ceiling appears to be rising, albeit slowly. Where targets such as HER2 overexpression and triple- negative biology are recognized, progress is being made. Patient eligibility criteria for neoadjuvant breast cancer studies at the time of this trial were quite broad, and it is now recognized that specific subsets of breast cancer respond differently to different classes of agents. Furthermore, our knowledge about breast cancer prognostic markers continues to expand. Had this study been designed in 2011, other data points such as Ki67 would have been collected. A recently published study on neoadjuvant triplenegative breast cancer found that only patients with baseline Ki67% expression > 10% achieved pCR.⁵⁶

Given the long-term implications of not achieving pCR, optimal treatment of patients in the adjuvant setting is critical. Although neoadjuvantly treated patients with ER-positive or HER2-positive disease go on to receive adjuvant agents (antihormonal therapy for ER-positive disease and trastuzumab for HER2-positive disease), patients with triple-negative disease lack long-term therapies of proven efficacy. Perhaps, as we edge closer to defining the optimal neoadjuvant agents for each subset of patients, this will be less of a concern. Many earlyphase neoadjuvant studies have been conducted, with promising reports, yet the results of larger, randomized trials continue to frustrate both investigators and clinicians. These deficits in care can only be answered by carefully planned randomized clinical trials.

Acknowledgment: Funding for this study was provided by sanofi-aventis, U.S.

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ABOUT THE AUTHORS

Aruna Mani, MD; Sandra X. Franco, MD; Grace Wang, MD: Neil Abramson, MD; Lee S. Schwartzberg, MD: James Jakub, MD; Elizabeth Tan-Chiu, MD: Alisha Stein, RNC, BSN, OCN; Alejandra T. Perez, MD; and Charles L Vogel, MD.

Affiliations: Dr. Mani is a breast medical oncologist at Memorial Cancer Institute, Pembroke Pines, FL. Dr. Franco is now Chief of Oncology at the Oncology Center, Clinica del Country, Bogota, Colombia. Dr. Wang is an oncologist at Advanced Medical Specialties, Miami, FL. Dr. Abramson is Clinical Professor of Medicine and Emeritus Director of Education and Research at Baptist Cancer Institute, University of Florida, Jacksonville, FL. Dr. Schwartzberg is Medical Director of The West Clinic, Memphis, TN. Dr. Jakub is now Assistant Professor of Surgery, Division of Gastroenterology and General Surgery, Mayo Clinic, Rochester, MN. Dr. Tan-Chiu is Medical Director of Florida Cancer Care, Davie, FL. Dr. Schwartz is Principal Investigator at Mount Sinai Medical Center, Miami Beach, FL. Ms. Frankel is Director of Oncology Clinical Research and Development at Memorial Cancer Institute, Hollywood, FL. Dr. Krill-Jackson is an oncologist at Mount Sinai Comprehensive Cancer Center, Miami, FL. Ms. Stein is now Oncology Clinical Coordinator at Genentech Inc., Fort Lauderdale, FL. Dr. Perez is Director of the Breast Cancer Center at Memorial Cancer Institute, Hollywood, FL. Dr. Vogel is Professor of Clinical Medicine and Director of the Women’s Center, Sylvester Comprehensive Cancer Center, Deerfield Beach, FL.

Conflicts of interest: Dr. Vogel has served as an advisor and is a member of the speakers’ bureaus of sanofi-aventis U.S. and Roche, as well as many other companies whose products were not part of the current study plan. The other authors have no pertinent conflicts of interest to disclose.

The standard of care for locally advanced breast cancer (LABC) is neoadjuvant chemotherapy,¹ with LABC including clinical stages IIA, IIB, and IIIA. The goals of preoperative chemotherapy are to downstage so as to render breast conservation feasible, to eradicate disease in the axillary nodes, and to allow in vivo testing of tumor drug sensitivity, all with the ultimate aim of improving prognosis. Clinical trials have demonstrated that the pathologic in-breast response generally correlates with pathologic response in the lymph nodes. Furthermore, nodal status at the time of surgery correlates with overall survival (OS) and disease-free survival (DFS).²,³ A combined analysis of two large prospective neoadjuvant chemotherapy trials demonstrated significantly higher 5-year OS and DFS in patients achieving in-breast pathologic complete response (pCR), compared with those who did not (OS, 89% vs 64%; DFS, 87% vs 58%, respectively).⁴

At the start of this trial, the most effective neoad- juvant regimen remained in question. Even now, National Comprehensive Cancer Center guidelines suggest that any recommended adjuvant regimen can be used in the neoadjuvant setting.¹ Numerous phase II and III trials have evaluated single-agent^5–8 and combination^{9– 32} chemotherapies, most of which are anthracycline- based, with pCR rates reported between 7% and 36%. In the NSABP-B27 study, patients treated preoperatively with four cycles of doxorubicin and cyclophosphamide (AC) followed by four cycles of docetaxel (Taxotere) had a 26% pCR rate versus a 13% pCR rate in those receiving preoperative AC and postoperative docetaxel. Despite the doubling of pCR with neoadjuvant docetaxel, there was no difference in DFS or OS.9 However, as reported by Kuerer et al, patients achieving a pCR after completion of neoadjuvant chemotherapy appeared to have superior survival.⁴

Many previous trials (including the study reported here) did not exclude patients with human epidermal growth factor receptor 2 (HER2)-positive disease. It is now well established that such patients should be treated with neoadjuvant regimens incorporating HER2-targeted therapy. In fact, an early neoadjuvant study of paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide with or without 24 weeks of concurrent trastuzumab (Herceptin) in patients with HER2-positive tumors was closed early because patients receiving trastuzumab had a pCR rate of 65%, compared with 26% in those who did not receive it.³³ Expanded clinical trials of this approach are in progress.

The selection of capecitabine (Xeloda) and docetaxel in the present trial was based on the hypothesis that the upregulation of thymidine phosphorylase by docetaxel should increase the activity of capecitabine. ^34–36 Single-agent docetaxel in the neoadjuvant setting has yielded pCR rates of 7%–20%.^6–8 Treatment with docetaxel and capecitabine together has been reported to produce pCR rates of 10%–21%.^37–39 The addition of carboplatin was based on studies by Hurley et al at the University of Miami^{39– 41} suggesting that platinum salts appeared quite active in the neoadjuvant setting, with the combination of docetaxel and cisplatin producing a pCR rate of 20%, with no residual disease in the breast or axilla.40 Other regimens incorporating cisplatin or carboplatin have pCR rates ranging from 16% to 24%.^27,42–44

Patients and methods

Study design

In this phase II multicenter study, patients were assigned to receive docetaxel (30 mg/m2 IV) and carboplatin (AUC 2 IV) on days 1, 8, and 15 of each 28-day cycle plus capecitabine (625 mg/m2 PO) twice daily on days 5–18. The capecitabine dose was based on observations that this dose was effective and relatively nontoxic in metastatic breast cancer (C.L. Vogel, empirical observations). Patients were to receive four cycles prior to surgical resection.

Given that this neoadjuvant regimen was under study, all of the patients were scheduled to receive a proven standard postoperative adjuvant chemotherapy regimen, starting 4–6 weeks postoperatively, with doxorubicin (60 mg/m2 IV) and cyclophosphamide (600 mg/m2 IV) every 21 days for 4 cycles. This sequential design was prompted by studies such as the NSABP B-27 and Aberdeen trials.^9,32

Radiation therapy after lumpectomy or mastectomy was given according to individual institution guidelines. Patients with hormone receptor–positive tumors received appropriate antihormonal therapy. Tumor measurements were assessed at baseline and on day 1 of each cycle by physical examination with calipers. No breast or other imaging was required during the period of neoadjuvant chemotherapy or immediately preoperatively. Patients were considered evaluable if they proceeded to surgery after all intended cycles of neoadjuvant chemotherapy or if they developed disease progression during neoadjuvant therapy.

Patients

Eligible patients were men and women regardless of menopausal status ≥ 18 years of age with coreneedle biopsy proven locally advanced or inflammatory breast cancer. Breast cancer characteristics such as estrogen receptor (ER), progesterone receptor (PR), or HER2 status were collected but not used for inclusion/exclusion. Eligible tumors were T2 requiring mastectomy; T3N0–2; T4; and any TN2–3 that by calipers was > 2 cm or with fixed or matted axillary or imaging-detected internal mammary nodes. Patients with prior ductal carcinoma in situ (DCIS) were included, as were those with ≤ T2N0M0 breast cancer > 5 years prior.

Other requirements were an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; life expectancy > 6 months; negative metastatic workup (bone scan and CT chest/abdomen/pelvis); adequate bone marrow, liver, and kidney function; and peripheral neuropathy ≤ grade 1. All patients of child-bearing potential were required to consent to dual methods of contraception during treatment and for 3 months afterward. A negative pregnancy test was required for these women before treatment, and any suspicion of pregnancy had to be reported to the treating physician.

Study endpoints

The primary endpoint of the study was the in-breast pCR after four cycles of platinum-based neoadjuvant chemotherapy. Pathologic complete response was defined as complete disappearance of invasive and in situ disease or invasive disease alone. During the course of this trial, it became generally acceptable to include patients with only residual DCIS as equivalent to pCR.⁴⁵

The secondary endpoints were pCR in the lymph nodes; clinical response rate; tolerability; breast conservation; time to disease progression (local, regional, and distant); and OS. Also recorded was minimal residual disease (MRD), which we arbitrarily defined as ≤ 1 cm invasive carcinoma at resection. The overall treatment plan included postoperative AC to provide a standard-of-care regimen to maximize curative potential.

Statistical analysis

Data were analyzed on an intentto- treat basis. Although pCR rates with doxorubicin plus either cyclophosphamide or docetaxel have been < 15%, the studies by Smith et al26 and Hurley et al39 with in-breast pCR rates of at least 20% served as comparators (albeit imprecise).

Applying the min/max statistical design, the procedure tests the null hypothesis H0: P ≤ 0.15 against the alternative hypothesis H1: P ≥ 0.30. The overall level of significance and power for this design are 5% and 80%, respectively. The sample size needed for the first stage was 23 evaluable patients. If three or fewer pCR responses were observed, then the study would be terminated and the treatment regimen would not be investigated further. Otherwise, an additional 25 evaluable patients would be accrued for a total of 48 study patients. If 11 or fewer responses were observed, then the study would be terminated. Otherwise, this treatment regimen would be recommended to proceed to phase III for further investigation.

Tolerability assessment

At each visit, toxicities were assessed and graded according to the National Cancer Institute Common Toxicity Criteria, version 2.46 Two dose reductions were allowed for all drugs.

Ethical considerations

The investigational nature of this study was fully disclosed to each patient. In accordance with institutional and federal guidelines, the patients were guided through and subsequently signed the informed consent approved by the appropriate site Institutional Review Board.

Literature review

The terms “neoadjuvant” and “breast” were used in a literature search on PubMed, with filters “English” and “clinical trials.” Abstracts for each of the 398 results were reviewed We used phase II or III trials with at least 30 patients, at least four cycles of chemotherapy, and clearly defined pCR for comparison to this study.

Results Patients

Between June 2003 and December 2006, 50 women with a median age of 49 years (range, 28–75 years) were enrolled. One patient was ineligible due to preceding lumpectomy. The 49 eligible patients were treated with ≥ 1 cycle of neoadjuvant chemotherapy between June 27, 2003, and April 12, 2007.

The baseline characteristics of the 49 eligible patients are summarized in Table 3. Thirty-one patients (63%) were premenopausal. Twenty patients (41%) were positive for either ER or PR and were negative for HER2. Eight patients (16%) had HER2- positive tumors, and 23 (46%) had triple-negative tumors. At baseline, 22 patients (45%) had clinical lymphadenopathy, and 1 patient (2%) had inflammatory breast cancer.

The 41 patients (83%) who completed all four cycles of therapy were evaluable for response; 8 (16%) were inevaluable due to noncompliance (1), grade 3 or 4 toxicity (5), or withdrawal of consent (2). The following efficacy assessments apply to the 41 evaluable patients, whereas the toxicity assessments include the 49 patients who received at least one full cycle of chemotherapy.

Clinical response

At study onset, of the 49 eligible patients, 38 (78%) had a palpable inbreast tumor (median size, 5.5 cm); 22 (45%) had enlarged nodes, and 34 (69%) had confirmed nodal involvement (by biopsy or imaging). A clinical complete response (cCR) rate in the breast was seen in 23 of 41 (56%) evaluable patients. Of 22 patients with baseline lymphadenopathy (by imaging or physical examination), 13 had axillary assessment by physical examination throughout treatment, with 12 (92%) exhibiting a cCR in the axilla.

Pathologic response

After four cycles of chemotherapy, an in-breast pCR (the primary endpoint) was demonstrated in 6 of 41 patients (15%). One of these six patients had residual DCIS and is listed separately. All of these patients had nodal pCR, whereas overall, 20 patients (49%) had negative nodes at resection.

The pathology reports of two patients were read as having invasive tumor within lymphatics and lymphovascular invasion (one each) with no measurable disease, with tumor thus sized as Tx. Neither of these patients had involved lymph nodes. Fourteen patients (34%) had MRD in the breast, and 8 of these 14 patients (57%) had residual nodal disease. Nine patients (22%) had T1c tumors (> 1–2 cm), with five of these nine patients (55%) having nodal disease. Seven patients (17%) had T2 tumors (> 2–5 cm) tumors, with five of these seven patients (71%) having nodal disease. These findings are summarized in Table 4. The correlation between in-breast cCR and pCR was 26%.

Biologic features of responders

Of interest, five of the six patients with a pCR had triple-negative tumors. This translates to a 22% pCR rate (5 of 23) in the triple-negative subset, and a pCR rate of 6% (1 of 18) in patients with ER-positive and/ or PR-positive tumors. The remaining patient with a pCR had ER-, PR-, and HER2-positive disease.

One patient had inflammatory breast cancer at diagnosis, and another developed this during the course of chemotherapy; the latter patient was removed from the study for progressive disease. Interestingly, the patient who presented with inflammatory breast cancer was one of the six patients with a pCR. Both of these inflammatory disease patients had triple-negative tumors.

Conversion to breast conservation

Breast conservation was offered to patients if it was deemed appropriate by the treating surgeon. Preoperative imaging was not mandated and thus was not routinely performed. Mastectomy was ultimately performed in 4 of the 6 patients (67%) with pCR and in 22 of the 35 patients (63%) with less than a pCR. Thus, the choice for breast conservation did not correlate well with response to chemotherapy.

Time to disease progression

At a median follow-up of 48 months (range, 7–63), 36 of 41 patients (88%) remained free of disease (range, 19–63 months). Two patients had progressive disease while they were on study treatment and had T3 tumors on resection. Another three patients were found to have progressive disease at 10, 41, and 50 months from study day 1.

Of the nine patients with T1c disease, only one patient (who had positive nodes at resection) had a recurrence (at 41 months). Overall, the patients who had a recurrence had MRD (one patient), T1c (one patient), T2 (one patient), and T3 (the same two patients whose disease progressed while they were on treatment and continued to progress after surgery).

Disease-free and overall survival

Three patients were lost to followup, with point of last contact at 19, 34, and 59 months. Of the 41 evaluable patients, 5 patients developed progressive disease, with 2 of these patients progressing during the study treatment. Disease-free survival at 12, 24, and 36 months was 89%, 89%, and 78%, respectively. Overall survival at these same time points was 95%, 90%, and 76%. None of the patients with a pCR is known to have recurrent disease. Of the six patients achieving pCR, two were lost to follow-up after 34 and 59 months, and four continued diseasefree at 38, 39, 55, and 62 months.

Adverse events

Five patients were removed from the study secondary to toxicities. Grade 3 and 4 toxicity events are summarized in Table 5. Grade 3 toxicities were anemia (4), diarrhea (2), epigastric pain (1), fatigue (2), hand-foot syndrome (1), infection (1), leukopenia (9), pain (5), and peripheral sensory neuropathy (1). Grade 4 toxicities were depression (1) and leukopenia (4). Toxicities (all grades) occurring in ≥ 10% of the 49 treated patients were anemia (76%), leukopenia (70%), fatigue (67%), nausea (59%), alopecia (49%), thrombocytopenia (47%), diarrhea (47%), constipation (37%), pain (35%), vomiting (31%), epigastric pain (27%), nail changes (22%), epiphora (22%), hand-foot syndrome (20%), infection (18%), edema (16%), rash (16%), anorexia (16%), and depression (10%). In the intent-to-treat population, there were nine dose reductions among nine patients, and 19 dose delays among 15 patients.

Discussion

The combination of agents tested thus far in the neoadjuvant setting consistently produce pCR rates far less than 50% in unselected populations. This study was begun prior to the widespread use of personalized medicine. Most prior published trials had utilized anthracycline-based chemotherapy, with response rates generally ranging between 7% and 36%.6,9–26,28–31,41,42

The idea of thymidine phosphorylase upregulation by the combination of capecitabine and docetaxel upon which this study was largely based^34–36 has since been disputed.⁴⁷ The primary endpoint of this trial of a novel platinum- based regimen was a pCR rate of 15%. It is significant that 83% of the pCRs were in triple-negative tumors. A secondary endpoint of MRD was calculated, as this was in the original design of the study, but ultimately was not relevant to the primary endpoint.

Ultimately, pCR is the more relevant point of discussion for the modern era. The 15% pCR rate seen in this phase II study was within range of those achieved in numerous other phase II/III neoadjuvant chemotherapy trials with ≥ 25 patients, ≥ 3 cycles of chemotherapy, and pCR defined as absence of carcinoma in the breast and axilla. To date, no patient in our study with a pCR has been noted to have recurrent disease. However, a recently published French study found a 22% recurrence rate at 11 years in patients with triple-negative breast cancer achieving pCR, highlighting the importance of longer-term follow- up.⁴⁸.

The inclusion of patients with HER2-positive disease in neoadjuvant studies without HER2-targeted therapy was standard at the time that this study was conducted, but is no longer appropriate. If we were to exclude the eight HER2-positive patients from analysis, then there would be only 34 patients evaluable for response, with a pCR rate of 18%. Buzdar et al33 demonstrated a 65% pCR rate in women with HER2-positive disease treated with neoadjuvant chemotherapy plus trastuzumab. The improvement in pCR with the addition of trastuzumab is supported by other confirmatory trials. Authors of a single-arm trial of dose-dense epirubicin and cyclophosphamide followed by dosedense docetaxel and trastuzumab in a HER2-positive population reported a pCR rate of 57%.⁴⁹ The randomized NOAH study50 achieved a pCR rate of 23% in 115 patients treated with trastuzumab-based chemotherapy.

It is interesting to note that five of six patients (83%) achieving a pCR in our study had triple-negative tumors. Investigators at the University of Miami presented a retrospective review of locally advanced triple-negative breast cancer treated with docetaxel and a platinum salt, with 61% of patients also receiving AC. The authors reported a pCR rate of 34% overall and 40% for patients receiving AC.⁵¹ A pCR rate of 60% was noted in the triplenegative subset of patients in another study evaluating docetaxel, doxorubicin, and cyclophosphamide with or without vinorelbine/capecitabine (GeparTrio Study).⁵² Further, a pCR rate of 72% was achieved with singleagent cisplatin in a group of 25 women with BRCA1 mutations, suggesting, if confirmed by others, that this largely triple- negative population may be exquisitely sensitive to platinum salts.⁴³ In contrast, in a previous study of cisplatin in BRCA mutation carriers, Garber et al44 reported a pCR rate of 22%, suggesting that further trials are needed specifically in BRCA carriers and in triple-negative tumors to see whether these specific patient subsets preferentially derive benefit from platinum salts in the neoadjuvant setting.

The results of the current study are consistent with others indicating a low likelihood of pCR in patients with ERpositive tumors. In fact, none of our ER-positive patients had a pCR. Neoadjuvant endocrine therapy in postmenopausal women with ER- and/ or PR-positive disease is a reasonable treatment option for selected patients, but endpoints other than pCR have often been used.^53,54 It is therefore difficult to directly compare these two strategies. Currently, investigators are comparing the three aromatase inhibitors head to head in the neoadjuvant setting for postmenopausal women with hormone receptor–positive tumors.⁵⁵

The historic pCR ceiling appears to be rising, albeit slowly. Where targets such as HER2 overexpression and triple- negative biology are recognized, progress is being made. Patient eligibility criteria for neoadjuvant breast cancer studies at the time of this trial were quite broad, and it is now recognized that specific subsets of breast cancer respond differently to different classes of agents. Furthermore, our knowledge about breast cancer prognostic markers continues to expand. Had this study been designed in 2011, other data points such as Ki67 would have been collected. A recently published study on neoadjuvant triplenegative breast cancer found that only patients with baseline Ki67% expression > 10% achieved pCR.⁵⁶

Given the long-term implications of not achieving pCR, optimal treatment of patients in the adjuvant setting is critical. Although neoadjuvantly treated patients with ER-positive or HER2-positive disease go on to receive adjuvant agents (antihormonal therapy for ER-positive disease and trastuzumab for HER2-positive disease), patients with triple-negative disease lack long-term therapies of proven efficacy. Perhaps, as we edge closer to defining the optimal neoadjuvant agents for each subset of patients, this will be less of a concern. Many earlyphase neoadjuvant studies have been conducted, with promising reports, yet the results of larger, randomized trials continue to frustrate both investigators and clinicians. These deficits in care can only be answered by carefully planned randomized clinical trials.

Acknowledgment: Funding for this study was provided by sanofi-aventis, U.S.

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ABOUT THE AUTHORS

Aruna Mani, MD; Sandra X. Franco, MD; Grace Wang, MD: Neil Abramson, MD; Lee S. Schwartzberg, MD: James Jakub, MD; Elizabeth Tan-Chiu, MD: Alisha Stein, RNC, BSN, OCN; Alejandra T. Perez, MD; and Charles L Vogel, MD.

Affiliations: Dr. Mani is a breast medical oncologist at Memorial Cancer Institute, Pembroke Pines, FL. Dr. Franco is now Chief of Oncology at the Oncology Center, Clinica del Country, Bogota, Colombia. Dr. Wang is an oncologist at Advanced Medical Specialties, Miami, FL. Dr. Abramson is Clinical Professor of Medicine and Emeritus Director of Education and Research at Baptist Cancer Institute, University of Florida, Jacksonville, FL. Dr. Schwartzberg is Medical Director of The West Clinic, Memphis, TN. Dr. Jakub is now Assistant Professor of Surgery, Division of Gastroenterology and General Surgery, Mayo Clinic, Rochester, MN. Dr. Tan-Chiu is Medical Director of Florida Cancer Care, Davie, FL. Dr. Schwartz is Principal Investigator at Mount Sinai Medical Center, Miami Beach, FL. Ms. Frankel is Director of Oncology Clinical Research and Development at Memorial Cancer Institute, Hollywood, FL. Dr. Krill-Jackson is an oncologist at Mount Sinai Comprehensive Cancer Center, Miami, FL. Ms. Stein is now Oncology Clinical Coordinator at Genentech Inc., Fort Lauderdale, FL. Dr. Perez is Director of the Breast Cancer Center at Memorial Cancer Institute, Hollywood, FL. Dr. Vogel is Professor of Clinical Medicine and Director of the Women’s Center, Sylvester Comprehensive Cancer Center, Deerfield Beach, FL.

Conflicts of interest: Dr. Vogel has served as an advisor and is a member of the speakers’ bureaus of sanofi-aventis U.S. and Roche, as well as many other companies whose products were not part of the current study plan. The other authors have no pertinent conflicts of interest to disclose.