Breast Cancer

Daughters of known carriers of BRCA1 or BRCA2 gene mutations are understandably stressed, reported A. Farkas Patenaude, PhD, in a paper, “What do young adult daughters of BRCA mutation carriers know about hereditary risk and how much do they worry,” presented at The Era of Hope Conference in Orlando, Florida, August 2–6.

These 18-to-24-year-olds are at a 50% to 85% risk for breast and related ovarian cancers²—significantly more so than that of the general population (at 30 years, a 0.43% risk).¹ In addition, these types of breast and ovarian cancer often occur at an unusually young age.²

Although ACOG recommends that annual screening mammograms begin at age 40,³ daughters of women who are known gene-mutation carriers should begin screening mammography at age 25.⁴ The ability of these women to make informed health decisions depends on their becoming knowledgeable about the risks, the availability of genetic testing, and options for screening and risk-reducing prophylactic surgery.

Although the daughters expressed worry about hereditary breast cancer, they had limited understanding of screening and risk-reduction options. If they did have the information, Dr. Patenaude’s study found, the young women were often afraid to have the testing.^2,4

“Young, high-risk women have little knowledge about the probabilities and options for managing the cancers for which their risks are remarkably increased. Further, many report intense anxiety related to their potential cancer development,” said Dr. Patenaude of the Dana Farber Cancer Institute. “These data support the need and can provide the foundation for the development of targeted educational materials to reduce that anxiety and ultimately improve participation in effective screening and risk-reducing interventions that can improve survival and quality of life for these young women.”²

The Era of Hope Conference provides a forum for scientists and clinicians from a variety of disciplines to join breast cancer survivors and advocates to discuss the advances made by the Congressionally Directed Breast Cancer Research Programs BCRP awardees, and to identify innovative, high-impact approaches for future research. Recognized as one of the premiere breast cancer research meetings.⁵

We want to hear from you! Tell us what you think.

Daughters of known carriers of BRCA1 or BRCA2 gene mutations are understandably stressed, reported A. Farkas Patenaude, PhD, in a paper, “What do young adult daughters of BRCA mutation carriers know about hereditary risk and how much do they worry,” presented at The Era of Hope Conference in Orlando, Florida, August 2–6.

These 18-to-24-year-olds are at a 50% to 85% risk for breast and related ovarian cancers²—significantly more so than that of the general population (at 30 years, a 0.43% risk).¹ In addition, these types of breast and ovarian cancer often occur at an unusually young age.²

Although ACOG recommends that annual screening mammograms begin at age 40,³ daughters of women who are known gene-mutation carriers should begin screening mammography at age 25.⁴ The ability of these women to make informed health decisions depends on their becoming knowledgeable about the risks, the availability of genetic testing, and options for screening and risk-reducing prophylactic surgery.

Although the daughters expressed worry about hereditary breast cancer, they had limited understanding of screening and risk-reduction options. If they did have the information, Dr. Patenaude’s study found, the young women were often afraid to have the testing.^2,4

“Young, high-risk women have little knowledge about the probabilities and options for managing the cancers for which their risks are remarkably increased. Further, many report intense anxiety related to their potential cancer development,” said Dr. Patenaude of the Dana Farber Cancer Institute. “These data support the need and can provide the foundation for the development of targeted educational materials to reduce that anxiety and ultimately improve participation in effective screening and risk-reducing interventions that can improve survival and quality of life for these young women.”²

The Era of Hope Conference provides a forum for scientists and clinicians from a variety of disciplines to join breast cancer survivors and advocates to discuss the advances made by the Congressionally Directed Breast Cancer Research Programs BCRP awardees, and to identify innovative, high-impact approaches for future research. Recognized as one of the premiere breast cancer research meetings.⁵

We want to hear from you! Tell us what you think.

Daughters of known carriers of BRCA1 or BRCA2 gene mutations are understandably stressed, reported A. Farkas Patenaude, PhD, in a paper, “What do young adult daughters of BRCA mutation carriers know about hereditary risk and how much do they worry,” presented at The Era of Hope Conference in Orlando, Florida, August 2–6.

These 18-to-24-year-olds are at a 50% to 85% risk for breast and related ovarian cancers²—significantly more so than that of the general population (at 30 years, a 0.43% risk).¹ In addition, these types of breast and ovarian cancer often occur at an unusually young age.²

Although ACOG recommends that annual screening mammograms begin at age 40,³ daughters of women who are known gene-mutation carriers should begin screening mammography at age 25.⁴ The ability of these women to make informed health decisions depends on their becoming knowledgeable about the risks, the availability of genetic testing, and options for screening and risk-reducing prophylactic surgery.

Although the daughters expressed worry about hereditary breast cancer, they had limited understanding of screening and risk-reduction options. If they did have the information, Dr. Patenaude’s study found, the young women were often afraid to have the testing.^2,4

“Young, high-risk women have little knowledge about the probabilities and options for managing the cancers for which their risks are remarkably increased. Further, many report intense anxiety related to their potential cancer development,” said Dr. Patenaude of the Dana Farber Cancer Institute. “These data support the need and can provide the foundation for the development of targeted educational materials to reduce that anxiety and ultimately improve participation in effective screening and risk-reducing interventions that can improve survival and quality of life for these young women.”²

The Era of Hope Conference provides a forum for scientists and clinicians from a variety of disciplines to join breast cancer survivors and advocates to discuss the advances made by the Congressionally Directed Breast Cancer Research Programs BCRP awardees, and to identify innovative, high-impact approaches for future research. Recognized as one of the premiere breast cancer research meetings.⁵

We want to hear from you! Tell us what you think.

STOCKHOLM – Coupling everolimus with exemestane has produced such dramatic disease control in women with advanced hormone resistant, estrogen receptor-positive breast cancer that it is expected to transform the management of these patients.

A preplanned interim analysis of the phase III BOLERO-2 trial found that everolimus (Afinitor) increased the primary end point of progression-free survival, by local assessment, from a median of 2.8 months with exemestane (Aromasin) alone to 6.9 months. This corresponds to a 57% risk reduction (hazard ratio 0.43; P less than .0001).

Based on central assessment, everolimus produced a 64% reduction in the risk of progression or death (10.6 months vs. 4.1 months; HR = 0.36; P less than .0001). The trial was stopped early based on the benefit shown in the interim data.

"Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory estrogen receptor (ER)–positive patients," lead author Dr. José Baselga said at the European Multidisciplinary Cancer Congress.

"Our results could represent a paradigm shift in the management of patients with hormone receptor-positive breast cancer," he added

Invited discussant Dr. Fabrice André, from the Institut Gustave Roussy in Villejuif, France, called everolimus the most important advance in breast cancer since trastuzumab (Herceptin).

"The efficacy of everolimus in the BOLERO-2 trial is in the range of the most important advances in medical oncology," he said.

Novartis plans to submit the data for worldwide regulatory approval of everolimus as a treatment for ER-positive advanced breast cancer by year’s end, although the medical oncology community could embrace off-label use in this indication since both drugs are already available.

Everolimus is approved in the United States for progressive neuroendocrine tumors of pancreatic origin, subependymal giant cell astrocytoma associated with inoperable tuberous sclerosis and advanced renal cell carcinoma after sunitinib (Sutent) or sorafenib (Nexavar) treatment failure. Exemestane, an aromatase inhibitor, is approved as neoadjuvant therapy for hormone receptor–positive disease in postmenopausal women.

Everolimus was evaluated because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy, said Dr. Baselga, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston.

BOLERO-2 enrolled 724 women postmenopausal women with advanced ER-positive, HER2-negative breast cancer who were refractory to letrozole (Femara) or anastrozole (Arimidex). Prior treatment also included chemotherapy for metastatic disease in roughly 25%, tamoxifen in 48% and fulvestrant (Faslodex) in about 16%. Patients were randomized to everolimus 10 mg daily or placebo, with both arms receiving exemestane 25 mg daily.

The overall response rate was 9.5% for the everolimus arm and 0.4% for the placebo arm (P less than .0001).

The clinical benefit rate was 33.4% and 18%, respectively (P less than .0001), Dr. Baselga said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

A progression-free survival subgroup analysis showed consistent results across all subgroups.

At the time of the interim analysis, 83 deaths had occurred (10.6% in the everolimus arm and 13% in the placebo arm), but the data are immature, he said.

Adverse events were consistent with previous everolimus experience including stomatitis, fatigue, noninfectious pneumonitis, and hyperglycemia, Dr. Baselga said.

Dr. André said BOLERO-2 provides robust and clinically relevant data, but added that "preclinical data suggest we can do even better." He pointed out that inhibiting mTORC1 alone is not optimal because of the activation of alternative compensatory or parallel pathways, and he suggested moving to combination trials to inhibit alternative pathways and reverse resistance.

"BOLERO-2 is just part of the iceberg coming," Dr. Jean-Charles Soria, cochair of the Congress scientific program and a cancer specialist at Institut Gustave Roussy in Villejuif, France, said in an interview. "The whole question now is about building a triplet combination that is not too toxic and that is feasible."

He referenced the ongoing phase III BOLERO-1 and BOLERO-3 trials assessing everolimus in combination with paclitaxel and trastuzumab in HER2-positive metastatic breast cancer and the triple combination of everolimus, vinorelbine, and trastuzumab in HER2-positive, locally advanced, taxane-pretreated disease resistant to trastuzumab (Herceptin).

"I’m pretty convinced from what I’ve seen in phase I and II, that the phase IIIs in combination with Herceptin might also come out as positive," he said. "So, the way we think about breast cancer is probably going to change with mTOR inhibitors."

Dr. Baselga reports consulting for several pharmaceutical companies including the study sponsor, Novartis. Dr. André has previously reported no conflicts. Dr. Soria has previously reported consulting for Boehringer Ingelheim, Roche, AstraZeneca Pharmaceuticals, and Pfizer.

STOCKHOLM – Coupling everolimus with exemestane has produced such dramatic disease control in women with advanced hormone resistant, estrogen receptor-positive breast cancer that it is expected to transform the management of these patients.

A preplanned interim analysis of the phase III BOLERO-2 trial found that everolimus (Afinitor) increased the primary end point of progression-free survival, by local assessment, from a median of 2.8 months with exemestane (Aromasin) alone to 6.9 months. This corresponds to a 57% risk reduction (hazard ratio 0.43; P less than .0001).

Based on central assessment, everolimus produced a 64% reduction in the risk of progression or death (10.6 months vs. 4.1 months; HR = 0.36; P less than .0001). The trial was stopped early based on the benefit shown in the interim data.

"Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory estrogen receptor (ER)–positive patients," lead author Dr. José Baselga said at the European Multidisciplinary Cancer Congress.

"Our results could represent a paradigm shift in the management of patients with hormone receptor-positive breast cancer," he added

Invited discussant Dr. Fabrice André, from the Institut Gustave Roussy in Villejuif, France, called everolimus the most important advance in breast cancer since trastuzumab (Herceptin).

"The efficacy of everolimus in the BOLERO-2 trial is in the range of the most important advances in medical oncology," he said.

Novartis plans to submit the data for worldwide regulatory approval of everolimus as a treatment for ER-positive advanced breast cancer by year’s end, although the medical oncology community could embrace off-label use in this indication since both drugs are already available.

Everolimus is approved in the United States for progressive neuroendocrine tumors of pancreatic origin, subependymal giant cell astrocytoma associated with inoperable tuberous sclerosis and advanced renal cell carcinoma after sunitinib (Sutent) or sorafenib (Nexavar) treatment failure. Exemestane, an aromatase inhibitor, is approved as neoadjuvant therapy for hormone receptor–positive disease in postmenopausal women.

Everolimus was evaluated because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy, said Dr. Baselga, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston.

BOLERO-2 enrolled 724 women postmenopausal women with advanced ER-positive, HER2-negative breast cancer who were refractory to letrozole (Femara) or anastrozole (Arimidex). Prior treatment also included chemotherapy for metastatic disease in roughly 25%, tamoxifen in 48% and fulvestrant (Faslodex) in about 16%. Patients were randomized to everolimus 10 mg daily or placebo, with both arms receiving exemestane 25 mg daily.

The overall response rate was 9.5% for the everolimus arm and 0.4% for the placebo arm (P less than .0001).

The clinical benefit rate was 33.4% and 18%, respectively (P less than .0001), Dr. Baselga said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

A progression-free survival subgroup analysis showed consistent results across all subgroups.

At the time of the interim analysis, 83 deaths had occurred (10.6% in the everolimus arm and 13% in the placebo arm), but the data are immature, he said.

Adverse events were consistent with previous everolimus experience including stomatitis, fatigue, noninfectious pneumonitis, and hyperglycemia, Dr. Baselga said.

Dr. André said BOLERO-2 provides robust and clinically relevant data, but added that "preclinical data suggest we can do even better." He pointed out that inhibiting mTORC1 alone is not optimal because of the activation of alternative compensatory or parallel pathways, and he suggested moving to combination trials to inhibit alternative pathways and reverse resistance.

"BOLERO-2 is just part of the iceberg coming," Dr. Jean-Charles Soria, cochair of the Congress scientific program and a cancer specialist at Institut Gustave Roussy in Villejuif, France, said in an interview. "The whole question now is about building a triplet combination that is not too toxic and that is feasible."

He referenced the ongoing phase III BOLERO-1 and BOLERO-3 trials assessing everolimus in combination with paclitaxel and trastuzumab in HER2-positive metastatic breast cancer and the triple combination of everolimus, vinorelbine, and trastuzumab in HER2-positive, locally advanced, taxane-pretreated disease resistant to trastuzumab (Herceptin).

"I’m pretty convinced from what I’ve seen in phase I and II, that the phase IIIs in combination with Herceptin might also come out as positive," he said. "So, the way we think about breast cancer is probably going to change with mTOR inhibitors."

Dr. Baselga reports consulting for several pharmaceutical companies including the study sponsor, Novartis. Dr. André has previously reported no conflicts. Dr. Soria has previously reported consulting for Boehringer Ingelheim, Roche, AstraZeneca Pharmaceuticals, and Pfizer.

STOCKHOLM – Coupling everolimus with exemestane has produced such dramatic disease control in women with advanced hormone resistant, estrogen receptor-positive breast cancer that it is expected to transform the management of these patients.

A preplanned interim analysis of the phase III BOLERO-2 trial found that everolimus (Afinitor) increased the primary end point of progression-free survival, by local assessment, from a median of 2.8 months with exemestane (Aromasin) alone to 6.9 months. This corresponds to a 57% risk reduction (hazard ratio 0.43; P less than .0001).

Based on central assessment, everolimus produced a 64% reduction in the risk of progression or death (10.6 months vs. 4.1 months; HR = 0.36; P less than .0001). The trial was stopped early based on the benefit shown in the interim data.

"Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory estrogen receptor (ER)–positive patients," lead author Dr. José Baselga said at the European Multidisciplinary Cancer Congress.

"Our results could represent a paradigm shift in the management of patients with hormone receptor-positive breast cancer," he added

Invited discussant Dr. Fabrice André, from the Institut Gustave Roussy in Villejuif, France, called everolimus the most important advance in breast cancer since trastuzumab (Herceptin).

"The efficacy of everolimus in the BOLERO-2 trial is in the range of the most important advances in medical oncology," he said.

Novartis plans to submit the data for worldwide regulatory approval of everolimus as a treatment for ER-positive advanced breast cancer by year’s end, although the medical oncology community could embrace off-label use in this indication since both drugs are already available.

Everolimus is approved in the United States for progressive neuroendocrine tumors of pancreatic origin, subependymal giant cell astrocytoma associated with inoperable tuberous sclerosis and advanced renal cell carcinoma after sunitinib (Sutent) or sorafenib (Nexavar) treatment failure. Exemestane, an aromatase inhibitor, is approved as neoadjuvant therapy for hormone receptor–positive disease in postmenopausal women.

Everolimus was evaluated because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy, said Dr. Baselga, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston.

BOLERO-2 enrolled 724 women postmenopausal women with advanced ER-positive, HER2-negative breast cancer who were refractory to letrozole (Femara) or anastrozole (Arimidex). Prior treatment also included chemotherapy for metastatic disease in roughly 25%, tamoxifen in 48% and fulvestrant (Faslodex) in about 16%. Patients were randomized to everolimus 10 mg daily or placebo, with both arms receiving exemestane 25 mg daily.

The overall response rate was 9.5% for the everolimus arm and 0.4% for the placebo arm (P less than .0001).

The clinical benefit rate was 33.4% and 18%, respectively (P less than .0001), Dr. Baselga said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

A progression-free survival subgroup analysis showed consistent results across all subgroups.

At the time of the interim analysis, 83 deaths had occurred (10.6% in the everolimus arm and 13% in the placebo arm), but the data are immature, he said.

Adverse events were consistent with previous everolimus experience including stomatitis, fatigue, noninfectious pneumonitis, and hyperglycemia, Dr. Baselga said.

Dr. André said BOLERO-2 provides robust and clinically relevant data, but added that "preclinical data suggest we can do even better." He pointed out that inhibiting mTORC1 alone is not optimal because of the activation of alternative compensatory or parallel pathways, and he suggested moving to combination trials to inhibit alternative pathways and reverse resistance.

"BOLERO-2 is just part of the iceberg coming," Dr. Jean-Charles Soria, cochair of the Congress scientific program and a cancer specialist at Institut Gustave Roussy in Villejuif, France, said in an interview. "The whole question now is about building a triplet combination that is not too toxic and that is feasible."

He referenced the ongoing phase III BOLERO-1 and BOLERO-3 trials assessing everolimus in combination with paclitaxel and trastuzumab in HER2-positive metastatic breast cancer and the triple combination of everolimus, vinorelbine, and trastuzumab in HER2-positive, locally advanced, taxane-pretreated disease resistant to trastuzumab (Herceptin).

"I’m pretty convinced from what I’ve seen in phase I and II, that the phase IIIs in combination with Herceptin might also come out as positive," he said. "So, the way we think about breast cancer is probably going to change with mTOR inhibitors."

Dr. Baselga reports consulting for several pharmaceutical companies including the study sponsor, Novartis. Dr. André has previously reported no conflicts. Dr. Soria has previously reported consulting for Boehringer Ingelheim, Roche, AstraZeneca Pharmaceuticals, and Pfizer.

STOCKHOLM – Novel antibody-guided trastuzumab emtansine therapy not only improved progression-free survival by 5 months in women with HER2-positive metastatic breast cancer, but it also had an impressively tame side effect profile, according to Dr. Sara Hurvitz.*

Treatment with trastuzumab emtansine (T-DM1) resulted in a median progression-free survival of 14 months vs. 9 months with trastuzumab (Herceptin) and docetaxel (Taxotere) in a phase II open-label study with 137 women. T-DM1 reduced the relative risk of disease progression by 41% with a hazard ratio of 0.59 (P = .0353), she reported at the European Multidisciplinary Cancer Congress.

"These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index," said Dr. Hurvitz of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

An antibody drug conjugate, T-DM1 retains the targeting properties of monoclonal antibody trastuzumab in HER2-positive breast cancer while transporting a potent cytotoxic agent (DM1) that inhibits tubulin polymerization and microtubule dynamics into cancer cells.

Invited discussant Dr. Martine J. Piccart-Gebhart talked excitedly about the results, but also urged caution.

"You have to remember that this is an open-label study. I am saying that because I believe that T-DM1 is the magic drug for medical oncologists – the drug that we have been waiting for, for so many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell," said Dr. Piccart-Gebhart of the Jules Bordet Institute at the Université Libre de Bruxelles in Belgium.

However, "in an open-label study, you have to worry a little bit because we want to give this T-DM1 drug to our patients," so it may be tempting to interpret the results too favorably, she told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The researchers recruited 137 women with HER2-positive, recurrent locally advanced breast cancer or metastatic breast cancer. The patients were randomized to receive either trastuzumab and docetaxel or T-DM1 alone.

Trastuzumab was given as an 8-mg/kg loading dose and then as 6 mg/kg every 3 weeks. Docetaxel was given in a dose of 75 mg/m² or 100 mg/m² for 3 weeks. T-DM1 was given intravenously at a dose of 3.6 mg/kg every 3 weeks. In all, 70 women received trastuzumab and docetaxel and 67 received T-DM1.

The primary end points were progression-free survival by investigator assessment and safety. Data analyses were based on clinical data as of Nov. 15, 2010, and prior to any T-DM1 crossover. Overall survival data are expected in 2012. Quality of life data will be presented as a poster at the San Antonio Breast Cancer Symposium this December.

Most of the patients in each group (85%) had centrally confirmed HER2-positive breast cancer. "Relatively few patients had received neoadjuvant or adjuvant trastuzumab. This was likely owing to the international nature of the study and the lack of availability at some centers for trastuzumab in the adjuvant setting," said Dr. Hurvitz.

Dr. Piccart-Gebhart observed that one-third of patients in this study were stage IV at diagnosis and only 20%-25% were exposed to adjuvant trastuzumab. These numbers are likely to change with time, as more patients are exposed to trastuzumab.

At the time of data cutoff, 21% of patients on trastuzumab and docetaxel were still on the treatment, compared with 43% of those in the T-DM1 arm. "The majority of patients came off of treatment for disease progression," she said.

The objective response rate was similar – 58% for the T-DM1 arm vs. 64% for the control arm. Patients in the trastuzumab/docetaxel arm had a median duration of response of 9.5 months. The duration of response in the T-DM1 arm has not yet been reached.

"In terms of safety and tolerability, it is very clear that the safety profile of T-DM1 is far better than the one for docetaxel and trastuzumab," said Dr. Piccart-Gebhart. Patients who received T-DM1 had many fewer adverse events of grade 3 or greater – 32 vs. 59.

Among hematologic adverse events, neutropenia of any grade was more common in the control arm – 63.6% compared with 17.4% – but any grade thrombocytopenia was more common in the T-DM1 arm (30% vs. 6%).

Among nonhematologic events, any grade alopecia was less than 4% for the T-DM1 arm compared with 67% for the control arm. Likewise, the incidence of any grade diarrhea was much lower in the T-DM1 arm – 16% for those on T-DM1 compared with 46% for those on the trastuzumab/docetaxel. Peripheral edema of any grade was also much lower in the T-DM1 arm (10% vs. 44%).

"Cardiac safety is important to look at whenever you’re talking about HER-2 targeting agent," said Dr. Hurvitz.

Adjuvant anthracyclines were given to 45% and 49% of patients in the T-DM1 arm and control arm. On local assessment two patients in the control arm, compared with none in the T-DM1 arm, had a postbaseline left ventricular ejection fraction of 40% or less.

"There were no clinically significant cardiac events reported," she noted.

Dr. Hurvitz and Dr. Piccart-Gebhart agreed that large phase III trials are needed to confirm these findings. The drug is being evaluated in three large phase III clinical trials for HER2-postive metastatic breast cancer.

The study was funded by F. Hoffmann-La Roche. Dr. Hurvitz reported that she has no relevant financial disclosures. Dr. Piccart-Gebhart has previously reported that she is a consultant for and has received research support from several pharmaceutical companies, including Roche.

* Clarification, 9/29/2011: The original version of this article stated that trastuzumab emtansine improved disease-free progression. However, it is more accurate to say that it improved progression-free survival. This version has been updated.

STOCKHOLM – Novel antibody-guided trastuzumab emtansine therapy not only improved progression-free survival by 5 months in women with HER2-positive metastatic breast cancer, but it also had an impressively tame side effect profile, according to Dr. Sara Hurvitz.*

Treatment with trastuzumab emtansine (T-DM1) resulted in a median progression-free survival of 14 months vs. 9 months with trastuzumab (Herceptin) and docetaxel (Taxotere) in a phase II open-label study with 137 women. T-DM1 reduced the relative risk of disease progression by 41% with a hazard ratio of 0.59 (P = .0353), she reported at the European Multidisciplinary Cancer Congress.

"These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index," said Dr. Hurvitz of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

An antibody drug conjugate, T-DM1 retains the targeting properties of monoclonal antibody trastuzumab in HER2-positive breast cancer while transporting a potent cytotoxic agent (DM1) that inhibits tubulin polymerization and microtubule dynamics into cancer cells.

Invited discussant Dr. Martine J. Piccart-Gebhart talked excitedly about the results, but also urged caution.

"You have to remember that this is an open-label study. I am saying that because I believe that T-DM1 is the magic drug for medical oncologists – the drug that we have been waiting for, for so many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell," said Dr. Piccart-Gebhart of the Jules Bordet Institute at the Université Libre de Bruxelles in Belgium.

However, "in an open-label study, you have to worry a little bit because we want to give this T-DM1 drug to our patients," so it may be tempting to interpret the results too favorably, she told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The researchers recruited 137 women with HER2-positive, recurrent locally advanced breast cancer or metastatic breast cancer. The patients were randomized to receive either trastuzumab and docetaxel or T-DM1 alone.

Trastuzumab was given as an 8-mg/kg loading dose and then as 6 mg/kg every 3 weeks. Docetaxel was given in a dose of 75 mg/m² or 100 mg/m² for 3 weeks. T-DM1 was given intravenously at a dose of 3.6 mg/kg every 3 weeks. In all, 70 women received trastuzumab and docetaxel and 67 received T-DM1.

The primary end points were progression-free survival by investigator assessment and safety. Data analyses were based on clinical data as of Nov. 15, 2010, and prior to any T-DM1 crossover. Overall survival data are expected in 2012. Quality of life data will be presented as a poster at the San Antonio Breast Cancer Symposium this December.

Most of the patients in each group (85%) had centrally confirmed HER2-positive breast cancer. "Relatively few patients had received neoadjuvant or adjuvant trastuzumab. This was likely owing to the international nature of the study and the lack of availability at some centers for trastuzumab in the adjuvant setting," said Dr. Hurvitz.

Dr. Piccart-Gebhart observed that one-third of patients in this study were stage IV at diagnosis and only 20%-25% were exposed to adjuvant trastuzumab. These numbers are likely to change with time, as more patients are exposed to trastuzumab.

At the time of data cutoff, 21% of patients on trastuzumab and docetaxel were still on the treatment, compared with 43% of those in the T-DM1 arm. "The majority of patients came off of treatment for disease progression," she said.

The objective response rate was similar – 58% for the T-DM1 arm vs. 64% for the control arm. Patients in the trastuzumab/docetaxel arm had a median duration of response of 9.5 months. The duration of response in the T-DM1 arm has not yet been reached.

"In terms of safety and tolerability, it is very clear that the safety profile of T-DM1 is far better than the one for docetaxel and trastuzumab," said Dr. Piccart-Gebhart. Patients who received T-DM1 had many fewer adverse events of grade 3 or greater – 32 vs. 59.

Among hematologic adverse events, neutropenia of any grade was more common in the control arm – 63.6% compared with 17.4% – but any grade thrombocytopenia was more common in the T-DM1 arm (30% vs. 6%).

Among nonhematologic events, any grade alopecia was less than 4% for the T-DM1 arm compared with 67% for the control arm. Likewise, the incidence of any grade diarrhea was much lower in the T-DM1 arm – 16% for those on T-DM1 compared with 46% for those on the trastuzumab/docetaxel. Peripheral edema of any grade was also much lower in the T-DM1 arm (10% vs. 44%).

"Cardiac safety is important to look at whenever you’re talking about HER-2 targeting agent," said Dr. Hurvitz.

Adjuvant anthracyclines were given to 45% and 49% of patients in the T-DM1 arm and control arm. On local assessment two patients in the control arm, compared with none in the T-DM1 arm, had a postbaseline left ventricular ejection fraction of 40% or less.

"There were no clinically significant cardiac events reported," she noted.

Dr. Hurvitz and Dr. Piccart-Gebhart agreed that large phase III trials are needed to confirm these findings. The drug is being evaluated in three large phase III clinical trials for HER2-postive metastatic breast cancer.

The study was funded by F. Hoffmann-La Roche. Dr. Hurvitz reported that she has no relevant financial disclosures. Dr. Piccart-Gebhart has previously reported that she is a consultant for and has received research support from several pharmaceutical companies, including Roche.

* Clarification, 9/29/2011: The original version of this article stated that trastuzumab emtansine improved disease-free progression. However, it is more accurate to say that it improved progression-free survival. This version has been updated.

STOCKHOLM – Novel antibody-guided trastuzumab emtansine therapy not only improved progression-free survival by 5 months in women with HER2-positive metastatic breast cancer, but it also had an impressively tame side effect profile, according to Dr. Sara Hurvitz.*

Treatment with trastuzumab emtansine (T-DM1) resulted in a median progression-free survival of 14 months vs. 9 months with trastuzumab (Herceptin) and docetaxel (Taxotere) in a phase II open-label study with 137 women. T-DM1 reduced the relative risk of disease progression by 41% with a hazard ratio of 0.59 (P = .0353), she reported at the European Multidisciplinary Cancer Congress.

"These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index," said Dr. Hurvitz of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

An antibody drug conjugate, T-DM1 retains the targeting properties of monoclonal antibody trastuzumab in HER2-positive breast cancer while transporting a potent cytotoxic agent (DM1) that inhibits tubulin polymerization and microtubule dynamics into cancer cells.

Invited discussant Dr. Martine J. Piccart-Gebhart talked excitedly about the results, but also urged caution.

"You have to remember that this is an open-label study. I am saying that because I believe that T-DM1 is the magic drug for medical oncologists – the drug that we have been waiting for, for so many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell," said Dr. Piccart-Gebhart of the Jules Bordet Institute at the Université Libre de Bruxelles in Belgium.

However, "in an open-label study, you have to worry a little bit because we want to give this T-DM1 drug to our patients," so it may be tempting to interpret the results too favorably, she told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The researchers recruited 137 women with HER2-positive, recurrent locally advanced breast cancer or metastatic breast cancer. The patients were randomized to receive either trastuzumab and docetaxel or T-DM1 alone.

Trastuzumab was given as an 8-mg/kg loading dose and then as 6 mg/kg every 3 weeks. Docetaxel was given in a dose of 75 mg/m² or 100 mg/m² for 3 weeks. T-DM1 was given intravenously at a dose of 3.6 mg/kg every 3 weeks. In all, 70 women received trastuzumab and docetaxel and 67 received T-DM1.

The primary end points were progression-free survival by investigator assessment and safety. Data analyses were based on clinical data as of Nov. 15, 2010, and prior to any T-DM1 crossover. Overall survival data are expected in 2012. Quality of life data will be presented as a poster at the San Antonio Breast Cancer Symposium this December.

Most of the patients in each group (85%) had centrally confirmed HER2-positive breast cancer. "Relatively few patients had received neoadjuvant or adjuvant trastuzumab. This was likely owing to the international nature of the study and the lack of availability at some centers for trastuzumab in the adjuvant setting," said Dr. Hurvitz.

Dr. Piccart-Gebhart observed that one-third of patients in this study were stage IV at diagnosis and only 20%-25% were exposed to adjuvant trastuzumab. These numbers are likely to change with time, as more patients are exposed to trastuzumab.

At the time of data cutoff, 21% of patients on trastuzumab and docetaxel were still on the treatment, compared with 43% of those in the T-DM1 arm. "The majority of patients came off of treatment for disease progression," she said.

The objective response rate was similar – 58% for the T-DM1 arm vs. 64% for the control arm. Patients in the trastuzumab/docetaxel arm had a median duration of response of 9.5 months. The duration of response in the T-DM1 arm has not yet been reached.

"In terms of safety and tolerability, it is very clear that the safety profile of T-DM1 is far better than the one for docetaxel and trastuzumab," said Dr. Piccart-Gebhart. Patients who received T-DM1 had many fewer adverse events of grade 3 or greater – 32 vs. 59.

Among hematologic adverse events, neutropenia of any grade was more common in the control arm – 63.6% compared with 17.4% – but any grade thrombocytopenia was more common in the T-DM1 arm (30% vs. 6%).

Among nonhematologic events, any grade alopecia was less than 4% for the T-DM1 arm compared with 67% for the control arm. Likewise, the incidence of any grade diarrhea was much lower in the T-DM1 arm – 16% for those on T-DM1 compared with 46% for those on the trastuzumab/docetaxel. Peripheral edema of any grade was also much lower in the T-DM1 arm (10% vs. 44%).

"Cardiac safety is important to look at whenever you’re talking about HER-2 targeting agent," said Dr. Hurvitz.

Adjuvant anthracyclines were given to 45% and 49% of patients in the T-DM1 arm and control arm. On local assessment two patients in the control arm, compared with none in the T-DM1 arm, had a postbaseline left ventricular ejection fraction of 40% or less.

"There were no clinically significant cardiac events reported," she noted.

Dr. Hurvitz and Dr. Piccart-Gebhart agreed that large phase III trials are needed to confirm these findings. The drug is being evaluated in three large phase III clinical trials for HER2-postive metastatic breast cancer.

The study was funded by F. Hoffmann-La Roche. Dr. Hurvitz reported that she has no relevant financial disclosures. Dr. Piccart-Gebhart has previously reported that she is a consultant for and has received research support from several pharmaceutical companies, including Roche.

* Clarification, 9/29/2011: The original version of this article stated that trastuzumab emtansine improved disease-free progression. However, it is more accurate to say that it improved progression-free survival. This version has been updated.

SAN FRANCISCO – Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987-2005.

Results showed that with a median follow-up of 7-8 years, the rate of freedom from locoregional recurrence was high (90% or greater at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

"For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy," Dr. Mittendorf, a surgical oncologist, commented, adding, "It is important to obtain a negative margin at the time of surgery."

"It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy," she said.

However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of "oversimplification of [a] complex issue ... especially in the era of personalized therapy."

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

"The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important," commented Dr. Fowble. "Initial stage, molecular subtype, and response to therapy will impact on outcome."

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor–negative disease, and to have multifocal disease. Median durations of follow-up were 7.2 and 7.9 years.

In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%) (P less than .001).

"Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy," Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P less than .001). For example, the 10-year rate was 90% with the former and 94% with the latter.

"Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors," she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence.

Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (hazard ratio, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor–negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor–positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence–free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

SAN FRANCISCO – Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987-2005.

Results showed that with a median follow-up of 7-8 years, the rate of freedom from locoregional recurrence was high (90% or greater at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

"For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy," Dr. Mittendorf, a surgical oncologist, commented, adding, "It is important to obtain a negative margin at the time of surgery."

"It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy," she said.

However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of "oversimplification of [a] complex issue ... especially in the era of personalized therapy."

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

"The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important," commented Dr. Fowble. "Initial stage, molecular subtype, and response to therapy will impact on outcome."

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor–negative disease, and to have multifocal disease. Median durations of follow-up were 7.2 and 7.9 years.

In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%) (P less than .001).

"Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy," Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P less than .001). For example, the 10-year rate was 90% with the former and 94% with the latter.

"Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors," she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence.

Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (hazard ratio, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor–negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor–positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence–free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

SAN FRANCISCO – Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987-2005.

Results showed that with a median follow-up of 7-8 years, the rate of freedom from locoregional recurrence was high (90% or greater at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

"For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy," Dr. Mittendorf, a surgical oncologist, commented, adding, "It is important to obtain a negative margin at the time of surgery."

"It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy," she said.

However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of "oversimplification of [a] complex issue ... especially in the era of personalized therapy."

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

"The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important," commented Dr. Fowble. "Initial stage, molecular subtype, and response to therapy will impact on outcome."

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor–negative disease, and to have multifocal disease. Median durations of follow-up were 7.2 and 7.9 years.

In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%) (P less than .001).

"Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy," Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P less than .001). For example, the 10-year rate was 90% with the former and 94% with the latter.

"Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors," she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence.

Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (hazard ratio, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor–negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor–positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence–free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

SAN FRANCISCO – A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor–positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor–positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole (Femara) or placebo.

Study results, reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled.

The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor–positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

"If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component," he explained.

"If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy," he continued. "For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials."

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase–polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

"We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually," he noted. "In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence."

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = .014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = .019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported. In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = .037).

"Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = .02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I," he said. "These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy."

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

SAN FRANCISCO – A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor–positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor–positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole (Femara) or placebo.

Study results, reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled.

The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor–positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

"If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component," he explained.

"If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy," he continued. "For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials."

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase–polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

"We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually," he noted. "In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence."

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = .014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = .019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported. In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = .037).

"Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = .02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I," he said. "These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy."

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

SAN FRANCISCO – A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor–positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor–positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole (Femara) or placebo.

Study results, reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled.

The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor–positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

"If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component," he explained.

"If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy," he continued. "For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials."

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase–polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

"We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually," he noted. "In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence."

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = .014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = .019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported. In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = .037).

"Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = .02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I," he said. "These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy."

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

WASHINGTON – Magnetic resonance imaging screening for breast cancer is feasible and cost effective for high-risk underserved women, according to a study conducted by Duke University Medical Center researchers.

The investigators, led by Dr. Anne C. Ford, assistant professor of obstetrics and gynecology at the center, wanted to determine whether targeting MRI screening, which has the potential to increase the number of benign biopsies, would increase costs.

The researchers included 299 women who participate in a high-risk clinic at Duke, who were given a digital mammogram followed by an MRI, as well as 299 average-risk women recruited through an outreach program to serve as controls. High risk was defined as a greater than 20% lifetime risk of breast cancer, the investigators reported at a conference sponsored by the American Association for Cancer Research.

The women were racially diverse. The mammography group was 40% African American, 25% white, 25% Hispanic, and 10% other. The MRI group was 62% white, 33% African American, 3% Hispanic, and 2% other.

Women found to have an abnormal mammogram were evaluated by ultrasound, ultrasound-guided biopsy, and/or stereotactic biopsy. Women with an abnormal breast MRI were evaluated with ultrasound, ultrasound-guided biopsy, and/or MRI-guided biopsy. Patient navigators accompanied all women to all appointments, including follow-up care.

Overall, there were seven benign biopsies conducted in the mammography group. One cancer was found, for a detection rate of 12%. Thirty-one benign biopsies were done in the combination group; seven cancers were discovered, for a detection rate of 18%.

Of the cancers that were staged, the MRI had detected one stage 0 tumor, four that were stage I, and one each that were stage II and III. The mammogram detected one tumor that was stage II. So the MRI detected some cancers in an early stage.

For screening alone, the cost per diagnosis was $37,375 for mammography, compared with $27,722 for MRI.

These figures, however, were calculated using a lower MRI rate than many institutions might pay. For the study, the cost of the MRI was negotiated to a reduced rate of $649. Dr. Ford said in an interview that the calculation might change if the MRI rate were more or less.

There also was a very good compliance rate with follow-up studies. Most likely, that is because those services were offered free of charge to participants and because they were constantly interacting with patient navigators, said Dr. Ford.

Six of seven women in the mammography group who were referred for follow-up complied. Twenty-eight of the 31 MRI screening patients returned for follow-up.

The study was supported by the Susan G. Komen for the Cure, the Avon Foundation Breast Care Fund, the Kate B. Reynolds Charitable Trust, and the Breast Cancer Relief Foundation.

WASHINGTON – Magnetic resonance imaging screening for breast cancer is feasible and cost effective for high-risk underserved women, according to a study conducted by Duke University Medical Center researchers.

The investigators, led by Dr. Anne C. Ford, assistant professor of obstetrics and gynecology at the center, wanted to determine whether targeting MRI screening, which has the potential to increase the number of benign biopsies, would increase costs.

The researchers included 299 women who participate in a high-risk clinic at Duke, who were given a digital mammogram followed by an MRI, as well as 299 average-risk women recruited through an outreach program to serve as controls. High risk was defined as a greater than 20% lifetime risk of breast cancer, the investigators reported at a conference sponsored by the American Association for Cancer Research.

The women were racially diverse. The mammography group was 40% African American, 25% white, 25% Hispanic, and 10% other. The MRI group was 62% white, 33% African American, 3% Hispanic, and 2% other.

Women found to have an abnormal mammogram were evaluated by ultrasound, ultrasound-guided biopsy, and/or stereotactic biopsy. Women with an abnormal breast MRI were evaluated with ultrasound, ultrasound-guided biopsy, and/or MRI-guided biopsy. Patient navigators accompanied all women to all appointments, including follow-up care.

Overall, there were seven benign biopsies conducted in the mammography group. One cancer was found, for a detection rate of 12%. Thirty-one benign biopsies were done in the combination group; seven cancers were discovered, for a detection rate of 18%.

Of the cancers that were staged, the MRI had detected one stage 0 tumor, four that were stage I, and one each that were stage II and III. The mammogram detected one tumor that was stage II. So the MRI detected some cancers in an early stage.

For screening alone, the cost per diagnosis was $37,375 for mammography, compared with $27,722 for MRI.

These figures, however, were calculated using a lower MRI rate than many institutions might pay. For the study, the cost of the MRI was negotiated to a reduced rate of $649. Dr. Ford said in an interview that the calculation might change if the MRI rate were more or less.

There also was a very good compliance rate with follow-up studies. Most likely, that is because those services were offered free of charge to participants and because they were constantly interacting with patient navigators, said Dr. Ford.

Six of seven women in the mammography group who were referred for follow-up complied. Twenty-eight of the 31 MRI screening patients returned for follow-up.

The study was supported by the Susan G. Komen for the Cure, the Avon Foundation Breast Care Fund, the Kate B. Reynolds Charitable Trust, and the Breast Cancer Relief Foundation.

WASHINGTON – Magnetic resonance imaging screening for breast cancer is feasible and cost effective for high-risk underserved women, according to a study conducted by Duke University Medical Center researchers.

The investigators, led by Dr. Anne C. Ford, assistant professor of obstetrics and gynecology at the center, wanted to determine whether targeting MRI screening, which has the potential to increase the number of benign biopsies, would increase costs.

The researchers included 299 women who participate in a high-risk clinic at Duke, who were given a digital mammogram followed by an MRI, as well as 299 average-risk women recruited through an outreach program to serve as controls. High risk was defined as a greater than 20% lifetime risk of breast cancer, the investigators reported at a conference sponsored by the American Association for Cancer Research.

The women were racially diverse. The mammography group was 40% African American, 25% white, 25% Hispanic, and 10% other. The MRI group was 62% white, 33% African American, 3% Hispanic, and 2% other.

Women found to have an abnormal mammogram were evaluated by ultrasound, ultrasound-guided biopsy, and/or stereotactic biopsy. Women with an abnormal breast MRI were evaluated with ultrasound, ultrasound-guided biopsy, and/or MRI-guided biopsy. Patient navigators accompanied all women to all appointments, including follow-up care.

Overall, there were seven benign biopsies conducted in the mammography group. One cancer was found, for a detection rate of 12%. Thirty-one benign biopsies were done in the combination group; seven cancers were discovered, for a detection rate of 18%.

Of the cancers that were staged, the MRI had detected one stage 0 tumor, four that were stage I, and one each that were stage II and III. The mammogram detected one tumor that was stage II. So the MRI detected some cancers in an early stage.

For screening alone, the cost per diagnosis was $37,375 for mammography, compared with $27,722 for MRI.

These figures, however, were calculated using a lower MRI rate than many institutions might pay. For the study, the cost of the MRI was negotiated to a reduced rate of $649. Dr. Ford said in an interview that the calculation might change if the MRI rate were more or less.

There also was a very good compliance rate with follow-up studies. Most likely, that is because those services were offered free of charge to participants and because they were constantly interacting with patient navigators, said Dr. Ford.

Six of seven women in the mammography group who were referred for follow-up complied. Twenty-eight of the 31 MRI screening patients returned for follow-up.

The study was supported by the Susan G. Komen for the Cure, the Avon Foundation Breast Care Fund, the Kate B. Reynolds Charitable Trust, and the Breast Cancer Relief Foundation.

WASHINGTON – Higher levels of stress may partially account for aggressive tumor growth in African American and Hispanic women with breast cancer, according to Garth H. Rauscher, Ph.D., of the University of Illinois at Chicago.

This is one of the first studies to look closely at the potential role of psychosocial stress on tumor progression in breast cancer, said Dr. Rauscher, an associate professor of epidemiology at the university’s School of Public Health. However, he acknowledged that the study is "flawed" because it is cross-sectional and has other limitations. "This is definitely an exploratory study," Dr. Rauscher said at the American Association for Cancer Research Science of Cancer Health Disparities meeting.

It was already known, especially in Chicago, that there was a wide disparity in mortality rates between black women and white women, said Dr. Rauscher. The data are not as well defined for Hispanic women, he said. Tumor aggressiveness likely contributes to higher mortality rates in the minorities. Both African Americans and Hispanics generally have higher-grade tumors and hormone receptor–negative tumors, said Dr. Rauscher. The researchers wanted to investigate why these women have the more aggressive tumor types.

They chose to examine psychosocial factors.

Dr. Rauscher and his colleagues examined associations between patient-reported stress and aggressive breast cancer in a cross-sectional study of 397 non-Hispanic whites, 411 non-Hispanic blacks, and 181 Hispanics. Data were collected through patient interviews and medical record extraction. Stress was assessed using the four-item Cohen Perceived Stress Subscale, the UCLA Loneliness Scale, and the Cockburn psychological consequences scale. The three scales were combined into a single, standardized stress score.

Patients were interviewed just after their diagnosis of breast cancer. Dr. Rauscher explained that the researchers assumed that if patients were experiencing high stress post diagnosis, they were likely to have been under stress before diagnosis as well. But he acknowledged that this assumption is a major limitation of the study.

Of 989 patients, the researchers were able to get tumor grades for 772: 149 had low-grade tumors; 308 were intermediate, and 315 were high-grade tumors. A total of 21% (66 of 315) of patients with high-grade tumors reported elevated stress, 19% (58 of 308) of patients with intermediate-grade tumors reported elevated stress, and 11% (16 of 149) of patients with low-grade tumors reported elevated stress.

The differences were statistically significant, until Dr. Rauscher and his colleagues adjusted for age, treatment, income, and other factors.

A total of 28% of women with hormone receptor–negative tumors reported stress, compared with 14% of those with receptor-positive growths. Patients with hormone receptor–negative disease reported one-third of a standard deviation higher than did patients with receptor-positive disease (P = .0003). The difference held up after adjustment, Dr. Rauscher said.

Overall, psychosocial stress scores were higher for black and Hispanic women than for whites.

There’s still no way to know, however, what accounts for those differences, said Dr. Rauscher. "If you have a more aggressive diagnosis, does that make you worry more? You could certainly put that out there as a possibility," he said. Patients with more aggressive disease might also undergo more aggressive treatment, which could also lead to greater stress, he said. "There could be causal arrows going in both directions here, but we can’t tease that out." Even so, he said, "our results are consistent with a role for stress in the etiology of aggressive breast cancer."

Dr. Rauscher suggested that other researchers could help confirm his work by delving further into existing cohort studies that measured stress and had banked tumor samples. By comparing tumor type to patients reporting stress, they might be able to tease out an association, he said.

Dr. Rauscher reported no conflicts.

WASHINGTON – Higher levels of stress may partially account for aggressive tumor growth in African American and Hispanic women with breast cancer, according to Garth H. Rauscher, Ph.D., of the University of Illinois at Chicago.

This is one of the first studies to look closely at the potential role of psychosocial stress on tumor progression in breast cancer, said Dr. Rauscher, an associate professor of epidemiology at the university’s School of Public Health. However, he acknowledged that the study is "flawed" because it is cross-sectional and has other limitations. "This is definitely an exploratory study," Dr. Rauscher said at the American Association for Cancer Research Science of Cancer Health Disparities meeting.

It was already known, especially in Chicago, that there was a wide disparity in mortality rates between black women and white women, said Dr. Rauscher. The data are not as well defined for Hispanic women, he said. Tumor aggressiveness likely contributes to higher mortality rates in the minorities. Both African Americans and Hispanics generally have higher-grade tumors and hormone receptor–negative tumors, said Dr. Rauscher. The researchers wanted to investigate why these women have the more aggressive tumor types.

They chose to examine psychosocial factors.

Dr. Rauscher and his colleagues examined associations between patient-reported stress and aggressive breast cancer in a cross-sectional study of 397 non-Hispanic whites, 411 non-Hispanic blacks, and 181 Hispanics. Data were collected through patient interviews and medical record extraction. Stress was assessed using the four-item Cohen Perceived Stress Subscale, the UCLA Loneliness Scale, and the Cockburn psychological consequences scale. The three scales were combined into a single, standardized stress score.

Patients were interviewed just after their diagnosis of breast cancer. Dr. Rauscher explained that the researchers assumed that if patients were experiencing high stress post diagnosis, they were likely to have been under stress before diagnosis as well. But he acknowledged that this assumption is a major limitation of the study.

Of 989 patients, the researchers were able to get tumor grades for 772: 149 had low-grade tumors; 308 were intermediate, and 315 were high-grade tumors. A total of 21% (66 of 315) of patients with high-grade tumors reported elevated stress, 19% (58 of 308) of patients with intermediate-grade tumors reported elevated stress, and 11% (16 of 149) of patients with low-grade tumors reported elevated stress.

The differences were statistically significant, until Dr. Rauscher and his colleagues adjusted for age, treatment, income, and other factors.

A total of 28% of women with hormone receptor–negative tumors reported stress, compared with 14% of those with receptor-positive growths. Patients with hormone receptor–negative disease reported one-third of a standard deviation higher than did patients with receptor-positive disease (P = .0003). The difference held up after adjustment, Dr. Rauscher said.

Overall, psychosocial stress scores were higher for black and Hispanic women than for whites.

There’s still no way to know, however, what accounts for those differences, said Dr. Rauscher. "If you have a more aggressive diagnosis, does that make you worry more? You could certainly put that out there as a possibility," he said. Patients with more aggressive disease might also undergo more aggressive treatment, which could also lead to greater stress, he said. "There could be causal arrows going in both directions here, but we can’t tease that out." Even so, he said, "our results are consistent with a role for stress in the etiology of aggressive breast cancer."

Dr. Rauscher suggested that other researchers could help confirm his work by delving further into existing cohort studies that measured stress and had banked tumor samples. By comparing tumor type to patients reporting stress, they might be able to tease out an association, he said.

Dr. Rauscher reported no conflicts.

WASHINGTON – Higher levels of stress may partially account for aggressive tumor growth in African American and Hispanic women with breast cancer, according to Garth H. Rauscher, Ph.D., of the University of Illinois at Chicago.

This is one of the first studies to look closely at the potential role of psychosocial stress on tumor progression in breast cancer, said Dr. Rauscher, an associate professor of epidemiology at the university’s School of Public Health. However, he acknowledged that the study is "flawed" because it is cross-sectional and has other limitations. "This is definitely an exploratory study," Dr. Rauscher said at the American Association for Cancer Research Science of Cancer Health Disparities meeting.

It was already known, especially in Chicago, that there was a wide disparity in mortality rates between black women and white women, said Dr. Rauscher. The data are not as well defined for Hispanic women, he said. Tumor aggressiveness likely contributes to higher mortality rates in the minorities. Both African Americans and Hispanics generally have higher-grade tumors and hormone receptor–negative tumors, said Dr. Rauscher. The researchers wanted to investigate why these women have the more aggressive tumor types.

They chose to examine psychosocial factors.

Dr. Rauscher and his colleagues examined associations between patient-reported stress and aggressive breast cancer in a cross-sectional study of 397 non-Hispanic whites, 411 non-Hispanic blacks, and 181 Hispanics. Data were collected through patient interviews and medical record extraction. Stress was assessed using the four-item Cohen Perceived Stress Subscale, the UCLA Loneliness Scale, and the Cockburn psychological consequences scale. The three scales were combined into a single, standardized stress score.

Patients were interviewed just after their diagnosis of breast cancer. Dr. Rauscher explained that the researchers assumed that if patients were experiencing high stress post diagnosis, they were likely to have been under stress before diagnosis as well. But he acknowledged that this assumption is a major limitation of the study.

Of 989 patients, the researchers were able to get tumor grades for 772: 149 had low-grade tumors; 308 were intermediate, and 315 were high-grade tumors. A total of 21% (66 of 315) of patients with high-grade tumors reported elevated stress, 19% (58 of 308) of patients with intermediate-grade tumors reported elevated stress, and 11% (16 of 149) of patients with low-grade tumors reported elevated stress.

The differences were statistically significant, until Dr. Rauscher and his colleagues adjusted for age, treatment, income, and other factors.

A total of 28% of women with hormone receptor–negative tumors reported stress, compared with 14% of those with receptor-positive growths. Patients with hormone receptor–negative disease reported one-third of a standard deviation higher than did patients with receptor-positive disease (P = .0003). The difference held up after adjustment, Dr. Rauscher said.

Overall, psychosocial stress scores were higher for black and Hispanic women than for whites.

There’s still no way to know, however, what accounts for those differences, said Dr. Rauscher. "If you have a more aggressive diagnosis, does that make you worry more? You could certainly put that out there as a possibility," he said. Patients with more aggressive disease might also undergo more aggressive treatment, which could also lead to greater stress, he said. "There could be causal arrows going in both directions here, but we can’t tease that out." Even so, he said, "our results are consistent with a role for stress in the etiology of aggressive breast cancer."

Dr. Rauscher suggested that other researchers could help confirm his work by delving further into existing cohort studies that measured stress and had banked tumor samples. By comparing tumor type to patients reporting stress, they might be able to tease out an association, he said.

Dr. Rauscher reported no conflicts.

SAN FRANCISCO – The development of taxane-induced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data show.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial involving 4,554 women, 13%-22% developed peripheral neuropathy, depending on which of four taxane regimens they received.

The women who developed peripheral neuropathy did not have better recurrence-free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups. Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received.

He noted that the findings are important, given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

"Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome," he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that "at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points."

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted.

"The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients," concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel (Taxol) every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel (Taxotere) every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grade 2-4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio, 1.47), and were marginally more likely if they were black, obese, or postmenopausal.

Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel vs. paclitaxel every 3 week (HR, 1.52), paclitaxel every 3 weeks vs. weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks vs. docetaxel every 3 weeks (HR, 1.91).

In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence-free, disease-free, or overall survival.

The findings contrast with those of an earlier study in which women receiving paclitaxel-containing chemotherapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

"Every-3-week docetaxel and weekly paclitaxel are viable therapeutic options for breast cancer," commented Dr. Schneider. The former is associated with more grade 3/4 toxicity in general, whereas the latter is associated with more peripheral neuropathy.

"Our goal is to study SNPs that have previously been shown to predict neuropathy in E1199," he concluded. "We hope to validate those top SNPs and ultimately identify which therapy has the optimal risk-benefit ratio for a given subgroup based on genotype."

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

SAN FRANCISCO – The development of taxane-induced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data show.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial involving 4,554 women, 13%-22% developed peripheral neuropathy, depending on which of four taxane regimens they received.

The women who developed peripheral neuropathy did not have better recurrence-free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups. Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received.

He noted that the findings are important, given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

"Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome," he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that "at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points."

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted.

"The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients," concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel (Taxol) every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel (Taxotere) every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grade 2-4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio, 1.47), and were marginally more likely if they were black, obese, or postmenopausal.

Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel vs. paclitaxel every 3 week (HR, 1.52), paclitaxel every 3 weeks vs. weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks vs. docetaxel every 3 weeks (HR, 1.91).

In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence-free, disease-free, or overall survival.

The findings contrast with those of an earlier study in which women receiving paclitaxel-containing chemotherapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

"Every-3-week docetaxel and weekly paclitaxel are viable therapeutic options for breast cancer," commented Dr. Schneider. The former is associated with more grade 3/4 toxicity in general, whereas the latter is associated with more peripheral neuropathy.

"Our goal is to study SNPs that have previously been shown to predict neuropathy in E1199," he concluded. "We hope to validate those top SNPs and ultimately identify which therapy has the optimal risk-benefit ratio for a given subgroup based on genotype."

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

SAN FRANCISCO – The development of taxane-induced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data show.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial involving 4,554 women, 13%-22% developed peripheral neuropathy, depending on which of four taxane regimens they received.

The women who developed peripheral neuropathy did not have better recurrence-free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups. Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received.

He noted that the findings are important, given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

"Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome," he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that "at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points."

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted.

"The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients," concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel (Taxol) every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel (Taxotere) every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grade 2-4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio, 1.47), and were marginally more likely if they were black, obese, or postmenopausal.

Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel vs. paclitaxel every 3 week (HR, 1.52), paclitaxel every 3 weeks vs. weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks vs. docetaxel every 3 weeks (HR, 1.91).

In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence-free, disease-free, or overall survival.

The findings contrast with those of an earlier study in which women receiving paclitaxel-containing chemotherapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

"Every-3-week docetaxel and weekly paclitaxel are viable therapeutic options for breast cancer," commented Dr. Schneider. The former is associated with more grade 3/4 toxicity in general, whereas the latter is associated with more peripheral neuropathy.

"Our goal is to study SNPs that have previously been shown to predict neuropathy in E1199," he concluded. "We hope to validate those top SNPs and ultimately identify which therapy has the optimal risk-benefit ratio for a given subgroup based on genotype."

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

Depression emerged as a significant barrier to secondary cancer screening in Latina survivors of breast cancer in a thought-provoking study released Sept. 19 at the American Association of Cancer Research Conference on the Science of Cancer Health Disparities in Washington.

The cross-sectional study explored adherence to recommended screening guidelines for ovarian and colorectal cancer among 117 Latina breast cancer survivors. Not surprisingly, but disturbingly, adherence was low among this very-high-risk group. Nearly 60% (69 of 117) failed to receive standard screening for either disease.

One would hope that these high-risk women knew, based on their prior treatment, how to negotiate financial and logistical barriers to care. It would seem likely that they formed relationships with health care professionals. Certainly, it would be expected that they learned that early detection saves lives; perhaps, it had already saved theirs.

So what happened? How did the prevention message fail to reach women who had already directly faced the reality of a cancer diagnosis, and survived?

One sobering possibility lies in the fact that nearly a third of Latinas in the study met the criteria for depression, according to scores for the simple but comprehensive CES-D (Center for Epidemiologic Studies) screening tool.

The self-administered questionnaire assesses mood "("I felt that I could not shake off the blues, even with help from family or friends"; "I [did not] feel hopeful about the future"), somatic symptoms ("I did not feel like eating; my appetite was poor"), behavior ("I talked less than usual"), and self-concept ("I thought my life had been a failure").

Depression was associated with poor rates of ovarian screening, along with language barriers, unemployment, worries about the cost of screening, and the lack of a family history of cancer.

Poor rates of colorectal cancer screening were associated with being unmarried.

In online video interview from a 2010 AACR breast cancer meeting, the current study’s primary investigator, Amelie G. Ramirez, Dr. P.H., spoke of challenging issues surrounding Latina access to cancer prevention and care, driven by cultural as well as socioeconomic issues.

Sheer terror of cancer, she explained, wields a powerful influence over portions of the Latina community.

"When they hear the word cancer, it’s very fearful for them. It almost shuts down all ... communication," said Dr. Ramirez, director of the Institute for Health Promotion Research and professor of epidemiology and biostatistics at the University of Texas, San Antonio.

Depression, too, casts a dark, silent cloud over the Latino community.

In a 2009 study, University of California, Los Angeles, researchers identified a strong link between self-perceived stigma and secrecy surrounding depressive symptoms, less likelihood of taking antidepressants, and – importantly with regard to the current screening study – more missed medical appointments among Latinos.

Taken together, these studies and observations begin to paint a picture of the type of woman whose life might be reflected in the numbers in Dr. Ramirez’s study. She is poor and unemployed; she struggles with English. She survived a disease that is unspeakably terrifying in her community and perhaps in her family as well. She may be unmarried.

And now, with bills and scars still reminding her of the trauma, a new, equally unmentionable burden shadows her days. She sleeps restlessly and cannot eat; she is quiet and withdrawn; she cannot shake off the blues. She feels that her life has been a failure.

Assuming the best possible scenario, a card arrives in the mail, reminding her that she is due for cancer screening: an annual pelvic exam, perhaps, or a colonoscopy.

Is it any wonder she fails to comply?

Dr. Freed is a clinical psychologist in Santa Barbara, Calif., and a medical journalist. She has no relevant financial disclosures.

Depression emerged as a significant barrier to secondary cancer screening in Latina survivors of breast cancer in a thought-provoking study released Sept. 19 at the American Association of Cancer Research Conference on the Science of Cancer Health Disparities in Washington.

The cross-sectional study explored adherence to recommended screening guidelines for ovarian and colorectal cancer among 117 Latina breast cancer survivors. Not surprisingly, but disturbingly, adherence was low among this very-high-risk group. Nearly 60% (69 of 117) failed to receive standard screening for either disease.

One would hope that these high-risk women knew, based on their prior treatment, how to negotiate financial and logistical barriers to care. It would seem likely that they formed relationships with health care professionals. Certainly, it would be expected that they learned that early detection saves lives; perhaps, it had already saved theirs.

So what happened? How did the prevention message fail to reach women who had already directly faced the reality of a cancer diagnosis, and survived?

One sobering possibility lies in the fact that nearly a third of Latinas in the study met the criteria for depression, according to scores for the simple but comprehensive CES-D (Center for Epidemiologic Studies) screening tool.

The self-administered questionnaire assesses mood "("I felt that I could not shake off the blues, even with help from family or friends"; "I [did not] feel hopeful about the future"), somatic symptoms ("I did not feel like eating; my appetite was poor"), behavior ("I talked less than usual"), and self-concept ("I thought my life had been a failure").

Depression was associated with poor rates of ovarian screening, along with language barriers, unemployment, worries about the cost of screening, and the lack of a family history of cancer.

Poor rates of colorectal cancer screening were associated with being unmarried.

In online video interview from a 2010 AACR breast cancer meeting, the current study’s primary investigator, Amelie G. Ramirez, Dr. P.H., spoke of challenging issues surrounding Latina access to cancer prevention and care, driven by cultural as well as socioeconomic issues.

Sheer terror of cancer, she explained, wields a powerful influence over portions of the Latina community.

"When they hear the word cancer, it’s very fearful for them. It almost shuts down all ... communication," said Dr. Ramirez, director of the Institute for Health Promotion Research and professor of epidemiology and biostatistics at the University of Texas, San Antonio.

Depression, too, casts a dark, silent cloud over the Latino community.

In a 2009 study, University of California, Los Angeles, researchers identified a strong link between self-perceived stigma and secrecy surrounding depressive symptoms, less likelihood of taking antidepressants, and – importantly with regard to the current screening study – more missed medical appointments among Latinos.

Taken together, these studies and observations begin to paint a picture of the type of woman whose life might be reflected in the numbers in Dr. Ramirez’s study. She is poor and unemployed; she struggles with English. She survived a disease that is unspeakably terrifying in her community and perhaps in her family as well. She may be unmarried.

And now, with bills and scars still reminding her of the trauma, a new, equally unmentionable burden shadows her days. She sleeps restlessly and cannot eat; she is quiet and withdrawn; she cannot shake off the blues. She feels that her life has been a failure.

Assuming the best possible scenario, a card arrives in the mail, reminding her that she is due for cancer screening: an annual pelvic exam, perhaps, or a colonoscopy.

Is it any wonder she fails to comply?

Dr. Freed is a clinical psychologist in Santa Barbara, Calif., and a medical journalist. She has no relevant financial disclosures.

Depression emerged as a significant barrier to secondary cancer screening in Latina survivors of breast cancer in a thought-provoking study released Sept. 19 at the American Association of Cancer Research Conference on the Science of Cancer Health Disparities in Washington.

The cross-sectional study explored adherence to recommended screening guidelines for ovarian and colorectal cancer among 117 Latina breast cancer survivors. Not surprisingly, but disturbingly, adherence was low among this very-high-risk group. Nearly 60% (69 of 117) failed to receive standard screening for either disease.

One would hope that these high-risk women knew, based on their prior treatment, how to negotiate financial and logistical barriers to care. It would seem likely that they formed relationships with health care professionals. Certainly, it would be expected that they learned that early detection saves lives; perhaps, it had already saved theirs.

So what happened? How did the prevention message fail to reach women who had already directly faced the reality of a cancer diagnosis, and survived?

One sobering possibility lies in the fact that nearly a third of Latinas in the study met the criteria for depression, according to scores for the simple but comprehensive CES-D (Center for Epidemiologic Studies) screening tool.

The self-administered questionnaire assesses mood "("I felt that I could not shake off the blues, even with help from family or friends"; "I [did not] feel hopeful about the future"), somatic symptoms ("I did not feel like eating; my appetite was poor"), behavior ("I talked less than usual"), and self-concept ("I thought my life had been a failure").

Depression was associated with poor rates of ovarian screening, along with language barriers, unemployment, worries about the cost of screening, and the lack of a family history of cancer.

Poor rates of colorectal cancer screening were associated with being unmarried.

In online video interview from a 2010 AACR breast cancer meeting, the current study’s primary investigator, Amelie G. Ramirez, Dr. P.H., spoke of challenging issues surrounding Latina access to cancer prevention and care, driven by cultural as well as socioeconomic issues.

Sheer terror of cancer, she explained, wields a powerful influence over portions of the Latina community.

"When they hear the word cancer, it’s very fearful for them. It almost shuts down all ... communication," said Dr. Ramirez, director of the Institute for Health Promotion Research and professor of epidemiology and biostatistics at the University of Texas, San Antonio.

Depression, too, casts a dark, silent cloud over the Latino community.

In a 2009 study, University of California, Los Angeles, researchers identified a strong link between self-perceived stigma and secrecy surrounding depressive symptoms, less likelihood of taking antidepressants, and – importantly with regard to the current screening study – more missed medical appointments among Latinos.

Taken together, these studies and observations begin to paint a picture of the type of woman whose life might be reflected in the numbers in Dr. Ramirez’s study. She is poor and unemployed; she struggles with English. She survived a disease that is unspeakably terrifying in her community and perhaps in her family as well. She may be unmarried.

And now, with bills and scars still reminding her of the trauma, a new, equally unmentionable burden shadows her days. She sleeps restlessly and cannot eat; she is quiet and withdrawn; she cannot shake off the blues. She feels that her life has been a failure.

Assuming the best possible scenario, a card arrives in the mail, reminding her that she is due for cancer screening: an annual pelvic exam, perhaps, or a colonoscopy.

Is it any wonder she fails to comply?

Dr. Freed is a clinical psychologist in Santa Barbara, Calif., and a medical journalist. She has no relevant financial disclosures.

The Prolia brand of denosumab has been approved as a treatment for bone loss in people receiving hormone ablation therapy for prostate or breast cancer, according to a statement from Amgen, the manufacturer.

The approved indications are for increasing bone mass in women at high risk for fracture on adjuvant aromatase inhibitor therapy for breast cancer and in men at high risk for fracture on androgen deprivation therapy (ADT) for nonmetastatic prostate cancer, the company's statement said.

Denosumab, a RANK ligand inhibitor, was first approved in June 2010 for treating postmenopausal women with osteoporosis at high risk of fracture and is marketed as Prolia for this indication. Prolia is administered in a subcutaneous injection once every 6 months, at a dose of 60 mg.

In November 2010, denosumab was also approved for preventing skeletal-related events in patients with bone metastases from solid tumors. It is marketed as Xgeva and administered more frequently at a higher dose for this indication.

Approval of the new indications for Prolia was based on phase III studies of these two groups of patients, according to Amgen. In an international study of almost 1,500 men with nonmetastatic prostate cancer who were being treated with ADT, bone mineral density at the lumbar spine after 2 years of treatment was significantly higher among men who had received denosumab compared with those who received placebo. After 3 years of treatment, the incidence of new vertebral fractures was 1.5% among those treated with denosumab, compared with 3.9% for those on placebo, a risk reduction of 62%, the company said.

And in a study of 252 postmenopausal women with breast cancer under treatment with an aromatase inhibitor, bone mineral density at the lumbar spine was significantly higher among those treated with denosumab compared with those on placebo after 12 months of treatment, according to the statement.

Arthralgia and back pain were the most common adverse events associated with treatment in these two groups of patients. Hypocalcemia was also reported; denosumab is contraindicated in people with hypocalcemia. Treatment was associated with cataract events in men in the prostate cancer trial.

In the European Union, denosumab is approved for the osteoporosis indication as well as the prostate cancer indication just approved in the United States, according to Amgen.

The Prolia brand of denosumab has been approved as a treatment for bone loss in people receiving hormone ablation therapy for prostate or breast cancer, according to a statement from Amgen, the manufacturer.

The approved indications are for increasing bone mass in women at high risk for fracture on adjuvant aromatase inhibitor therapy for breast cancer and in men at high risk for fracture on androgen deprivation therapy (ADT) for nonmetastatic prostate cancer, the company's statement said.

Denosumab, a RANK ligand inhibitor, was first approved in June 2010 for treating postmenopausal women with osteoporosis at high risk of fracture and is marketed as Prolia for this indication. Prolia is administered in a subcutaneous injection once every 6 months, at a dose of 60 mg.

In November 2010, denosumab was also approved for preventing skeletal-related events in patients with bone metastases from solid tumors. It is marketed as Xgeva and administered more frequently at a higher dose for this indication.

Approval of the new indications for Prolia was based on phase III studies of these two groups of patients, according to Amgen. In an international study of almost 1,500 men with nonmetastatic prostate cancer who were being treated with ADT, bone mineral density at the lumbar spine after 2 years of treatment was significantly higher among men who had received denosumab compared with those who received placebo. After 3 years of treatment, the incidence of new vertebral fractures was 1.5% among those treated with denosumab, compared with 3.9% for those on placebo, a risk reduction of 62%, the company said.

And in a study of 252 postmenopausal women with breast cancer under treatment with an aromatase inhibitor, bone mineral density at the lumbar spine was significantly higher among those treated with denosumab compared with those on placebo after 12 months of treatment, according to the statement.

Arthralgia and back pain were the most common adverse events associated with treatment in these two groups of patients. Hypocalcemia was also reported; denosumab is contraindicated in people with hypocalcemia. Treatment was associated with cataract events in men in the prostate cancer trial.

In the European Union, denosumab is approved for the osteoporosis indication as well as the prostate cancer indication just approved in the United States, according to Amgen.

The Prolia brand of denosumab has been approved as a treatment for bone loss in people receiving hormone ablation therapy for prostate or breast cancer, according to a statement from Amgen, the manufacturer.

The approved indications are for increasing bone mass in women at high risk for fracture on adjuvant aromatase inhibitor therapy for breast cancer and in men at high risk for fracture on androgen deprivation therapy (ADT) for nonmetastatic prostate cancer, the company's statement said.

Denosumab, a RANK ligand inhibitor, was first approved in June 2010 for treating postmenopausal women with osteoporosis at high risk of fracture and is marketed as Prolia for this indication. Prolia is administered in a subcutaneous injection once every 6 months, at a dose of 60 mg.

In November 2010, denosumab was also approved for preventing skeletal-related events in patients with bone metastases from solid tumors. It is marketed as Xgeva and administered more frequently at a higher dose for this indication.

Approval of the new indications for Prolia was based on phase III studies of these two groups of patients, according to Amgen. In an international study of almost 1,500 men with nonmetastatic prostate cancer who were being treated with ADT, bone mineral density at the lumbar spine after 2 years of treatment was significantly higher among men who had received denosumab compared with those who received placebo. After 3 years of treatment, the incidence of new vertebral fractures was 1.5% among those treated with denosumab, compared with 3.9% for those on placebo, a risk reduction of 62%, the company said.

And in a study of 252 postmenopausal women with breast cancer under treatment with an aromatase inhibitor, bone mineral density at the lumbar spine was significantly higher among those treated with denosumab compared with those on placebo after 12 months of treatment, according to the statement.

Arthralgia and back pain were the most common adverse events associated with treatment in these two groups of patients. Hypocalcemia was also reported; denosumab is contraindicated in people with hypocalcemia. Treatment was associated with cataract events in men in the prostate cancer trial.

In the European Union, denosumab is approved for the osteoporosis indication as well as the prostate cancer indication just approved in the United States, according to Amgen.