Breast Cancer

SAN FRANCISCO – Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase-II trial suggest.

Investigators studied 130 women with estrogen receptor–positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane (Aromasin) plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.

"The combination ... is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy," principal investigator Dr. Denise A. Yardley reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

"These results support our plans for a global, pivotal phase-III study due to begin enrollment in 2012," added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.

In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy. These data reveal "for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes," she noted.

Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as "very, very promising," saying, "I agree that it’s time for a phase III" trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.

A particularly impressive finding was the long progression-free survival seen in hyperacetylators, according to Dr. O’Shaughnessy. It will be important to determine whether this correlates with toxicity, as lack of toxicity might then identify patients who could benefit from dose-escalation of entinostat. "They need to really carefully look at that because you really want to optimize it for all the people in the phase-III trial," she commented.

Giving some mechanistic background to the trial, Dr. Yardley noted that HDAC inhibitors interfere with the condensation of chromatin and the silencing of genes, such as tumor suppressor genes.

Resistance to AIs occurs from upregulation and activation of growth factor signaling pathways that are not estrogen dependent. "Entinostat targets these growth factor signaling pathways, ultimately inhibiting tumor cell growth," she explained. Preclinical data also suggest that the drug resensitizes tumors to AIs.

The randomized phase-II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor–positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.

The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values less than .1 were considered statistically significant.

Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.

With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs. 2.27 months; hazard ratio, 0.73; P = .06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.

In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an above-median percent change in lysines that were acetylated during the first cycle of treatment.

These findings "suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment," said Dr. Yardley.

Furthermore, the association raises the "question, if you can identify early on a group that is not acetylating, whether increasing the dose may get them to be hyperacetylators and derive more benefit from the HDAC inhibitor," she said. Additionally, ongoing analyses are looking at whether hyperacetylation correlated with toxicity and could then be used as a surrogate for efficacy.

"We are going to have more correlative work planned as a part of the phase-III trial that is coming up," Dr. Yardley added.

In an analysis that was exploratory because follow-up is still short, entinostat was also associated with better overall survival (26.9 vs. 20.3 months; HR, 0.56; P = .027). Additional data with longer follow-up will be reported at the San Antonio Breast Cancer Symposium later this year.

The combination of entinostat and exemestane was well tolerated, with no unexpected safety signals. The most common grade 3/4 adverse events in the entinostat group were fatigue (13%), neutropenia (13%), nausea (5%), and vomiting (5%). The rate of discontinuation because of adverse events was 1% in the placebo group and 11% in the entinostat group.

Dr. Yardley reported that she had no relevant conflicts of interest. Syndax Pharmaceuticals, developer of entinostat, was not among Dr. O’Shaughnessy’s disclosures.

SAN FRANCISCO – Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase-II trial suggest.

Investigators studied 130 women with estrogen receptor–positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane (Aromasin) plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.

"The combination ... is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy," principal investigator Dr. Denise A. Yardley reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

"These results support our plans for a global, pivotal phase-III study due to begin enrollment in 2012," added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.

In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy. These data reveal "for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes," she noted.

Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as "very, very promising," saying, "I agree that it’s time for a phase III" trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.

A particularly impressive finding was the long progression-free survival seen in hyperacetylators, according to Dr. O’Shaughnessy. It will be important to determine whether this correlates with toxicity, as lack of toxicity might then identify patients who could benefit from dose-escalation of entinostat. "They need to really carefully look at that because you really want to optimize it for all the people in the phase-III trial," she commented.

Giving some mechanistic background to the trial, Dr. Yardley noted that HDAC inhibitors interfere with the condensation of chromatin and the silencing of genes, such as tumor suppressor genes.

Resistance to AIs occurs from upregulation and activation of growth factor signaling pathways that are not estrogen dependent. "Entinostat targets these growth factor signaling pathways, ultimately inhibiting tumor cell growth," she explained. Preclinical data also suggest that the drug resensitizes tumors to AIs.

The randomized phase-II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor–positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.

The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values less than .1 were considered statistically significant.

Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.

With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs. 2.27 months; hazard ratio, 0.73; P = .06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.

In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an above-median percent change in lysines that were acetylated during the first cycle of treatment.

These findings "suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment," said Dr. Yardley.

Furthermore, the association raises the "question, if you can identify early on a group that is not acetylating, whether increasing the dose may get them to be hyperacetylators and derive more benefit from the HDAC inhibitor," she said. Additionally, ongoing analyses are looking at whether hyperacetylation correlated with toxicity and could then be used as a surrogate for efficacy.

"We are going to have more correlative work planned as a part of the phase-III trial that is coming up," Dr. Yardley added.

In an analysis that was exploratory because follow-up is still short, entinostat was also associated with better overall survival (26.9 vs. 20.3 months; HR, 0.56; P = .027). Additional data with longer follow-up will be reported at the San Antonio Breast Cancer Symposium later this year.

The combination of entinostat and exemestane was well tolerated, with no unexpected safety signals. The most common grade 3/4 adverse events in the entinostat group were fatigue (13%), neutropenia (13%), nausea (5%), and vomiting (5%). The rate of discontinuation because of adverse events was 1% in the placebo group and 11% in the entinostat group.

Dr. Yardley reported that she had no relevant conflicts of interest. Syndax Pharmaceuticals, developer of entinostat, was not among Dr. O’Shaughnessy’s disclosures.

SAN FRANCISCO – Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase-II trial suggest.

Investigators studied 130 women with estrogen receptor–positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane (Aromasin) plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.

"The combination ... is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy," principal investigator Dr. Denise A. Yardley reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

"These results support our plans for a global, pivotal phase-III study due to begin enrollment in 2012," added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.

In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy. These data reveal "for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes," she noted.

Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as "very, very promising," saying, "I agree that it’s time for a phase III" trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.

A particularly impressive finding was the long progression-free survival seen in hyperacetylators, according to Dr. O’Shaughnessy. It will be important to determine whether this correlates with toxicity, as lack of toxicity might then identify patients who could benefit from dose-escalation of entinostat. "They need to really carefully look at that because you really want to optimize it for all the people in the phase-III trial," she commented.

Giving some mechanistic background to the trial, Dr. Yardley noted that HDAC inhibitors interfere with the condensation of chromatin and the silencing of genes, such as tumor suppressor genes.

Resistance to AIs occurs from upregulation and activation of growth factor signaling pathways that are not estrogen dependent. "Entinostat targets these growth factor signaling pathways, ultimately inhibiting tumor cell growth," she explained. Preclinical data also suggest that the drug resensitizes tumors to AIs.

The randomized phase-II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor–positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.

The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values less than .1 were considered statistically significant.

Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.

With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs. 2.27 months; hazard ratio, 0.73; P = .06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.

In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an above-median percent change in lysines that were acetylated during the first cycle of treatment.

These findings "suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment," said Dr. Yardley.

Furthermore, the association raises the "question, if you can identify early on a group that is not acetylating, whether increasing the dose may get them to be hyperacetylators and derive more benefit from the HDAC inhibitor," she said. Additionally, ongoing analyses are looking at whether hyperacetylation correlated with toxicity and could then be used as a surrogate for efficacy.

"We are going to have more correlative work planned as a part of the phase-III trial that is coming up," Dr. Yardley added.

In an analysis that was exploratory because follow-up is still short, entinostat was also associated with better overall survival (26.9 vs. 20.3 months; HR, 0.56; P = .027). Additional data with longer follow-up will be reported at the San Antonio Breast Cancer Symposium later this year.

The combination of entinostat and exemestane was well tolerated, with no unexpected safety signals. The most common grade 3/4 adverse events in the entinostat group were fatigue (13%), neutropenia (13%), nausea (5%), and vomiting (5%). The rate of discontinuation because of adverse events was 1% in the placebo group and 11% in the entinostat group.

Dr. Yardley reported that she had no relevant conflicts of interest. Syndax Pharmaceuticals, developer of entinostat, was not among Dr. O’Shaughnessy’s disclosures.

Venlafaxine and clonidine both outperformed placebo in controlling hot flashes among women with breast cancer in a study published online Sept. 12 in the Journal of Clinical Oncology.

Effective treatments for hot flashes may improve these patients’ ability to continue their anticancer therapies, said Dr. Annelies H. Boekhout of The Netherlands Cancer Institute, Amsterdam, and her associates.

The SSNRI venlafaxine (Effexor) and the antihypertensive clonidine "both are often prescribed treatments and are recommended in clinical guidelines in the management of hot flashes. However, a three-arm trial comparing clonidine, venlafaxine, and placebo in patients with breast cancer has not been conducted" until now, they noted.

In their double-blind study at three Dutch hospitals, 102 women with breast cancer who experienced at least two hot flashes per day were stratified by age, duration of symptoms, concurrent endocrine therapy, and previous chemotherapy, and randomly assigned to receive 75 mg venlafaxine (41 patients), 0.1 mg clonidine (41 patients), or matching placebo (20 patients) daily for 12 weeks.

The women completed daily diaries recording the frequency and severity of hot flashes. They also reported every week on adverse events such as reduced appetite, nausea, sleepiness, dizziness, fatigue, dry mouth, and constipation. They recorded their sleep quality, anxiety, depression, and sexual function at 4 weeks and at the conclusion of treatment.

A total of 22 subjects (22%) either dropped out of the study or were lost to follow-up. Two patients (5%) in the venlafaxine group and six (15%) in the clonidine group cited adverse effects such as somnolence, dizziness, and dry mouth as their reason for discontinuing. Another 9% of patients discontinued because of noncompliance, which "had some effect on the observed differences between treatments in this study."

Among the 35 women assigned to venlafaxine who completed the trial, there was a 42% decline in hot flashes during weeks 1-4, compared with the placebo group. Over the entire study period, the reduction in hot flashes was 41% with venlafaxine, compared with placebo.

Among the 28 women assigned to clonidine who completed the trial, hot flashes declined by only 26% during weeks 1-4 but then declined another 22% during the remainder of the study, for an overall reduction of approximately 45%.

Thus, both active agents decreased the frequency and severity of hot flashes compared with placebo, with no discernible difference between the two by week 12. "A more rapid reduction of hot flashes suggests that venlafaxine is to be preferred over clonidine," Dr. Boekhout and her colleagues said (J. Clin. Oncol. 2011 Sept. 12 [doi:10.1200/JCO.2010.33.1298]).

They added that it is "advisable to treat patients to manage hot flashes with venlafaxine 37.5 mg daily in the first week and increase the venlafaxine dose to 75 mg if greater efficacy is desired."

A total of 14 patients (34%) in the clonidine group, 23 (56%) in the venlafaxine group, and 4 (20%) in the placebo group said they wished to continue the study treatment at the end of the trial.

Women taking clonidine reported more symptoms of anxiety and women taking venlafaxine reported more symptoms of depression. Sexual function and sleep quality did not differ between the two groups. However, the duration of this study may have been too short to adequately assess these adverse effects, the researchers noted.

No conflicts of interest were reported.

Venlafaxine and clonidine both outperformed placebo in controlling hot flashes among women with breast cancer in a study published online Sept. 12 in the Journal of Clinical Oncology.

Effective treatments for hot flashes may improve these patients’ ability to continue their anticancer therapies, said Dr. Annelies H. Boekhout of The Netherlands Cancer Institute, Amsterdam, and her associates.

The SSNRI venlafaxine (Effexor) and the antihypertensive clonidine "both are often prescribed treatments and are recommended in clinical guidelines in the management of hot flashes. However, a three-arm trial comparing clonidine, venlafaxine, and placebo in patients with breast cancer has not been conducted" until now, they noted.

In their double-blind study at three Dutch hospitals, 102 women with breast cancer who experienced at least two hot flashes per day were stratified by age, duration of symptoms, concurrent endocrine therapy, and previous chemotherapy, and randomly assigned to receive 75 mg venlafaxine (41 patients), 0.1 mg clonidine (41 patients), or matching placebo (20 patients) daily for 12 weeks.

The women completed daily diaries recording the frequency and severity of hot flashes. They also reported every week on adverse events such as reduced appetite, nausea, sleepiness, dizziness, fatigue, dry mouth, and constipation. They recorded their sleep quality, anxiety, depression, and sexual function at 4 weeks and at the conclusion of treatment.

A total of 22 subjects (22%) either dropped out of the study or were lost to follow-up. Two patients (5%) in the venlafaxine group and six (15%) in the clonidine group cited adverse effects such as somnolence, dizziness, and dry mouth as their reason for discontinuing. Another 9% of patients discontinued because of noncompliance, which "had some effect on the observed differences between treatments in this study."

Among the 35 women assigned to venlafaxine who completed the trial, there was a 42% decline in hot flashes during weeks 1-4, compared with the placebo group. Over the entire study period, the reduction in hot flashes was 41% with venlafaxine, compared with placebo.

Among the 28 women assigned to clonidine who completed the trial, hot flashes declined by only 26% during weeks 1-4 but then declined another 22% during the remainder of the study, for an overall reduction of approximately 45%.

Thus, both active agents decreased the frequency and severity of hot flashes compared with placebo, with no discernible difference between the two by week 12. "A more rapid reduction of hot flashes suggests that venlafaxine is to be preferred over clonidine," Dr. Boekhout and her colleagues said (J. Clin. Oncol. 2011 Sept. 12 [doi:10.1200/JCO.2010.33.1298]).

They added that it is "advisable to treat patients to manage hot flashes with venlafaxine 37.5 mg daily in the first week and increase the venlafaxine dose to 75 mg if greater efficacy is desired."

A total of 14 patients (34%) in the clonidine group, 23 (56%) in the venlafaxine group, and 4 (20%) in the placebo group said they wished to continue the study treatment at the end of the trial.

Women taking clonidine reported more symptoms of anxiety and women taking venlafaxine reported more symptoms of depression. Sexual function and sleep quality did not differ between the two groups. However, the duration of this study may have been too short to adequately assess these adverse effects, the researchers noted.

No conflicts of interest were reported.

Venlafaxine and clonidine both outperformed placebo in controlling hot flashes among women with breast cancer in a study published online Sept. 12 in the Journal of Clinical Oncology.

Effective treatments for hot flashes may improve these patients’ ability to continue their anticancer therapies, said Dr. Annelies H. Boekhout of The Netherlands Cancer Institute, Amsterdam, and her associates.

The SSNRI venlafaxine (Effexor) and the antihypertensive clonidine "both are often prescribed treatments and are recommended in clinical guidelines in the management of hot flashes. However, a three-arm trial comparing clonidine, venlafaxine, and placebo in patients with breast cancer has not been conducted" until now, they noted.

In their double-blind study at three Dutch hospitals, 102 women with breast cancer who experienced at least two hot flashes per day were stratified by age, duration of symptoms, concurrent endocrine therapy, and previous chemotherapy, and randomly assigned to receive 75 mg venlafaxine (41 patients), 0.1 mg clonidine (41 patients), or matching placebo (20 patients) daily for 12 weeks.

The women completed daily diaries recording the frequency and severity of hot flashes. They also reported every week on adverse events such as reduced appetite, nausea, sleepiness, dizziness, fatigue, dry mouth, and constipation. They recorded their sleep quality, anxiety, depression, and sexual function at 4 weeks and at the conclusion of treatment.

A total of 22 subjects (22%) either dropped out of the study or were lost to follow-up. Two patients (5%) in the venlafaxine group and six (15%) in the clonidine group cited adverse effects such as somnolence, dizziness, and dry mouth as their reason for discontinuing. Another 9% of patients discontinued because of noncompliance, which "had some effect on the observed differences between treatments in this study."

Among the 35 women assigned to venlafaxine who completed the trial, there was a 42% decline in hot flashes during weeks 1-4, compared with the placebo group. Over the entire study period, the reduction in hot flashes was 41% with venlafaxine, compared with placebo.

Among the 28 women assigned to clonidine who completed the trial, hot flashes declined by only 26% during weeks 1-4 but then declined another 22% during the remainder of the study, for an overall reduction of approximately 45%.

Thus, both active agents decreased the frequency and severity of hot flashes compared with placebo, with no discernible difference between the two by week 12. "A more rapid reduction of hot flashes suggests that venlafaxine is to be preferred over clonidine," Dr. Boekhout and her colleagues said (J. Clin. Oncol. 2011 Sept. 12 [doi:10.1200/JCO.2010.33.1298]).

They added that it is "advisable to treat patients to manage hot flashes with venlafaxine 37.5 mg daily in the first week and increase the venlafaxine dose to 75 mg if greater efficacy is desired."

A total of 14 patients (34%) in the clonidine group, 23 (56%) in the venlafaxine group, and 4 (20%) in the placebo group said they wished to continue the study treatment at the end of the trial.

Women taking clonidine reported more symptoms of anxiety and women taking venlafaxine reported more symptoms of depression. Sexual function and sleep quality did not differ between the two groups. However, the duration of this study may have been too short to adequately assess these adverse effects, the researchers noted.

No conflicts of interest were reported.

ADELPHI, MD. – Data on the safety and effectiveness of bisphosphonate drugs for the long-term treatment of osteoporosis is lacking and direly needed, according to a joint Food and Drug Administration advisory committee meeting.

Specifically, the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 17-6 on Sept. 9 that labeling for these drugs should be changed to clarify the duration of use for this drug class.

The agency convened the joint meeting to evaluate particular concerns about the long-term use bisphosphonate drugs, given reports of atypical subtrochanteric and femoral fractures, jaw osteonecrosis, and esophageal cancer associated with bisphosphonate use.

The labels of bisphosphonate drugs – alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast) – already include "important limitation of use" information. This labeling states that the optimal duration of treatment (for an individual drug) has not been determined and that all patients on bisphosphonate therapy should be periodically reassessed for the necessity of continued therapy.

While the panel voted to clarify the label language, they were emphatic that much more data are needed to establish the long-term efficacy and safety of bisphosphonates in general and with special regard to atypical fractures, jaw osteonecrosis, and esophageal cancer.

The two committees also were asked to assess the strength of data on the long-term use of bisphosphonates; the overall risks and benefits of continuous long-term use (3-5 years or more); whether restricting the duration of use or implementing a drug holiday would be beneficial; which outcomes require further evidence; and how should this data be obtained.

The expert consensus is that existing data – some of which go out to roughly 10 years for one drug – do not address the efficacy of the long-term use of bisphosphonates. They recommended that (in no particular order) additional data are needed with regard to the occurrence of atypical fractures, osteonecrosis of the jaw, esophageal cancer, osteoporotic fracture reduction efficacy with long-term (at least 3-5 years) continuous bisphosphonate use, and the effect of a "drug holiday" on drug safety and effectiveness.

Osteoporosis currently affects approximately 10 million Americans, according to the American Society for Bone and Mineral Research. An additional 34 million have low bone mass, which may progress to osteoporosis.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally a panelist may be given a waiver, but none were given at this meeting.

ADELPHI, MD. – Data on the safety and effectiveness of bisphosphonate drugs for the long-term treatment of osteoporosis is lacking and direly needed, according to a joint Food and Drug Administration advisory committee meeting.

Specifically, the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 17-6 on Sept. 9 that labeling for these drugs should be changed to clarify the duration of use for this drug class.

The agency convened the joint meeting to evaluate particular concerns about the long-term use bisphosphonate drugs, given reports of atypical subtrochanteric and femoral fractures, jaw osteonecrosis, and esophageal cancer associated with bisphosphonate use.

The labels of bisphosphonate drugs – alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast) – already include "important limitation of use" information. This labeling states that the optimal duration of treatment (for an individual drug) has not been determined and that all patients on bisphosphonate therapy should be periodically reassessed for the necessity of continued therapy.

While the panel voted to clarify the label language, they were emphatic that much more data are needed to establish the long-term efficacy and safety of bisphosphonates in general and with special regard to atypical fractures, jaw osteonecrosis, and esophageal cancer.

The two committees also were asked to assess the strength of data on the long-term use of bisphosphonates; the overall risks and benefits of continuous long-term use (3-5 years or more); whether restricting the duration of use or implementing a drug holiday would be beneficial; which outcomes require further evidence; and how should this data be obtained.

The expert consensus is that existing data – some of which go out to roughly 10 years for one drug – do not address the efficacy of the long-term use of bisphosphonates. They recommended that (in no particular order) additional data are needed with regard to the occurrence of atypical fractures, osteonecrosis of the jaw, esophageal cancer, osteoporotic fracture reduction efficacy with long-term (at least 3-5 years) continuous bisphosphonate use, and the effect of a "drug holiday" on drug safety and effectiveness.

Osteoporosis currently affects approximately 10 million Americans, according to the American Society for Bone and Mineral Research. An additional 34 million have low bone mass, which may progress to osteoporosis.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally a panelist may be given a waiver, but none were given at this meeting.

ADELPHI, MD. – Data on the safety and effectiveness of bisphosphonate drugs for the long-term treatment of osteoporosis is lacking and direly needed, according to a joint Food and Drug Administration advisory committee meeting.

Specifically, the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 17-6 on Sept. 9 that labeling for these drugs should be changed to clarify the duration of use for this drug class.

The agency convened the joint meeting to evaluate particular concerns about the long-term use bisphosphonate drugs, given reports of atypical subtrochanteric and femoral fractures, jaw osteonecrosis, and esophageal cancer associated with bisphosphonate use.

The labels of bisphosphonate drugs – alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), and zoledronic acid (Reclast) – already include "important limitation of use" information. This labeling states that the optimal duration of treatment (for an individual drug) has not been determined and that all patients on bisphosphonate therapy should be periodically reassessed for the necessity of continued therapy.

While the panel voted to clarify the label language, they were emphatic that much more data are needed to establish the long-term efficacy and safety of bisphosphonates in general and with special regard to atypical fractures, jaw osteonecrosis, and esophageal cancer.

The two committees also were asked to assess the strength of data on the long-term use of bisphosphonates; the overall risks and benefits of continuous long-term use (3-5 years or more); whether restricting the duration of use or implementing a drug holiday would be beneficial; which outcomes require further evidence; and how should this data be obtained.

The expert consensus is that existing data – some of which go out to roughly 10 years for one drug – do not address the efficacy of the long-term use of bisphosphonates. They recommended that (in no particular order) additional data are needed with regard to the occurrence of atypical fractures, osteonecrosis of the jaw, esophageal cancer, osteoporotic fracture reduction efficacy with long-term (at least 3-5 years) continuous bisphosphonate use, and the effect of a "drug holiday" on drug safety and effectiveness.

Osteoporosis currently affects approximately 10 million Americans, according to the American Society for Bone and Mineral Research. An additional 34 million have low bone mass, which may progress to osteoporosis.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally a panelist may be given a waiver, but none were given at this meeting.

SAN FRANCISCO – The more metabolically active a woman’s bone metastases of breast cancer are on imaging, the greater her risk of death, researchers reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

In a retrospective cohort study of 269 women with newly diagnosed metastatic breast cancer, those whose bone metastases were "hotter" on a PET/CT – as assessed from maximum standardized uptake value (SUV-max) – had poorer overall survival.

Compared with their counterparts with values in the bottom tertile of SUV-max values, women with values in the middle and top tertiles were roughly two to three times more likely to die after other prognostic factors were taken into account.

"To our understanding, this is the first large retrospective series to correlate SUV-max at metastatic breast cancer diagnosis with overall survival," said lead author Dr. Komal Jhaveri of Memorial Sloan-Kettering Cancer Center, New York.

The risk of death also rose with increasing tertile of SUV-max in liver, lung, and lymph node metastases, but those associations were not significant. Their nonsignificance may have been due to the smaller numbers of patients having metastases in those sites, she said.

Session chair Dr. Robert R. Kuske, a radiation oncologist with Arizona Breast Cancer Specialists in Scottsdale, noted that SUV-max is a surrogate for how rapidly the tumor cells are proliferating and, hence, the tumor’s aggressiveness. "So there should be a strong correlation between this SUV on the PET and the Ki-67 [histologic proliferation index]," he said.

"This gives us another tool in our tool chest to evaluate how patients are going to do," he commented. "Now [oncologists] can look at a metastasis on PET, measure the SUV, and get a handle on what the future of that patient is going to be – is it going to be a rapid slide to death, or is it going to be a very slow, indolent progression maybe over 10 or 15 years. And they can tailor the therapy based on the aggressiveness of the disease."

The PET/CT is usually done to determine whether the patient has metastases, so this additional prognostic information "is a little something extra you get from the test."

Will these new findings be practice changing? "I’ll start looking at SUV values in my patients with newly diagnosed metastasis," said Dr. Kuske. "Yes, it will change my practice."

In the study, Dr. Jhaveri and her coinvestigators reviewed records for women with metastatic breast cancer diagnosed between 2001 and 2008 who had a PET/CT scan performed within 60 days of the detection of metastases; had at least one avid metastasis in bone, liver, lung, or lymph node; and had not received chemotherapy in the month before the scan. Prior or current hormonal therapy was permitted.

The investigators determined the SUV-max for individual metastatic sites. They compared values only within a given site because of known variation across sites such as liver and lung, Dr. Jhaveri explained.

The women had a median age of 58 years. The median time elapsed between primary breast cancer diagnosis and PET/CT was 2.3 years. A fifth each had triple-negative disease and HER2-positive disease.

The median duration of follow-up was 40 months. In a multivariate analysis that included other prognostic factors (grade, tumor phenotype, and visceral metastases), overall survival differed across tertiles of SUV-max for bone metastases (P = .006). Women with values in the middle and top tertiles were 1.87 and 2.67 times more likely to die, respectively, than their counterparts with values in the bottom tertile.

"Given the variation in SUV and the differential impact on survival by site, it is possible that SUV-max may not be the most optimal PET variable," Dr. Jhaveri commented. She proposed that an alternate variable, called total lesion glycolysis (TLG), which incorporates tumor lesion size, might perform better and be more informative.

"Ultimately, prospective studies are required to further delineate the role of PET/CT as a prognostic tool in metastatic breast cancer," she concluded.

Dr. Jhaveri and Dr. Kuske reported having no relevant conflicts of interest.

SAN FRANCISCO – The more metabolically active a woman’s bone metastases of breast cancer are on imaging, the greater her risk of death, researchers reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

In a retrospective cohort study of 269 women with newly diagnosed metastatic breast cancer, those whose bone metastases were "hotter" on a PET/CT – as assessed from maximum standardized uptake value (SUV-max) – had poorer overall survival.

Compared with their counterparts with values in the bottom tertile of SUV-max values, women with values in the middle and top tertiles were roughly two to three times more likely to die after other prognostic factors were taken into account.

"To our understanding, this is the first large retrospective series to correlate SUV-max at metastatic breast cancer diagnosis with overall survival," said lead author Dr. Komal Jhaveri of Memorial Sloan-Kettering Cancer Center, New York.

The risk of death also rose with increasing tertile of SUV-max in liver, lung, and lymph node metastases, but those associations were not significant. Their nonsignificance may have been due to the smaller numbers of patients having metastases in those sites, she said.

Session chair Dr. Robert R. Kuske, a radiation oncologist with Arizona Breast Cancer Specialists in Scottsdale, noted that SUV-max is a surrogate for how rapidly the tumor cells are proliferating and, hence, the tumor’s aggressiveness. "So there should be a strong correlation between this SUV on the PET and the Ki-67 [histologic proliferation index]," he said.

"This gives us another tool in our tool chest to evaluate how patients are going to do," he commented. "Now [oncologists] can look at a metastasis on PET, measure the SUV, and get a handle on what the future of that patient is going to be – is it going to be a rapid slide to death, or is it going to be a very slow, indolent progression maybe over 10 or 15 years. And they can tailor the therapy based on the aggressiveness of the disease."

The PET/CT is usually done to determine whether the patient has metastases, so this additional prognostic information "is a little something extra you get from the test."

Will these new findings be practice changing? "I’ll start looking at SUV values in my patients with newly diagnosed metastasis," said Dr. Kuske. "Yes, it will change my practice."

In the study, Dr. Jhaveri and her coinvestigators reviewed records for women with metastatic breast cancer diagnosed between 2001 and 2008 who had a PET/CT scan performed within 60 days of the detection of metastases; had at least one avid metastasis in bone, liver, lung, or lymph node; and had not received chemotherapy in the month before the scan. Prior or current hormonal therapy was permitted.

The investigators determined the SUV-max for individual metastatic sites. They compared values only within a given site because of known variation across sites such as liver and lung, Dr. Jhaveri explained.

The women had a median age of 58 years. The median time elapsed between primary breast cancer diagnosis and PET/CT was 2.3 years. A fifth each had triple-negative disease and HER2-positive disease.

The median duration of follow-up was 40 months. In a multivariate analysis that included other prognostic factors (grade, tumor phenotype, and visceral metastases), overall survival differed across tertiles of SUV-max for bone metastases (P = .006). Women with values in the middle and top tertiles were 1.87 and 2.67 times more likely to die, respectively, than their counterparts with values in the bottom tertile.

"Given the variation in SUV and the differential impact on survival by site, it is possible that SUV-max may not be the most optimal PET variable," Dr. Jhaveri commented. She proposed that an alternate variable, called total lesion glycolysis (TLG), which incorporates tumor lesion size, might perform better and be more informative.

"Ultimately, prospective studies are required to further delineate the role of PET/CT as a prognostic tool in metastatic breast cancer," she concluded.

Dr. Jhaveri and Dr. Kuske reported having no relevant conflicts of interest.

SAN FRANCISCO – The more metabolically active a woman’s bone metastases of breast cancer are on imaging, the greater her risk of death, researchers reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

In a retrospective cohort study of 269 women with newly diagnosed metastatic breast cancer, those whose bone metastases were "hotter" on a PET/CT – as assessed from maximum standardized uptake value (SUV-max) – had poorer overall survival.

Compared with their counterparts with values in the bottom tertile of SUV-max values, women with values in the middle and top tertiles were roughly two to three times more likely to die after other prognostic factors were taken into account.

"To our understanding, this is the first large retrospective series to correlate SUV-max at metastatic breast cancer diagnosis with overall survival," said lead author Dr. Komal Jhaveri of Memorial Sloan-Kettering Cancer Center, New York.

The risk of death also rose with increasing tertile of SUV-max in liver, lung, and lymph node metastases, but those associations were not significant. Their nonsignificance may have been due to the smaller numbers of patients having metastases in those sites, she said.

Session chair Dr. Robert R. Kuske, a radiation oncologist with Arizona Breast Cancer Specialists in Scottsdale, noted that SUV-max is a surrogate for how rapidly the tumor cells are proliferating and, hence, the tumor’s aggressiveness. "So there should be a strong correlation between this SUV on the PET and the Ki-67 [histologic proliferation index]," he said.

"This gives us another tool in our tool chest to evaluate how patients are going to do," he commented. "Now [oncologists] can look at a metastasis on PET, measure the SUV, and get a handle on what the future of that patient is going to be – is it going to be a rapid slide to death, or is it going to be a very slow, indolent progression maybe over 10 or 15 years. And they can tailor the therapy based on the aggressiveness of the disease."

The PET/CT is usually done to determine whether the patient has metastases, so this additional prognostic information "is a little something extra you get from the test."

Will these new findings be practice changing? "I’ll start looking at SUV values in my patients with newly diagnosed metastasis," said Dr. Kuske. "Yes, it will change my practice."

In the study, Dr. Jhaveri and her coinvestigators reviewed records for women with metastatic breast cancer diagnosed between 2001 and 2008 who had a PET/CT scan performed within 60 days of the detection of metastases; had at least one avid metastasis in bone, liver, lung, or lymph node; and had not received chemotherapy in the month before the scan. Prior or current hormonal therapy was permitted.

The investigators determined the SUV-max for individual metastatic sites. They compared values only within a given site because of known variation across sites such as liver and lung, Dr. Jhaveri explained.

The women had a median age of 58 years. The median time elapsed between primary breast cancer diagnosis and PET/CT was 2.3 years. A fifth each had triple-negative disease and HER2-positive disease.

The median duration of follow-up was 40 months. In a multivariate analysis that included other prognostic factors (grade, tumor phenotype, and visceral metastases), overall survival differed across tertiles of SUV-max for bone metastases (P = .006). Women with values in the middle and top tertiles were 1.87 and 2.67 times more likely to die, respectively, than their counterparts with values in the bottom tertile.

"Given the variation in SUV and the differential impact on survival by site, it is possible that SUV-max may not be the most optimal PET variable," Dr. Jhaveri commented. She proposed that an alternate variable, called total lesion glycolysis (TLG), which incorporates tumor lesion size, might perform better and be more informative.

"Ultimately, prospective studies are required to further delineate the role of PET/CT as a prognostic tool in metastatic breast cancer," she concluded.

Dr. Jhaveri and Dr. Kuske reported having no relevant conflicts of interest.

Young women with early breast cancer need not have a mastectomy instead of a breast-conserving therapy if the rationale is based solely on their age, investigators concluded in a pair of retrospective cohort studies being reported at the ASCO Breast Cancer Symposium.

In the studies, conducted among more than 15,000 women aged 40 years or younger having median follow-up of about 6 years, rates of locoregional recurrence, overall survival, and breast cancer–specific survival were statistically indistinguishable from those who had breast conservation and their counterparts who had mastectomy, according to data presented in a premeeting press briefing.

Collectively, the results suggest that contemporary management of breast cancer has helped to offset the poorer outcomes historically associated with younger age at diagnosis, commented Dr. Andrew D. Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York.

"This is an important revisitation of the conventional wisdom that young women who have breast cancer really need to have mastectomy," he said. "There certainly are differences in the biology of the disease in young women, compared to older women."

He suggested these new findings likely reflect changing influences on breast cancer management, such as use of genetic testing to better identify women with deleterious mutations and possibly breast MRI.

"It’s reassuring to younger women that simply young age alone does not seem to mandate the need for mastectomy, and one needs to look at other variables independent of age," Dr. Seidman said. Those variables will include factors like multicentricity or multifocality, BRCA mutations, family history, and, not least, women’s concerns about recurrence and second cancers.

Additionally, research is identifying biological subtypes of breast cancer that may be useful here, he noted. For example, among women with luminal type A breast cancer, emerging data suggest that Oncotype DX recurrence score may help assess risk of local relapse.

The bottom line, he stressed, is that "if a woman is told, you need to have mastectomy because you are young, the discussion needs to go beyond that," and individualized decision making is essential.

In the first study, Dr. Julliette M. Buckley and her colleagues at Massachusetts General Hospital in Boston reviewed the medical records of 628 women aged 40 years or younger who received a diagnosis of breast cancer up to stage III between 1996 and 2008 and were treated at their institution.

The women had a median age of 37 years. Overall, 71% had breast-conserving therapy, according to Dr. Buckley.

With a median follow-up of 72 months, the women had statistically indistinguishable rates of locoregional recurrence with breast conserving–therapy vs. mastectomy. Rates of locoregional and distant recurrence were 5.6% and 12% at 5 years, respectively, and 13% and 19% at 10 years. Rates of disease-free survival and overall survival were 82.5% and 93% at 5 years, respectively, and 87% and 68.5% at 10 years.

The findings suggest "that lumpectomy is indeed a safe option for young women," concluded Dr. Buckley, a breast surgery fellow.

"We believe that awareness of the genetic risk of breast cancer, advances in the screening for breast cancer, and improvements in systemic and radiation therapy have contributed to the longer overall survival for young women with breast cancer that we have demonstrated in this study," she said. "We feel that these results ... will give young women with breast cancer some reassurance if they choose to have a lumpectomy."

In the second study, investigators led by Dr. Usama Mahmood of the University of Texas M.D. Anderson Cancer Center in Houston analyzed data from the Surveillance, Epidemiology, and End Results database for 14,764 women 20-39 years old who received a diagnosis of early breast cancer between 1990 and 2007. Overall, 45% received breast-conserving therapy. The median duration of follow-up was 5.7 years.

In multivariate analyses that adjusted for potential confounders (including year of diagnosis, age, race/ethnicity, histology, grade, one vs. multiple regions of involvement, tumor size, number of positive lymph nodes, number of examined lymph nodes, estrogen receptor status, and progesterone receptor status), women treated with breast-conserving therapy did not differ significantly from their counterparts treated with mastectomy in terms of either overall survival (hazard ratio, 0.93; P = .16) or breast cancer–specific survival (hazard ratio, 0.93; P = .26).

The findings were similar in an additional analysis of a subset of 4,644 women from the two groups who were matched for patient and tumor characteristics, according to Dr. Mahmood, a fellow in radiation oncology, who did much of her search while at the University of Maryland’s Greenebaum Cancer Center in Baltimore. In this analysis, women treated with breast-conserving therapy and their counterparts treated with mastectomy again had similar 10-year overall survival (83.5% vs. 83.6%, P = .99) and breast cancer–specific survival (85.5% vs. 85.5%, P = .88).

"We found similar survival with either breast-conserving therapy or mastectomy in the treatment of young women with early-stage breast cancer," Dr. Mahmood concluded. "This just serves as a reminder that women should be counseled appropriately regarding their treatment options and should not choose a mastectomy based on an assumption of improved survival."

Dr. Seidman, Dr. Buckley, and Dr. Mahmood reported that they had no relevant conflicts of interest.

Young women with early breast cancer need not have a mastectomy instead of a breast-conserving therapy if the rationale is based solely on their age, investigators concluded in a pair of retrospective cohort studies being reported at the ASCO Breast Cancer Symposium.

In the studies, conducted among more than 15,000 women aged 40 years or younger having median follow-up of about 6 years, rates of locoregional recurrence, overall survival, and breast cancer–specific survival were statistically indistinguishable from those who had breast conservation and their counterparts who had mastectomy, according to data presented in a premeeting press briefing.

Collectively, the results suggest that contemporary management of breast cancer has helped to offset the poorer outcomes historically associated with younger age at diagnosis, commented Dr. Andrew D. Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York.

"This is an important revisitation of the conventional wisdom that young women who have breast cancer really need to have mastectomy," he said. "There certainly are differences in the biology of the disease in young women, compared to older women."

He suggested these new findings likely reflect changing influences on breast cancer management, such as use of genetic testing to better identify women with deleterious mutations and possibly breast MRI.

"It’s reassuring to younger women that simply young age alone does not seem to mandate the need for mastectomy, and one needs to look at other variables independent of age," Dr. Seidman said. Those variables will include factors like multicentricity or multifocality, BRCA mutations, family history, and, not least, women’s concerns about recurrence and second cancers.

Additionally, research is identifying biological subtypes of breast cancer that may be useful here, he noted. For example, among women with luminal type A breast cancer, emerging data suggest that Oncotype DX recurrence score may help assess risk of local relapse.

The bottom line, he stressed, is that "if a woman is told, you need to have mastectomy because you are young, the discussion needs to go beyond that," and individualized decision making is essential.

In the first study, Dr. Julliette M. Buckley and her colleagues at Massachusetts General Hospital in Boston reviewed the medical records of 628 women aged 40 years or younger who received a diagnosis of breast cancer up to stage III between 1996 and 2008 and were treated at their institution.

The women had a median age of 37 years. Overall, 71% had breast-conserving therapy, according to Dr. Buckley.

With a median follow-up of 72 months, the women had statistically indistinguishable rates of locoregional recurrence with breast conserving–therapy vs. mastectomy. Rates of locoregional and distant recurrence were 5.6% and 12% at 5 years, respectively, and 13% and 19% at 10 years. Rates of disease-free survival and overall survival were 82.5% and 93% at 5 years, respectively, and 87% and 68.5% at 10 years.

The findings suggest "that lumpectomy is indeed a safe option for young women," concluded Dr. Buckley, a breast surgery fellow.

"We believe that awareness of the genetic risk of breast cancer, advances in the screening for breast cancer, and improvements in systemic and radiation therapy have contributed to the longer overall survival for young women with breast cancer that we have demonstrated in this study," she said. "We feel that these results ... will give young women with breast cancer some reassurance if they choose to have a lumpectomy."

In the second study, investigators led by Dr. Usama Mahmood of the University of Texas M.D. Anderson Cancer Center in Houston analyzed data from the Surveillance, Epidemiology, and End Results database for 14,764 women 20-39 years old who received a diagnosis of early breast cancer between 1990 and 2007. Overall, 45% received breast-conserving therapy. The median duration of follow-up was 5.7 years.

In multivariate analyses that adjusted for potential confounders (including year of diagnosis, age, race/ethnicity, histology, grade, one vs. multiple regions of involvement, tumor size, number of positive lymph nodes, number of examined lymph nodes, estrogen receptor status, and progesterone receptor status), women treated with breast-conserving therapy did not differ significantly from their counterparts treated with mastectomy in terms of either overall survival (hazard ratio, 0.93; P = .16) or breast cancer–specific survival (hazard ratio, 0.93; P = .26).

The findings were similar in an additional analysis of a subset of 4,644 women from the two groups who were matched for patient and tumor characteristics, according to Dr. Mahmood, a fellow in radiation oncology, who did much of her search while at the University of Maryland’s Greenebaum Cancer Center in Baltimore. In this analysis, women treated with breast-conserving therapy and their counterparts treated with mastectomy again had similar 10-year overall survival (83.5% vs. 83.6%, P = .99) and breast cancer–specific survival (85.5% vs. 85.5%, P = .88).

"We found similar survival with either breast-conserving therapy or mastectomy in the treatment of young women with early-stage breast cancer," Dr. Mahmood concluded. "This just serves as a reminder that women should be counseled appropriately regarding their treatment options and should not choose a mastectomy based on an assumption of improved survival."

Dr. Seidman, Dr. Buckley, and Dr. Mahmood reported that they had no relevant conflicts of interest.

Young women with early breast cancer need not have a mastectomy instead of a breast-conserving therapy if the rationale is based solely on their age, investigators concluded in a pair of retrospective cohort studies being reported at the ASCO Breast Cancer Symposium.

In the studies, conducted among more than 15,000 women aged 40 years or younger having median follow-up of about 6 years, rates of locoregional recurrence, overall survival, and breast cancer–specific survival were statistically indistinguishable from those who had breast conservation and their counterparts who had mastectomy, according to data presented in a premeeting press briefing.

Collectively, the results suggest that contemporary management of breast cancer has helped to offset the poorer outcomes historically associated with younger age at diagnosis, commented Dr. Andrew D. Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York.

"This is an important revisitation of the conventional wisdom that young women who have breast cancer really need to have mastectomy," he said. "There certainly are differences in the biology of the disease in young women, compared to older women."

He suggested these new findings likely reflect changing influences on breast cancer management, such as use of genetic testing to better identify women with deleterious mutations and possibly breast MRI.

"It’s reassuring to younger women that simply young age alone does not seem to mandate the need for mastectomy, and one needs to look at other variables independent of age," Dr. Seidman said. Those variables will include factors like multicentricity or multifocality, BRCA mutations, family history, and, not least, women’s concerns about recurrence and second cancers.

Additionally, research is identifying biological subtypes of breast cancer that may be useful here, he noted. For example, among women with luminal type A breast cancer, emerging data suggest that Oncotype DX recurrence score may help assess risk of local relapse.

The bottom line, he stressed, is that "if a woman is told, you need to have mastectomy because you are young, the discussion needs to go beyond that," and individualized decision making is essential.

In the first study, Dr. Julliette M. Buckley and her colleagues at Massachusetts General Hospital in Boston reviewed the medical records of 628 women aged 40 years or younger who received a diagnosis of breast cancer up to stage III between 1996 and 2008 and were treated at their institution.

The women had a median age of 37 years. Overall, 71% had breast-conserving therapy, according to Dr. Buckley.

With a median follow-up of 72 months, the women had statistically indistinguishable rates of locoregional recurrence with breast conserving–therapy vs. mastectomy. Rates of locoregional and distant recurrence were 5.6% and 12% at 5 years, respectively, and 13% and 19% at 10 years. Rates of disease-free survival and overall survival were 82.5% and 93% at 5 years, respectively, and 87% and 68.5% at 10 years.

The findings suggest "that lumpectomy is indeed a safe option for young women," concluded Dr. Buckley, a breast surgery fellow.

"We believe that awareness of the genetic risk of breast cancer, advances in the screening for breast cancer, and improvements in systemic and radiation therapy have contributed to the longer overall survival for young women with breast cancer that we have demonstrated in this study," she said. "We feel that these results ... will give young women with breast cancer some reassurance if they choose to have a lumpectomy."

In the second study, investigators led by Dr. Usama Mahmood of the University of Texas M.D. Anderson Cancer Center in Houston analyzed data from the Surveillance, Epidemiology, and End Results database for 14,764 women 20-39 years old who received a diagnosis of early breast cancer between 1990 and 2007. Overall, 45% received breast-conserving therapy. The median duration of follow-up was 5.7 years.

In multivariate analyses that adjusted for potential confounders (including year of diagnosis, age, race/ethnicity, histology, grade, one vs. multiple regions of involvement, tumor size, number of positive lymph nodes, number of examined lymph nodes, estrogen receptor status, and progesterone receptor status), women treated with breast-conserving therapy did not differ significantly from their counterparts treated with mastectomy in terms of either overall survival (hazard ratio, 0.93; P = .16) or breast cancer–specific survival (hazard ratio, 0.93; P = .26).

The findings were similar in an additional analysis of a subset of 4,644 women from the two groups who were matched for patient and tumor characteristics, according to Dr. Mahmood, a fellow in radiation oncology, who did much of her search while at the University of Maryland’s Greenebaum Cancer Center in Baltimore. In this analysis, women treated with breast-conserving therapy and their counterparts treated with mastectomy again had similar 10-year overall survival (83.5% vs. 83.6%, P = .99) and breast cancer–specific survival (85.5% vs. 85.5%, P = .88).

"We found similar survival with either breast-conserving therapy or mastectomy in the treatment of young women with early-stage breast cancer," Dr. Mahmood concluded. "This just serves as a reminder that women should be counseled appropriately regarding their treatment options and should not choose a mastectomy based on an assumption of improved survival."

Dr. Seidman, Dr. Buckley, and Dr. Mahmood reported that they had no relevant conflicts of interest.

A new set of nomograms based on easily assessed risk factors accurately predicts a woman’s likelihood of developing lymphedema after axillary lymph node dissection for breast cancer, researchers are reporting at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The nomograms, which enable risk assessment throughout the course of treatment using data available at the time, had accuracy exceeding 70%, according to results presented in a press briefing before the meeting.

"The accuracy is the same as mammography to detect breast cancer. ... So that’s a very good statistical tool," said lead author Dr. Jose Bevilacqua, a surgical oncologist at the Hospital Sirio-Libanês in São Paulo, Brazil.

Being able to identify high-risk patients has several potential applications, he added. They could be monitored more closely and offered interventions that might prevent or reduce the severity of lymphedema, such as use of compression sleeves. "The earlier you detect [it], the better is the outcome," Dr. Bevilacqua said.

Additionally, high-risk patients with a positive sentinel lymph node could be counseled about the risk of further surgery. Thus, "you have physicians who make closer follow-up and [have] a better discussion with the patients."

Finally, the nomograms could be applied in clinical research. "These tools might help [ongoing] or new studies to select high-risk patients in order to avoid exposing the low-risk patients to unproven therapies," he explained.

Dr. Andrew Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York, commended the investigators for a study that "has real practical implications for patients."

"It allows us to identify patients who then can be appropriately triaged for early intervention and perhaps for clinical trials aimed at preventing what many consider inevitable, and that is the development of lymphedema."

The effectiveness of early interventions is controversial, according to Dr. Seidman, who did not report any relevant conflicts of interest. "There are believers and there are nonbelievers," he commented. "What I think this nomogram does is [allow] us in a scientific way to segregate out patients in terms of their risk, and by doing that, we can have more uniform cohorts for which early intervention can be studied more rigorously."

The researchers prospectively followed 1,054 women with unilateral breast cancer who underwent breast-conserving surgery or mastectomy with an axillary lymph node dissection in 2001-2002. Median follow-up was 41 months.

"As far as we know, we have established the largest prospective cohort specifically established to study the incidence and factors associated with lymphedema after axillary node dissection for breast cancer," commented Dr. Bevilacqua.

Using Data to Predict Lymphedema

The women had serial arm volume measurements starting before surgery. To facilitate this process, the researchers created a tool that is now available free online (www.armvolume.com).

They then developed and internally validated three multivariate nomograms (or statistical models) for predicting lymphedema using data available at various time points.

The first model, to be used preoperatively, incorporated age, body mass index, and number of cycles of neoadjuvant chemotherapy infusions in the ipsilateral arm.

The second model, to be used within the first 6 months after surgery, incorporated all the factors from the first plus the extent of axillary dissection, the location of radiation therapy field, and the number of cycles of adjuvant chemotherapy infusions in the ipsilateral arm.

The third model, to be used 6 months or later after surgery, incorporated all the factors from the second, plus the development of postoperative seroma and development of early edema.

Study results showed that within 5 years of axillary lymph node dissection, 30.3% of the women developed lymphedema (defined as a difference in volume of at least 200 mL between arms at 6 months or later after surgery).

All of the risk factors used in the models were significantly associated with the development of lymphedema, Dr. Bevilacqua reported.

"One of the novelties of our study is the [finding] that ipsilateral neoadjuvant chemotherapy infusion is as morbid as adjuvant chemotherapy infusion to increase the risk of lymphedema," he pointed out. "This is somewhat intuitive, but it has never been described, and the great majority of clinical oncologists are not aware of this fact."

For predicting the 5-year risk of lymphedema, the first, second, and third models had accuracy of 70.6%, 72.9%, and 73.6%, respectively. The investigators have converted the models into free, user-friendly calculators that are available online (www.lymphedemarisk.com) during the ASCO Breast Cancer Symposium (Sept. 8-10), but will be taken off line until the manuscript is published, after which they are to become available again.

Dr. Bevilacqua reported that he had no relevant conflicts of interest.

A new set of nomograms based on easily assessed risk factors accurately predicts a woman’s likelihood of developing lymphedema after axillary lymph node dissection for breast cancer, researchers are reporting at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The nomograms, which enable risk assessment throughout the course of treatment using data available at the time, had accuracy exceeding 70%, according to results presented in a press briefing before the meeting.

"The accuracy is the same as mammography to detect breast cancer. ... So that’s a very good statistical tool," said lead author Dr. Jose Bevilacqua, a surgical oncologist at the Hospital Sirio-Libanês in São Paulo, Brazil.

Being able to identify high-risk patients has several potential applications, he added. They could be monitored more closely and offered interventions that might prevent or reduce the severity of lymphedema, such as use of compression sleeves. "The earlier you detect [it], the better is the outcome," Dr. Bevilacqua said.

Additionally, high-risk patients with a positive sentinel lymph node could be counseled about the risk of further surgery. Thus, "you have physicians who make closer follow-up and [have] a better discussion with the patients."

Finally, the nomograms could be applied in clinical research. "These tools might help [ongoing] or new studies to select high-risk patients in order to avoid exposing the low-risk patients to unproven therapies," he explained.

Dr. Andrew Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York, commended the investigators for a study that "has real practical implications for patients."

"It allows us to identify patients who then can be appropriately triaged for early intervention and perhaps for clinical trials aimed at preventing what many consider inevitable, and that is the development of lymphedema."

The effectiveness of early interventions is controversial, according to Dr. Seidman, who did not report any relevant conflicts of interest. "There are believers and there are nonbelievers," he commented. "What I think this nomogram does is [allow] us in a scientific way to segregate out patients in terms of their risk, and by doing that, we can have more uniform cohorts for which early intervention can be studied more rigorously."

The researchers prospectively followed 1,054 women with unilateral breast cancer who underwent breast-conserving surgery or mastectomy with an axillary lymph node dissection in 2001-2002. Median follow-up was 41 months.

"As far as we know, we have established the largest prospective cohort specifically established to study the incidence and factors associated with lymphedema after axillary node dissection for breast cancer," commented Dr. Bevilacqua.

Using Data to Predict Lymphedema

The women had serial arm volume measurements starting before surgery. To facilitate this process, the researchers created a tool that is now available free online (www.armvolume.com).

They then developed and internally validated three multivariate nomograms (or statistical models) for predicting lymphedema using data available at various time points.

The first model, to be used preoperatively, incorporated age, body mass index, and number of cycles of neoadjuvant chemotherapy infusions in the ipsilateral arm.

The second model, to be used within the first 6 months after surgery, incorporated all the factors from the first plus the extent of axillary dissection, the location of radiation therapy field, and the number of cycles of adjuvant chemotherapy infusions in the ipsilateral arm.

The third model, to be used 6 months or later after surgery, incorporated all the factors from the second, plus the development of postoperative seroma and development of early edema.

Study results showed that within 5 years of axillary lymph node dissection, 30.3% of the women developed lymphedema (defined as a difference in volume of at least 200 mL between arms at 6 months or later after surgery).

All of the risk factors used in the models were significantly associated with the development of lymphedema, Dr. Bevilacqua reported.

"One of the novelties of our study is the [finding] that ipsilateral neoadjuvant chemotherapy infusion is as morbid as adjuvant chemotherapy infusion to increase the risk of lymphedema," he pointed out. "This is somewhat intuitive, but it has never been described, and the great majority of clinical oncologists are not aware of this fact."

For predicting the 5-year risk of lymphedema, the first, second, and third models had accuracy of 70.6%, 72.9%, and 73.6%, respectively. The investigators have converted the models into free, user-friendly calculators that are available online (www.lymphedemarisk.com) during the ASCO Breast Cancer Symposium (Sept. 8-10), but will be taken off line until the manuscript is published, after which they are to become available again.

Dr. Bevilacqua reported that he had no relevant conflicts of interest.

A new set of nomograms based on easily assessed risk factors accurately predicts a woman’s likelihood of developing lymphedema after axillary lymph node dissection for breast cancer, researchers are reporting at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The nomograms, which enable risk assessment throughout the course of treatment using data available at the time, had accuracy exceeding 70%, according to results presented in a press briefing before the meeting.

"The accuracy is the same as mammography to detect breast cancer. ... So that’s a very good statistical tool," said lead author Dr. Jose Bevilacqua, a surgical oncologist at the Hospital Sirio-Libanês in São Paulo, Brazil.

Being able to identify high-risk patients has several potential applications, he added. They could be monitored more closely and offered interventions that might prevent or reduce the severity of lymphedema, such as use of compression sleeves. "The earlier you detect [it], the better is the outcome," Dr. Bevilacqua said.

Additionally, high-risk patients with a positive sentinel lymph node could be counseled about the risk of further surgery. Thus, "you have physicians who make closer follow-up and [have] a better discussion with the patients."

Finally, the nomograms could be applied in clinical research. "These tools might help [ongoing] or new studies to select high-risk patients in order to avoid exposing the low-risk patients to unproven therapies," he explained.

Dr. Andrew Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York, commended the investigators for a study that "has real practical implications for patients."

"It allows us to identify patients who then can be appropriately triaged for early intervention and perhaps for clinical trials aimed at preventing what many consider inevitable, and that is the development of lymphedema."

The effectiveness of early interventions is controversial, according to Dr. Seidman, who did not report any relevant conflicts of interest. "There are believers and there are nonbelievers," he commented. "What I think this nomogram does is [allow] us in a scientific way to segregate out patients in terms of their risk, and by doing that, we can have more uniform cohorts for which early intervention can be studied more rigorously."

The researchers prospectively followed 1,054 women with unilateral breast cancer who underwent breast-conserving surgery or mastectomy with an axillary lymph node dissection in 2001-2002. Median follow-up was 41 months.

"As far as we know, we have established the largest prospective cohort specifically established to study the incidence and factors associated with lymphedema after axillary node dissection for breast cancer," commented Dr. Bevilacqua.

Using Data to Predict Lymphedema

The women had serial arm volume measurements starting before surgery. To facilitate this process, the researchers created a tool that is now available free online (www.armvolume.com).

They then developed and internally validated three multivariate nomograms (or statistical models) for predicting lymphedema using data available at various time points.

The first model, to be used preoperatively, incorporated age, body mass index, and number of cycles of neoadjuvant chemotherapy infusions in the ipsilateral arm.

The second model, to be used within the first 6 months after surgery, incorporated all the factors from the first plus the extent of axillary dissection, the location of radiation therapy field, and the number of cycles of adjuvant chemotherapy infusions in the ipsilateral arm.

The third model, to be used 6 months or later after surgery, incorporated all the factors from the second, plus the development of postoperative seroma and development of early edema.

Study results showed that within 5 years of axillary lymph node dissection, 30.3% of the women developed lymphedema (defined as a difference in volume of at least 200 mL between arms at 6 months or later after surgery).

All of the risk factors used in the models were significantly associated with the development of lymphedema, Dr. Bevilacqua reported.

"One of the novelties of our study is the [finding] that ipsilateral neoadjuvant chemotherapy infusion is as morbid as adjuvant chemotherapy infusion to increase the risk of lymphedema," he pointed out. "This is somewhat intuitive, but it has never been described, and the great majority of clinical oncologists are not aware of this fact."

For predicting the 5-year risk of lymphedema, the first, second, and third models had accuracy of 70.6%, 72.9%, and 73.6%, respectively. The investigators have converted the models into free, user-friendly calculators that are available online (www.lymphedemarisk.com) during the ASCO Breast Cancer Symposium (Sept. 8-10), but will be taken off line until the manuscript is published, after which they are to become available again.

Dr. Bevilacqua reported that he had no relevant conflicts of interest.

Many breast cancer patients would have more advanced disease at diagnosis and face harsher treatment if recently updated screening guidelines of the U.S. Preventive Services Task Force were widely adopted, suggests a retrospective cohort study of more than 5,000 women with breast cancer in Michigan.

Study results, being reported this week at a breast cancer symposium sponsored by the American Society of Clinical Oncology, show that nearly a third of the women’s cancers were detected by palpation. The guidelines do not advocate for self-exams at all and question the usefulness of clinical breast exams after age 40.

Additionally, nearly half of the cancers in women younger than 50 years were detected by mammography, while the guidelines now recommend against this practice in the 40- to 49-year age group.

Women with palpation-detected cancers had later-stage disease and were significantly more likely to undergo mastectomy and receive chemotherapy than were those with mammography-detected cancers.

"Annual screening mammograms and evaluation of palpable breast masses are important tools in breast cancer detection," second author Dr. Jamie Caughran said during a premeeting press briefing from the American Society of Clinical Oncology (ASCO).

She declined to say whether the study’s results contradict the U.S. Preventive Services Task Force (USPSTF) guidelines, as the investigators did not have adequate information on the women’s screening history.

But "we take this data to conclude that you’re better off if you can ... have your cancer detected by mammography – that you are more likely to have options and less likely to need aggressive treatment. So ... we would support the rest of the societies that continue to recommend annual screening mammography starting at age 40," she said.

Additionally, this study "highlights the still-significant number of women who present with a palpable mass that shouldn’t be overlooked by physicians even if they have a negative mammogram," pointed out Dr. Caughran, medical director of the Comprehensive Breast Center at the Lacks Cancer Center in Grand Rapids, Mich. "So it just continues to reinforce what we believe is inherently true."

Dr. Andrew Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York City, commented that the appropriate age for starting screening mammography remains controversial.

"A lot of the debate and focus regarding the utility of mammography have been on overall survival and breast cancer–specific survival, and I certainly think that is the most important end point," he said, noting that the study speaks to another important end point – reduced intensity of treatment.

"As a medical oncologist or chemotherapist, I think this is a very important gain, independent of any potential survival benefit," he said. "Having less disfiguring surgery and the ability to deliver less chemotherapy based on the stage at diagnosis are for me a step forward."

This newest study will not quell the debate, according to Dr. Seidman. "Undoubtedly, this area will continue to remain an area of controversy for some," he said. "But certainly, women in this age group would be well served to know about this data."

In the study, Dr. Caughran and her colleagues analyzed data from a statewide breast cancer registry managed by the Michigan Breast Oncology Quality Initiative, identifying 5,628 women who received a diagnosis of stage 0 to III breast cancer between 2006 and 2009. Their average age was 59.4 years.

In the cohort overall, 65.5% of breast cancers were detected by mammography, 29.8% by palpation, and 4.7% by other means.

Fully 90% of the cancers detected by palpation were detected by the patient herself, although "it’s unclear if the patients ... were practicing regular breast self-examination or if these were incidental findings," noted Dr. Caughran.

When analyses were restricted to women younger than 50 years of age, 48.3% of breast cancers were detected by mammography, 46.1% by palpation, and 5.6% by other means.

Palpation-detected cancers were of later stages (P less than .0001) – two-thirds were stage II or higher – and were more often treated with mastectomy (45.8% vs. 27.1%, P less than .0001) and with chemotherapy (22.7% vs. 15.7%, P less than .0001).

Dr. Caughran and Dr. Seidman reported that they had no relevant conflicts of interest.

Many breast cancer patients would have more advanced disease at diagnosis and face harsher treatment if recently updated screening guidelines of the U.S. Preventive Services Task Force were widely adopted, suggests a retrospective cohort study of more than 5,000 women with breast cancer in Michigan.

Study results, being reported this week at a breast cancer symposium sponsored by the American Society of Clinical Oncology, show that nearly a third of the women’s cancers were detected by palpation. The guidelines do not advocate for self-exams at all and question the usefulness of clinical breast exams after age 40.

Additionally, nearly half of the cancers in women younger than 50 years were detected by mammography, while the guidelines now recommend against this practice in the 40- to 49-year age group.

Women with palpation-detected cancers had later-stage disease and were significantly more likely to undergo mastectomy and receive chemotherapy than were those with mammography-detected cancers.

"Annual screening mammograms and evaluation of palpable breast masses are important tools in breast cancer detection," second author Dr. Jamie Caughran said during a premeeting press briefing from the American Society of Clinical Oncology (ASCO).

She declined to say whether the study’s results contradict the U.S. Preventive Services Task Force (USPSTF) guidelines, as the investigators did not have adequate information on the women’s screening history.

But "we take this data to conclude that you’re better off if you can ... have your cancer detected by mammography – that you are more likely to have options and less likely to need aggressive treatment. So ... we would support the rest of the societies that continue to recommend annual screening mammography starting at age 40," she said.

Additionally, this study "highlights the still-significant number of women who present with a palpable mass that shouldn’t be overlooked by physicians even if they have a negative mammogram," pointed out Dr. Caughran, medical director of the Comprehensive Breast Center at the Lacks Cancer Center in Grand Rapids, Mich. "So it just continues to reinforce what we believe is inherently true."

Dr. Andrew Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York City, commented that the appropriate age for starting screening mammography remains controversial.

"A lot of the debate and focus regarding the utility of mammography have been on overall survival and breast cancer–specific survival, and I certainly think that is the most important end point," he said, noting that the study speaks to another important end point – reduced intensity of treatment.

"As a medical oncologist or chemotherapist, I think this is a very important gain, independent of any potential survival benefit," he said. "Having less disfiguring surgery and the ability to deliver less chemotherapy based on the stage at diagnosis are for me a step forward."

This newest study will not quell the debate, according to Dr. Seidman. "Undoubtedly, this area will continue to remain an area of controversy for some," he said. "But certainly, women in this age group would be well served to know about this data."

In the study, Dr. Caughran and her colleagues analyzed data from a statewide breast cancer registry managed by the Michigan Breast Oncology Quality Initiative, identifying 5,628 women who received a diagnosis of stage 0 to III breast cancer between 2006 and 2009. Their average age was 59.4 years.

In the cohort overall, 65.5% of breast cancers were detected by mammography, 29.8% by palpation, and 4.7% by other means.

Fully 90% of the cancers detected by palpation were detected by the patient herself, although "it’s unclear if the patients ... were practicing regular breast self-examination or if these were incidental findings," noted Dr. Caughran.

When analyses were restricted to women younger than 50 years of age, 48.3% of breast cancers were detected by mammography, 46.1% by palpation, and 5.6% by other means.

Palpation-detected cancers were of later stages (P less than .0001) – two-thirds were stage II or higher – and were more often treated with mastectomy (45.8% vs. 27.1%, P less than .0001) and with chemotherapy (22.7% vs. 15.7%, P less than .0001).

Dr. Caughran and Dr. Seidman reported that they had no relevant conflicts of interest.

Many breast cancer patients would have more advanced disease at diagnosis and face harsher treatment if recently updated screening guidelines of the U.S. Preventive Services Task Force were widely adopted, suggests a retrospective cohort study of more than 5,000 women with breast cancer in Michigan.

Study results, being reported this week at a breast cancer symposium sponsored by the American Society of Clinical Oncology, show that nearly a third of the women’s cancers were detected by palpation. The guidelines do not advocate for self-exams at all and question the usefulness of clinical breast exams after age 40.

Additionally, nearly half of the cancers in women younger than 50 years were detected by mammography, while the guidelines now recommend against this practice in the 40- to 49-year age group.

Women with palpation-detected cancers had later-stage disease and were significantly more likely to undergo mastectomy and receive chemotherapy than were those with mammography-detected cancers.

"Annual screening mammograms and evaluation of palpable breast masses are important tools in breast cancer detection," second author Dr. Jamie Caughran said during a premeeting press briefing from the American Society of Clinical Oncology (ASCO).

She declined to say whether the study’s results contradict the U.S. Preventive Services Task Force (USPSTF) guidelines, as the investigators did not have adequate information on the women’s screening history.

But "we take this data to conclude that you’re better off if you can ... have your cancer detected by mammography – that you are more likely to have options and less likely to need aggressive treatment. So ... we would support the rest of the societies that continue to recommend annual screening mammography starting at age 40," she said.

Additionally, this study "highlights the still-significant number of women who present with a palpable mass that shouldn’t be overlooked by physicians even if they have a negative mammogram," pointed out Dr. Caughran, medical director of the Comprehensive Breast Center at the Lacks Cancer Center in Grand Rapids, Mich. "So it just continues to reinforce what we believe is inherently true."

Dr. Andrew Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York City, commented that the appropriate age for starting screening mammography remains controversial.

"A lot of the debate and focus regarding the utility of mammography have been on overall survival and breast cancer–specific survival, and I certainly think that is the most important end point," he said, noting that the study speaks to another important end point – reduced intensity of treatment.

"As a medical oncologist or chemotherapist, I think this is a very important gain, independent of any potential survival benefit," he said. "Having less disfiguring surgery and the ability to deliver less chemotherapy based on the stage at diagnosis are for me a step forward."

This newest study will not quell the debate, according to Dr. Seidman. "Undoubtedly, this area will continue to remain an area of controversy for some," he said. "But certainly, women in this age group would be well served to know about this data."

In the study, Dr. Caughran and her colleagues analyzed data from a statewide breast cancer registry managed by the Michigan Breast Oncology Quality Initiative, identifying 5,628 women who received a diagnosis of stage 0 to III breast cancer between 2006 and 2009. Their average age was 59.4 years.

In the cohort overall, 65.5% of breast cancers were detected by mammography, 29.8% by palpation, and 4.7% by other means.

Fully 90% of the cancers detected by palpation were detected by the patient herself, although "it’s unclear if the patients ... were practicing regular breast self-examination or if these were incidental findings," noted Dr. Caughran.

When analyses were restricted to women younger than 50 years of age, 48.3% of breast cancers were detected by mammography, 46.1% by palpation, and 5.6% by other means.

Palpation-detected cancers were of later stages (P less than .0001) – two-thirds were stage II or higher – and were more often treated with mastectomy (45.8% vs. 27.1%, P less than .0001) and with chemotherapy (22.7% vs. 15.7%, P less than .0001).

Dr. Caughran and Dr. Seidman reported that they had no relevant conflicts of interest.

I enjoyed the review article by Dr. Jeannie Shen (Community Oncology, December 2010), both for her succinct summary of the indications for postmastectomy plastic surgical reconstruction and the optimal timing of the procedure. Her salient presentation contained some of the most contemporary indications for postmastectomy radiotherapy (PMRT).

Along with the points Dr. Shen mentioned as indicators for PMRT— tumor size, regional nodal involvement, presence of lymphovascular space invasion, and patient youth—I would add estrogen receptor-negative disease as another tumor factor to consider for adjuvant radiotherapy. Many series, including some of those referenced by Dr. Shen and the American Society of Clinical Oncology in the composition of its recommendations, have demonstrated that estrogen receptor-negative status represents an independent risk factor for locoregionally recurrent disease after mastectomy and that the risk is significantly reduced by PMRT.^1–7 ...

* For a PDF of the full article, click in the link to the left of this introduction.

I enjoyed the review article by Dr. Jeannie Shen (Community Oncology, December 2010), both for her succinct summary of the indications for postmastectomy plastic surgical reconstruction and the optimal timing of the procedure. Her salient presentation contained some of the most contemporary indications for postmastectomy radiotherapy (PMRT).

Along with the points Dr. Shen mentioned as indicators for PMRT— tumor size, regional nodal involvement, presence of lymphovascular space invasion, and patient youth—I would add estrogen receptor-negative disease as another tumor factor to consider for adjuvant radiotherapy. Many series, including some of those referenced by Dr. Shen and the American Society of Clinical Oncology in the composition of its recommendations, have demonstrated that estrogen receptor-negative status represents an independent risk factor for locoregionally recurrent disease after mastectomy and that the risk is significantly reduced by PMRT.^1–7 ...

* For a PDF of the full article, click in the link to the left of this introduction.

I enjoyed the review article by Dr. Jeannie Shen (Community Oncology, December 2010), both for her succinct summary of the indications for postmastectomy plastic surgical reconstruction and the optimal timing of the procedure. Her salient presentation contained some of the most contemporary indications for postmastectomy radiotherapy (PMRT).

Along with the points Dr. Shen mentioned as indicators for PMRT— tumor size, regional nodal involvement, presence of lymphovascular space invasion, and patient youth—I would add estrogen receptor-negative disease as another tumor factor to consider for adjuvant radiotherapy. Many series, including some of those referenced by Dr. Shen and the American Society of Clinical Oncology in the composition of its recommendations, have demonstrated that estrogen receptor-negative status represents an independent risk factor for locoregionally recurrent disease after mastectomy and that the risk is significantly reduced by PMRT.^1–7 ...

* For a PDF of the full article, click in the link to the left of this introduction.

An independent committee of experts that develops guidance on behalf of the U.K. National Institute for Health and Clinical Excellence does not believe that fulvestrant, which can be used to delay the growth of a particular type of advanced breast cancer, represents a good use of National Health Service resources.

Draft guidance, published Aug. 22 for public comment, does not recommend fulvestrant (known commercially as Faslodex and manufactured by AstraZeneca) as an alternative to aromatase inhibitor therapy in postmenopausal women who have locally advanced or metastatic breast cancer that is estrogen-receptor positive.

In accordance with its marketing authorization, the committee’s provisional recommendation relates to the use of fulvestrant once antiestrogen treatments (such as tamoxifen) are no longer controlling the spread of the cancer. The committee has not been able to consider the clinical and cost effectiveness of fulvestrant when it is used outside of its marketing authorization (for example, after an aromatase inhibitor).

Sir Andrew Dillon, chief executive of NICE, said in a written statement that "while it is important for women with locally advanced or metastatic breast cancer to have a range of options, NICE has to ensure that the NHS provides treatments that bring benefits which are value for money.

"After analysing the evidence comparing fulvestrant’s clinical effectiveness with aromatase inhibitor therapy, our independent committee found that the estimates of overall survival and time to tumour progression were very uncertain. The Committee concluded that it had not been given any conclusive evidence that fulvestrant extends life or delays tumour progression any more than aromatase inhibitor therapy, which is currently used in the NHS."

NICE’s final guidance will determine whether the NHS is legally obliged to allocate funding for fulvestrant as an alternative to aromatase inhibitors for the treatment of locally advanced or metastatic breast cancer after antiestrogen treatment. Until NICE issues final guidance, these decisions should continue to be made locally by NHS bodies.

Those wishing to comment on NICE’s draft recommendations have until Sept. 13 to do so. NICE’s independent committee will then meet again to review the comments received. NICE expects to publish its final guidance for the NHS in January 2012.

An independent committee of experts that develops guidance on behalf of the U.K. National Institute for Health and Clinical Excellence does not believe that fulvestrant, which can be used to delay the growth of a particular type of advanced breast cancer, represents a good use of National Health Service resources.

Draft guidance, published Aug. 22 for public comment, does not recommend fulvestrant (known commercially as Faslodex and manufactured by AstraZeneca) as an alternative to aromatase inhibitor therapy in postmenopausal women who have locally advanced or metastatic breast cancer that is estrogen-receptor positive.

In accordance with its marketing authorization, the committee’s provisional recommendation relates to the use of fulvestrant once antiestrogen treatments (such as tamoxifen) are no longer controlling the spread of the cancer. The committee has not been able to consider the clinical and cost effectiveness of fulvestrant when it is used outside of its marketing authorization (for example, after an aromatase inhibitor).

Sir Andrew Dillon, chief executive of NICE, said in a written statement that "while it is important for women with locally advanced or metastatic breast cancer to have a range of options, NICE has to ensure that the NHS provides treatments that bring benefits which are value for money.

"After analysing the evidence comparing fulvestrant’s clinical effectiveness with aromatase inhibitor therapy, our independent committee found that the estimates of overall survival and time to tumour progression were very uncertain. The Committee concluded that it had not been given any conclusive evidence that fulvestrant extends life or delays tumour progression any more than aromatase inhibitor therapy, which is currently used in the NHS."

NICE’s final guidance will determine whether the NHS is legally obliged to allocate funding for fulvestrant as an alternative to aromatase inhibitors for the treatment of locally advanced or metastatic breast cancer after antiestrogen treatment. Until NICE issues final guidance, these decisions should continue to be made locally by NHS bodies.

Those wishing to comment on NICE’s draft recommendations have until Sept. 13 to do so. NICE’s independent committee will then meet again to review the comments received. NICE expects to publish its final guidance for the NHS in January 2012.

An independent committee of experts that develops guidance on behalf of the U.K. National Institute for Health and Clinical Excellence does not believe that fulvestrant, which can be used to delay the growth of a particular type of advanced breast cancer, represents a good use of National Health Service resources.

Draft guidance, published Aug. 22 for public comment, does not recommend fulvestrant (known commercially as Faslodex and manufactured by AstraZeneca) as an alternative to aromatase inhibitor therapy in postmenopausal women who have locally advanced or metastatic breast cancer that is estrogen-receptor positive.

In accordance with its marketing authorization, the committee’s provisional recommendation relates to the use of fulvestrant once antiestrogen treatments (such as tamoxifen) are no longer controlling the spread of the cancer. The committee has not been able to consider the clinical and cost effectiveness of fulvestrant when it is used outside of its marketing authorization (for example, after an aromatase inhibitor).

Sir Andrew Dillon, chief executive of NICE, said in a written statement that "while it is important for women with locally advanced or metastatic breast cancer to have a range of options, NICE has to ensure that the NHS provides treatments that bring benefits which are value for money.

"After analysing the evidence comparing fulvestrant’s clinical effectiveness with aromatase inhibitor therapy, our independent committee found that the estimates of overall survival and time to tumour progression were very uncertain. The Committee concluded that it had not been given any conclusive evidence that fulvestrant extends life or delays tumour progression any more than aromatase inhibitor therapy, which is currently used in the NHS."

NICE’s final guidance will determine whether the NHS is legally obliged to allocate funding for fulvestrant as an alternative to aromatase inhibitors for the treatment of locally advanced or metastatic breast cancer after antiestrogen treatment. Until NICE issues final guidance, these decisions should continue to be made locally by NHS bodies.

Those wishing to comment on NICE’s draft recommendations have until Sept. 13 to do so. NICE’s independent committee will then meet again to review the comments received. NICE expects to publish its final guidance for the NHS in January 2012.

To treat or not to treat? When it comes to deciding whether adjuvant chemotherapy is the appropriate management choice for patients with HER2 positive, node-negative breast cancer less than 1 cm in size, the only sure thing is that there is no sure thing, and seemingly conflicting research data exacerbates the uncertainty.

A recent study demonstrated that patients who did not receive adjuvant chemotherapy or trastuzumab for node-negative, non-metastasized HER2 positive T1a (less than or equal to 0.1 cm to 0.5 cm) or T1b (greater than 0.5 cm to 1.0 cm) tumors were at greater risk for worse recurrence-free survival and worse distant recurrence-free survival than patients with hormone-receptor–positive disease.

This was especially true for those younger than age 35 years – and also was the case in similarly staged patients with triple-negative breast cancer, according to the report from the University of Texas M.D. Anderson Cancer Center in Houston.

The authors concluded that planning systemic treatment based on disease stage alone "appears to lead to worse outcomes," and that individualized treatment plans may be better informed by taking into account aggressive biological subtypes of small, node-negative breast cancers, as well as age at diagnosis (Clin. Breast Cancer. 2011 July 15 [doi: 10.1016/j.clbc.2011.05.002]).

While the findings of this retrospective, single-institution study validate the large body of evidence suggesting that younger patients with aggressive tumor subtypes have worse outcomes when not treated with adjuvant chemotherapy or trastuzumab (Herceptin), the authors do not recommend universal treatment of this patient population.

Rather, the results provide a strong argument for the inclusion of women with small tumors that have biologically aggressive traits in prospective clinical trials "to evaluate the extent of therapeutic benefits," they wrote. Further, patient age and disease subtype "should be considered when counseling patients about treatment interventions."

No Treatment Not Worse for Some

With the absolute benefits of treatment yet to be determined, investigators also are looking closely at the risks associated with skipping adjuvant treatment.

The findings of an observational cohort study presented at the annual meeting of the American Society of Clinical Oncology (ASCO) suggest that women with early HER2 positive T1aN0M0 breast cancers can safely do so because of the low distant recurrence rate observed in this patient subgroup. A higher rate was observed in those with T1bN0M0, indicating that adjuvant systemic therapy may be more relevant in this patient population.

The study assessed outcomes among 237 women with HER2-positive T1a (116 patients) or T1b (121 patients) tumors diagnosed between 2000 and 2006, all of whom had negative nodes and no metastases. Most did not receive adjuvant chemotherapy or trastuzumab.

With a median duration of follow-up of 5.8 years, the rate of distant recurrence was 0.9% among patients with T1a tumors versus 5.8% among those with T1b, lead investigator Dr. Louis Fehrenbacher, an oncologist with Kaiser Permanente in Vallejo, Calif., reported in a poster presentation, analyzing data from the tumor registry of the Kaiser Permanente Clinical Care Program of Northern California.

The investigators chose distant recurrence-free survival as the main outcome measure, rather than the more commonly used disease-free survival rate, because they "did not want to include non-breast malignancies, contralateral malignancies, or deaths from any other cause," Dr. Fehrenbacher said. "That isn’t the real important factor in deciding to give intensive chemotherapy to these patients," he explained.

By tumor size, the rate of distant recurrence ranged from 0% to 5.8% for tumors measuring 0.1 cm to 0.9 cm, but it was 10.7% for the tumors measuring 1.0 cm. In other words, Dr. Fehrenbacher said, "the 1.0-cm tumors carried the burden of the distant recurrence risk."

Results for the actuarial distant recurrence-free interval showed a 5-year rate of 96.5% for the patients as a whole, with 99.1% and 94.0% in the T1a and T1b groups, respectively.

Overall, 25% of the study patients received chemotherapy and 8% received trastuzumab. "Most of these patients had only a smattering of chemotherapy or trastuzumab, and it didn't seem to affect outcome," Dr. Fehrenbacher commented, but he acknowledged that there may have been bias influencing who received chemotherapy. While 59% of the patients had tumors that were positive for estrogen receptors, there was little difference in recurrence rate according to estrogen receptor status, he said.

"The take-home message is, I think, the T1a’s have too low of a risk of distant invasive recurrence to justify chemotherapy or trastuzumab," Dr. Fehrenbacher said in an interview. "We need to specifically individualize the risk of the patient based on the size of their primary [tumor], because the T1a’s and T1b’s are quite different in our findings."

Dr. Lajos Pusztai, a professor in the department of breast medical oncology at M.D. Anderson, agrees with Dr. Fehrenbacher’s conclusion. "I think the findings are correct, as several other studies have also indicated a very low risk of recurrence for very small HER2-positive cancers," he said in an interview.

"It may also be important to remember that HER2 has not been considered by the ASCO biomarker review panels [to be] an important prognostic marker, but rather a predictive marker for trastuzumab therapy."

Review Warns of Cardiotoxicity

In a recent review article looking into whether the existing data supports a definitive treatment threshold for patients with T1aN0M0 or T1bN0M0 HER2-positive breast cancer, Dr. Pusztai, along with lead author Dr. Catherine M. Kelly of Waterford Regional Hospital in Waterford, Ireland and colleagues, wrote that "a blanket recommendation to treat all small HER2 positive breast cancer with trastuzumab-based therapy will almost certainly lead to clinically significant cardiotoxicity in some without any benefit in breast cancer recurrence."

Similarly, they noted, "withholding this form of adjuvant therapy from all small HER2 positive cancers will result in some otherwise avoidable breast cancer recurrence. Unfortunately, today we do not have accurate tools to identify precisely the subset of patients for whom the risks of trastuzumab outweigh the benefits."

Lacking such tools, shared medical decision making based on estimates achieved using established risk calculators and discussion of the risks with patients should be the order of the day, they said, with the decision depending upon the patients’ perspective and risk tolerance level. If trastuzumab-based treatment is an option, the authors stressed that regimens with the lowest risk of cardiotoxicity should be pursued (Ann. Oncol. 2011 Mar. 15 [doi:10.1093/annonc/mdq786]).

In the absence of randomized controlled trials to establish or refute the benefit from adjuvant trastuzumab in this patient subset, the authors called for the development of molecular predictors of prognosis within HER2 positive disease to further optimize risk/benefit estimates. The development of better prediction tools for more precise estimations of the risk of death from comorbid illnesses and the risk of cardiac death, in particular, are important, they said.

Level 1 Evidence Lacking

The lack of level 1 evidence from large, prospective trials contributes to the overall uncertainty surrounding the role of adjuvant chemotherapy in early HER2 breast cancer, according to Dr. Gabriel Hortobágyi, professor and chair of the department of Breast Medical Oncology at M.D. Anderson.

Studies examining the prognostic value of HER2 are limited by their reliance on retrospective database analyses and small cohort sized, Dr. Hortobágyi said in an interview. "I think it is critically important to perform a couple of larger trials with prospective collection of patients, HER2 checked centrally in a high-volume lab, and long enough follow-up to determine the real outcomes of these patients."

In this regard, the Southwest Oncology Group’s breast committee, chaired by Dr. Hortobágyi, is trying to activate a clinical trial for HER2 positive T1a and T1b patients comparing trastuzumab alone and in combination with lapatinib "to determine whether treatment with targeted chemotherapy would be effective enough for these patients." Additionally, he said investigators at Dana Farber Cancer Institute are completing recruitment to a single-arm trial for patients with small, HER2 positive breast cancer treated uniformly with paclitaxel and trastuzumab.

"Both trials will give us prospective data and should contribute significantly to our assessment of the real prognosis of this group of patients," he said.

In the meantime, Dr. Hortobágyi said that his group, and many others, "considers that risk of recurrence exceeding about 10% deserves adjuvant chemotherapy, and in the HER2 positive group we believe the risk exceeds, by far, that level. Therefore, we discuss trastuzumab and chemotherapy with all patients without significant comorbid conditions if they have any size-invasive, HER2 positive breast cancer."

The uncertainty regarding the role of adjuvant chemotherapy in early HER2 breast cancer touches on a "fascinating aspect of medicine: how to deal with and communicate uncertainty in diagnosis and treatment benefit," observed Dr. Pusztai.

"Medicine is a very imprecise science and the handling of imprecision is what makes it, as some would call it, an art," he said. "I suspect that what patients perceive as a ‘good’ vs. ‘not so good’ doctor often comes down to how efficiently one can make decisions under uncertainty of information and how effectively one communicates this uncertainty and the decision that is based on it."

Dr. Fehrenbacher, Dr. Pusztai, and Dr. Hortobágyi reported no relevant conflicts of interest with respect to the information presented.

Susan London contributed to this report.

To treat or not to treat? When it comes to deciding whether adjuvant chemotherapy is the appropriate management choice for patients with HER2 positive, node-negative breast cancer less than 1 cm in size, the only sure thing is that there is no sure thing, and seemingly conflicting research data exacerbates the uncertainty.

A recent study demonstrated that patients who did not receive adjuvant chemotherapy or trastuzumab for node-negative, non-metastasized HER2 positive T1a (less than or equal to 0.1 cm to 0.5 cm) or T1b (greater than 0.5 cm to 1.0 cm) tumors were at greater risk for worse recurrence-free survival and worse distant recurrence-free survival than patients with hormone-receptor–positive disease.

This was especially true for those younger than age 35 years – and also was the case in similarly staged patients with triple-negative breast cancer, according to the report from the University of Texas M.D. Anderson Cancer Center in Houston.

The authors concluded that planning systemic treatment based on disease stage alone "appears to lead to worse outcomes," and that individualized treatment plans may be better informed by taking into account aggressive biological subtypes of small, node-negative breast cancers, as well as age at diagnosis (Clin. Breast Cancer. 2011 July 15 [doi: 10.1016/j.clbc.2011.05.002]).

While the findings of this retrospective, single-institution study validate the large body of evidence suggesting that younger patients with aggressive tumor subtypes have worse outcomes when not treated with adjuvant chemotherapy or trastuzumab (Herceptin), the authors do not recommend universal treatment of this patient population.

Rather, the results provide a strong argument for the inclusion of women with small tumors that have biologically aggressive traits in prospective clinical trials "to evaluate the extent of therapeutic benefits," they wrote. Further, patient age and disease subtype "should be considered when counseling patients about treatment interventions."

No Treatment Not Worse for Some

With the absolute benefits of treatment yet to be determined, investigators also are looking closely at the risks associated with skipping adjuvant treatment.

The findings of an observational cohort study presented at the annual meeting of the American Society of Clinical Oncology (ASCO) suggest that women with early HER2 positive T1aN0M0 breast cancers can safely do so because of the low distant recurrence rate observed in this patient subgroup. A higher rate was observed in those with T1bN0M0, indicating that adjuvant systemic therapy may be more relevant in this patient population.

The study assessed outcomes among 237 women with HER2-positive T1a (116 patients) or T1b (121 patients) tumors diagnosed between 2000 and 2006, all of whom had negative nodes and no metastases. Most did not receive adjuvant chemotherapy or trastuzumab.

With a median duration of follow-up of 5.8 years, the rate of distant recurrence was 0.9% among patients with T1a tumors versus 5.8% among those with T1b, lead investigator Dr. Louis Fehrenbacher, an oncologist with Kaiser Permanente in Vallejo, Calif., reported in a poster presentation, analyzing data from the tumor registry of the Kaiser Permanente Clinical Care Program of Northern California.

The investigators chose distant recurrence-free survival as the main outcome measure, rather than the more commonly used disease-free survival rate, because they "did not want to include non-breast malignancies, contralateral malignancies, or deaths from any other cause," Dr. Fehrenbacher said. "That isn’t the real important factor in deciding to give intensive chemotherapy to these patients," he explained.

By tumor size, the rate of distant recurrence ranged from 0% to 5.8% for tumors measuring 0.1 cm to 0.9 cm, but it was 10.7% for the tumors measuring 1.0 cm. In other words, Dr. Fehrenbacher said, "the 1.0-cm tumors carried the burden of the distant recurrence risk."

Results for the actuarial distant recurrence-free interval showed a 5-year rate of 96.5% for the patients as a whole, with 99.1% and 94.0% in the T1a and T1b groups, respectively.

Overall, 25% of the study patients received chemotherapy and 8% received trastuzumab. "Most of these patients had only a smattering of chemotherapy or trastuzumab, and it didn't seem to affect outcome," Dr. Fehrenbacher commented, but he acknowledged that there may have been bias influencing who received chemotherapy. While 59% of the patients had tumors that were positive for estrogen receptors, there was little difference in recurrence rate according to estrogen receptor status, he said.

"The take-home message is, I think, the T1a’s have too low of a risk of distant invasive recurrence to justify chemotherapy or trastuzumab," Dr. Fehrenbacher said in an interview. "We need to specifically individualize the risk of the patient based on the size of their primary [tumor], because the T1a’s and T1b’s are quite different in our findings."

Dr. Lajos Pusztai, a professor in the department of breast medical oncology at M.D. Anderson, agrees with Dr. Fehrenbacher’s conclusion. "I think the findings are correct, as several other studies have also indicated a very low risk of recurrence for very small HER2-positive cancers," he said in an interview.

"It may also be important to remember that HER2 has not been considered by the ASCO biomarker review panels [to be] an important prognostic marker, but rather a predictive marker for trastuzumab therapy."

Review Warns of Cardiotoxicity

In a recent review article looking into whether the existing data supports a definitive treatment threshold for patients with T1aN0M0 or T1bN0M0 HER2-positive breast cancer, Dr. Pusztai, along with lead author Dr. Catherine M. Kelly of Waterford Regional Hospital in Waterford, Ireland and colleagues, wrote that "a blanket recommendation to treat all small HER2 positive breast cancer with trastuzumab-based therapy will almost certainly lead to clinically significant cardiotoxicity in some without any benefit in breast cancer recurrence."

Similarly, they noted, "withholding this form of adjuvant therapy from all small HER2 positive cancers will result in some otherwise avoidable breast cancer recurrence. Unfortunately, today we do not have accurate tools to identify precisely the subset of patients for whom the risks of trastuzumab outweigh the benefits."

Lacking such tools, shared medical decision making based on estimates achieved using established risk calculators and discussion of the risks with patients should be the order of the day, they said, with the decision depending upon the patients’ perspective and risk tolerance level. If trastuzumab-based treatment is an option, the authors stressed that regimens with the lowest risk of cardiotoxicity should be pursued (Ann. Oncol. 2011 Mar. 15 [doi:10.1093/annonc/mdq786]).

In the absence of randomized controlled trials to establish or refute the benefit from adjuvant trastuzumab in this patient subset, the authors called for the development of molecular predictors of prognosis within HER2 positive disease to further optimize risk/benefit estimates. The development of better prediction tools for more precise estimations of the risk of death from comorbid illnesses and the risk of cardiac death, in particular, are important, they said.

Level 1 Evidence Lacking

The lack of level 1 evidence from large, prospective trials contributes to the overall uncertainty surrounding the role of adjuvant chemotherapy in early HER2 breast cancer, according to Dr. Gabriel Hortobágyi, professor and chair of the department of Breast Medical Oncology at M.D. Anderson.

Studies examining the prognostic value of HER2 are limited by their reliance on retrospective database analyses and small cohort sized, Dr. Hortobágyi said in an interview. "I think it is critically important to perform a couple of larger trials with prospective collection of patients, HER2 checked centrally in a high-volume lab, and long enough follow-up to determine the real outcomes of these patients."

In this regard, the Southwest Oncology Group’s breast committee, chaired by Dr. Hortobágyi, is trying to activate a clinical trial for HER2 positive T1a and T1b patients comparing trastuzumab alone and in combination with lapatinib "to determine whether treatment with targeted chemotherapy would be effective enough for these patients." Additionally, he said investigators at Dana Farber Cancer Institute are completing recruitment to a single-arm trial for patients with small, HER2 positive breast cancer treated uniformly with paclitaxel and trastuzumab.

"Both trials will give us prospective data and should contribute significantly to our assessment of the real prognosis of this group of patients," he said.

In the meantime, Dr. Hortobágyi said that his group, and many others, "considers that risk of recurrence exceeding about 10% deserves adjuvant chemotherapy, and in the HER2 positive group we believe the risk exceeds, by far, that level. Therefore, we discuss trastuzumab and chemotherapy with all patients without significant comorbid conditions if they have any size-invasive, HER2 positive breast cancer."

The uncertainty regarding the role of adjuvant chemotherapy in early HER2 breast cancer touches on a "fascinating aspect of medicine: how to deal with and communicate uncertainty in diagnosis and treatment benefit," observed Dr. Pusztai.

"Medicine is a very imprecise science and the handling of imprecision is what makes it, as some would call it, an art," he said. "I suspect that what patients perceive as a ‘good’ vs. ‘not so good’ doctor often comes down to how efficiently one can make decisions under uncertainty of information and how effectively one communicates this uncertainty and the decision that is based on it."

Dr. Fehrenbacher, Dr. Pusztai, and Dr. Hortobágyi reported no relevant conflicts of interest with respect to the information presented.

Susan London contributed to this report.

To treat or not to treat? When it comes to deciding whether adjuvant chemotherapy is the appropriate management choice for patients with HER2 positive, node-negative breast cancer less than 1 cm in size, the only sure thing is that there is no sure thing, and seemingly conflicting research data exacerbates the uncertainty.

A recent study demonstrated that patients who did not receive adjuvant chemotherapy or trastuzumab for node-negative, non-metastasized HER2 positive T1a (less than or equal to 0.1 cm to 0.5 cm) or T1b (greater than 0.5 cm to 1.0 cm) tumors were at greater risk for worse recurrence-free survival and worse distant recurrence-free survival than patients with hormone-receptor–positive disease.

This was especially true for those younger than age 35 years – and also was the case in similarly staged patients with triple-negative breast cancer, according to the report from the University of Texas M.D. Anderson Cancer Center in Houston.

The authors concluded that planning systemic treatment based on disease stage alone "appears to lead to worse outcomes," and that individualized treatment plans may be better informed by taking into account aggressive biological subtypes of small, node-negative breast cancers, as well as age at diagnosis (Clin. Breast Cancer. 2011 July 15 [doi: 10.1016/j.clbc.2011.05.002]).

While the findings of this retrospective, single-institution study validate the large body of evidence suggesting that younger patients with aggressive tumor subtypes have worse outcomes when not treated with adjuvant chemotherapy or trastuzumab (Herceptin), the authors do not recommend universal treatment of this patient population.

Rather, the results provide a strong argument for the inclusion of women with small tumors that have biologically aggressive traits in prospective clinical trials "to evaluate the extent of therapeutic benefits," they wrote. Further, patient age and disease subtype "should be considered when counseling patients about treatment interventions."

No Treatment Not Worse for Some

With the absolute benefits of treatment yet to be determined, investigators also are looking closely at the risks associated with skipping adjuvant treatment.

The findings of an observational cohort study presented at the annual meeting of the American Society of Clinical Oncology (ASCO) suggest that women with early HER2 positive T1aN0M0 breast cancers can safely do so because of the low distant recurrence rate observed in this patient subgroup. A higher rate was observed in those with T1bN0M0, indicating that adjuvant systemic therapy may be more relevant in this patient population.

The study assessed outcomes among 237 women with HER2-positive T1a (116 patients) or T1b (121 patients) tumors diagnosed between 2000 and 2006, all of whom had negative nodes and no metastases. Most did not receive adjuvant chemotherapy or trastuzumab.

With a median duration of follow-up of 5.8 years, the rate of distant recurrence was 0.9% among patients with T1a tumors versus 5.8% among those with T1b, lead investigator Dr. Louis Fehrenbacher, an oncologist with Kaiser Permanente in Vallejo, Calif., reported in a poster presentation, analyzing data from the tumor registry of the Kaiser Permanente Clinical Care Program of Northern California.

The investigators chose distant recurrence-free survival as the main outcome measure, rather than the more commonly used disease-free survival rate, because they "did not want to include non-breast malignancies, contralateral malignancies, or deaths from any other cause," Dr. Fehrenbacher said. "That isn’t the real important factor in deciding to give intensive chemotherapy to these patients," he explained.

By tumor size, the rate of distant recurrence ranged from 0% to 5.8% for tumors measuring 0.1 cm to 0.9 cm, but it was 10.7% for the tumors measuring 1.0 cm. In other words, Dr. Fehrenbacher said, "the 1.0-cm tumors carried the burden of the distant recurrence risk."

Results for the actuarial distant recurrence-free interval showed a 5-year rate of 96.5% for the patients as a whole, with 99.1% and 94.0% in the T1a and T1b groups, respectively.

Overall, 25% of the study patients received chemotherapy and 8% received trastuzumab. "Most of these patients had only a smattering of chemotherapy or trastuzumab, and it didn't seem to affect outcome," Dr. Fehrenbacher commented, but he acknowledged that there may have been bias influencing who received chemotherapy. While 59% of the patients had tumors that were positive for estrogen receptors, there was little difference in recurrence rate according to estrogen receptor status, he said.

"The take-home message is, I think, the T1a’s have too low of a risk of distant invasive recurrence to justify chemotherapy or trastuzumab," Dr. Fehrenbacher said in an interview. "We need to specifically individualize the risk of the patient based on the size of their primary [tumor], because the T1a’s and T1b’s are quite different in our findings."

Dr. Lajos Pusztai, a professor in the department of breast medical oncology at M.D. Anderson, agrees with Dr. Fehrenbacher’s conclusion. "I think the findings are correct, as several other studies have also indicated a very low risk of recurrence for very small HER2-positive cancers," he said in an interview.

"It may also be important to remember that HER2 has not been considered by the ASCO biomarker review panels [to be] an important prognostic marker, but rather a predictive marker for trastuzumab therapy."

Review Warns of Cardiotoxicity

In a recent review article looking into whether the existing data supports a definitive treatment threshold for patients with T1aN0M0 or T1bN0M0 HER2-positive breast cancer, Dr. Pusztai, along with lead author Dr. Catherine M. Kelly of Waterford Regional Hospital in Waterford, Ireland and colleagues, wrote that "a blanket recommendation to treat all small HER2 positive breast cancer with trastuzumab-based therapy will almost certainly lead to clinically significant cardiotoxicity in some without any benefit in breast cancer recurrence."

Similarly, they noted, "withholding this form of adjuvant therapy from all small HER2 positive cancers will result in some otherwise avoidable breast cancer recurrence. Unfortunately, today we do not have accurate tools to identify precisely the subset of patients for whom the risks of trastuzumab outweigh the benefits."

Lacking such tools, shared medical decision making based on estimates achieved using established risk calculators and discussion of the risks with patients should be the order of the day, they said, with the decision depending upon the patients’ perspective and risk tolerance level. If trastuzumab-based treatment is an option, the authors stressed that regimens with the lowest risk of cardiotoxicity should be pursued (Ann. Oncol. 2011 Mar. 15 [doi:10.1093/annonc/mdq786]).

In the absence of randomized controlled trials to establish or refute the benefit from adjuvant trastuzumab in this patient subset, the authors called for the development of molecular predictors of prognosis within HER2 positive disease to further optimize risk/benefit estimates. The development of better prediction tools for more precise estimations of the risk of death from comorbid illnesses and the risk of cardiac death, in particular, are important, they said.

Level 1 Evidence Lacking

The lack of level 1 evidence from large, prospective trials contributes to the overall uncertainty surrounding the role of adjuvant chemotherapy in early HER2 breast cancer, according to Dr. Gabriel Hortobágyi, professor and chair of the department of Breast Medical Oncology at M.D. Anderson.

Studies examining the prognostic value of HER2 are limited by their reliance on retrospective database analyses and small cohort sized, Dr. Hortobágyi said in an interview. "I think it is critically important to perform a couple of larger trials with prospective collection of patients, HER2 checked centrally in a high-volume lab, and long enough follow-up to determine the real outcomes of these patients."

In this regard, the Southwest Oncology Group’s breast committee, chaired by Dr. Hortobágyi, is trying to activate a clinical trial for HER2 positive T1a and T1b patients comparing trastuzumab alone and in combination with lapatinib "to determine whether treatment with targeted chemotherapy would be effective enough for these patients." Additionally, he said investigators at Dana Farber Cancer Institute are completing recruitment to a single-arm trial for patients with small, HER2 positive breast cancer treated uniformly with paclitaxel and trastuzumab.

"Both trials will give us prospective data and should contribute significantly to our assessment of the real prognosis of this group of patients," he said.

In the meantime, Dr. Hortobágyi said that his group, and many others, "considers that risk of recurrence exceeding about 10% deserves adjuvant chemotherapy, and in the HER2 positive group we believe the risk exceeds, by far, that level. Therefore, we discuss trastuzumab and chemotherapy with all patients without significant comorbid conditions if they have any size-invasive, HER2 positive breast cancer."

The uncertainty regarding the role of adjuvant chemotherapy in early HER2 breast cancer touches on a "fascinating aspect of medicine: how to deal with and communicate uncertainty in diagnosis and treatment benefit," observed Dr. Pusztai.

"Medicine is a very imprecise science and the handling of imprecision is what makes it, as some would call it, an art," he said. "I suspect that what patients perceive as a ‘good’ vs. ‘not so good’ doctor often comes down to how efficiently one can make decisions under uncertainty of information and how effectively one communicates this uncertainty and the decision that is based on it."

Dr. Fehrenbacher, Dr. Pusztai, and Dr. Hortobágyi reported no relevant conflicts of interest with respect to the information presented.

Susan London contributed to this report.