Breast Cancer

SAN ANTONIO – Bevacizumab improved progression-free survival when added to standard treatment in a study of more than 400 women with HER2-positive locally recurrent or metastatic breast cancer.

That finding, which emerged from the AVEREL trial, adds another wrinkle in the ongoing controversy regarding use of bevacizumab (Avastin) in breast cancer treatment.

For the primary end point of investigator-assessed progression-free survival (PFS), conducted at a median follow-up of 26 months, the addition of bevacizumab resulted in a hazard ratio of 0.82 (P = .0775), compared with treatment with trastuzumab and docetaxel alone. This difference was not statistically significant. Median investigator-assessed PFS was 16.5 months with bevacizumab, compared with 13.7 months without it.

In an assessment by an independent review committee (IRC), however, a significant improvement in PFS was seen with the addition of bevacizumab (hazard ratio, 0.72; P = .0162). Median IRC-assessed PFS was 16.8 months with bevacizumab, compared with 13.9 months without it.

Lead investigator Dr. Luca Gianni reported the results at the San Antonio Breast Cancer Symposium. AVEREL is a randomized, placebo-controlled phase III trial designed to evaluate bevacizumab combined with trastuzumab (Herceptin) and docetaxel (Taxotere) as first-line therapy for HER2-positive, locally recurrent or metastatic breast cancer.

The findings add more data to support the effectiveness of the drug in particular subpopulations of patients with metastatic breast cancer.

In November 2011, the Food and Drug Administration announced it was revoking its approval of the metastatic breast cancer indication for bevacizumab after concluding the drug had not been shown safe and effective for that use.

Many in the breast cancer community consider the agency’s decision unwarranted. "Bevacizumab improves the response rate – about doubles it – which for my symptomatic patients is a clear benefit," said press conference moderator Dr. Lisa Carey, professor in the department of medicine at the University of North Carolina at Chapel Hill. "It improves the progression-free survival to a greater or lesser degree in every trial that it’s ever been studied."

She conceded that "it doesn’t do anything to overall survival." The FDA cited the lack of improvement in overall survival for metastatic breast cancer patients in its decision. Dr. Gianni noted, however, that "Survival is a very important end point, but it’s not the only end point in metastatic breast cancer."

Dr. Carey agreed. "I would love to have the availability of the drug routinely for my symptomatic patients, in whom I would like to have more than one agent given – particularly one that’s well-tolerated as [bevacizumab] is."

Patients were eligible for the AVEREL trial if they had measurable or evaluable HER2-positive locally recurrent or metastatic breast cancer with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. They could not have received prior chemotherapy for advanced disease. Patients with central nervous system metastases were excluded.

The researchers enrolled 424 women with previously untreated disease. The women were randomized to receive either trastuzumab plus docetaxel (n = 208) or the same regimen plus bevacizumab (n = 216). Intravenous trastuzumab was given with an 8-mg/kg loading dose that was followed by a dosage of 6 mg/kg given every 3 weeks. Docetaxel was given intravenously at a dosage of 100 mg/m² given every 3 weeks. Bevacizumab was given intravenously at a dosage of 15 mg/kg every 3 weeks.

Trastuzumab and bevacizumab were given until disease progression. Docetaxel was given for a planned minimum of six cycles or until progression or unacceptable toxicity occurred. The primary end point was investigator-assessed PFS. Secondary end points included overall survival (OS), overall response rate, duration of response, time to treatment failure, safety (including adverse events of special interest for bevacizumab), and quality of life. Exploratory analyses included PFS evaluated by an IRC (to comply with FDA recommendations) and biomarker assessment.

In terms of safety, "There were no new safety signals observed in this patient population with respect to what we really know from other patient populations exposed to Avastin," said Dr. Gianni, director of medical oncology at the San Raffaele Cancer Center in Milano, Italy.

The researchers also conducted an exploratory analyses of plasma vascular endothelial growth factor-alpha (VEGF-A). Their results suggest a potentially predictive effect – greater benefit with high VEGF-A levels – that are consistent with observations in HER2-negative locally recurrent or metastatic breast cancer.

The AVEREL trial was sponsored by Hoffman-La Roche. Dr. Gianni has disclosed that he is a consultant to Roche, Genentech, GSK, Wyeth, Novartis, Eisai, Pfizer, Millennium Takeda, Sanofi Aventis, Boehringer Ingelheim, Biogen Idec, AstraZeneca, Genomic Health, and Celgene. Dr. Carey reported that she has no relevant financial relationships to disclose.

*Correction, 12/9/11: An earlier version of this article incorrectly noted in the headline that Avastin improves breast cancer survival.

SAN ANTONIO – Bevacizumab improved progression-free survival when added to standard treatment in a study of more than 400 women with HER2-positive locally recurrent or metastatic breast cancer.

That finding, which emerged from the AVEREL trial, adds another wrinkle in the ongoing controversy regarding use of bevacizumab (Avastin) in breast cancer treatment.

For the primary end point of investigator-assessed progression-free survival (PFS), conducted at a median follow-up of 26 months, the addition of bevacizumab resulted in a hazard ratio of 0.82 (P = .0775), compared with treatment with trastuzumab and docetaxel alone. This difference was not statistically significant. Median investigator-assessed PFS was 16.5 months with bevacizumab, compared with 13.7 months without it.

In an assessment by an independent review committee (IRC), however, a significant improvement in PFS was seen with the addition of bevacizumab (hazard ratio, 0.72; P = .0162). Median IRC-assessed PFS was 16.8 months with bevacizumab, compared with 13.9 months without it.

Lead investigator Dr. Luca Gianni reported the results at the San Antonio Breast Cancer Symposium. AVEREL is a randomized, placebo-controlled phase III trial designed to evaluate bevacizumab combined with trastuzumab (Herceptin) and docetaxel (Taxotere) as first-line therapy for HER2-positive, locally recurrent or metastatic breast cancer.

The findings add more data to support the effectiveness of the drug in particular subpopulations of patients with metastatic breast cancer.

In November 2011, the Food and Drug Administration announced it was revoking its approval of the metastatic breast cancer indication for bevacizumab after concluding the drug had not been shown safe and effective for that use.

Many in the breast cancer community consider the agency’s decision unwarranted. "Bevacizumab improves the response rate – about doubles it – which for my symptomatic patients is a clear benefit," said press conference moderator Dr. Lisa Carey, professor in the department of medicine at the University of North Carolina at Chapel Hill. "It improves the progression-free survival to a greater or lesser degree in every trial that it’s ever been studied."

She conceded that "it doesn’t do anything to overall survival." The FDA cited the lack of improvement in overall survival for metastatic breast cancer patients in its decision. Dr. Gianni noted, however, that "Survival is a very important end point, but it’s not the only end point in metastatic breast cancer."

Dr. Carey agreed. "I would love to have the availability of the drug routinely for my symptomatic patients, in whom I would like to have more than one agent given – particularly one that’s well-tolerated as [bevacizumab] is."

Patients were eligible for the AVEREL trial if they had measurable or evaluable HER2-positive locally recurrent or metastatic breast cancer with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. They could not have received prior chemotherapy for advanced disease. Patients with central nervous system metastases were excluded.

The researchers enrolled 424 women with previously untreated disease. The women were randomized to receive either trastuzumab plus docetaxel (n = 208) or the same regimen plus bevacizumab (n = 216). Intravenous trastuzumab was given with an 8-mg/kg loading dose that was followed by a dosage of 6 mg/kg given every 3 weeks. Docetaxel was given intravenously at a dosage of 100 mg/m² given every 3 weeks. Bevacizumab was given intravenously at a dosage of 15 mg/kg every 3 weeks.

Trastuzumab and bevacizumab were given until disease progression. Docetaxel was given for a planned minimum of six cycles or until progression or unacceptable toxicity occurred. The primary end point was investigator-assessed PFS. Secondary end points included overall survival (OS), overall response rate, duration of response, time to treatment failure, safety (including adverse events of special interest for bevacizumab), and quality of life. Exploratory analyses included PFS evaluated by an IRC (to comply with FDA recommendations) and biomarker assessment.

In terms of safety, "There were no new safety signals observed in this patient population with respect to what we really know from other patient populations exposed to Avastin," said Dr. Gianni, director of medical oncology at the San Raffaele Cancer Center in Milano, Italy.

The researchers also conducted an exploratory analyses of plasma vascular endothelial growth factor-alpha (VEGF-A). Their results suggest a potentially predictive effect – greater benefit with high VEGF-A levels – that are consistent with observations in HER2-negative locally recurrent or metastatic breast cancer.

The AVEREL trial was sponsored by Hoffman-La Roche. Dr. Gianni has disclosed that he is a consultant to Roche, Genentech, GSK, Wyeth, Novartis, Eisai, Pfizer, Millennium Takeda, Sanofi Aventis, Boehringer Ingelheim, Biogen Idec, AstraZeneca, Genomic Health, and Celgene. Dr. Carey reported that she has no relevant financial relationships to disclose.

*Correction, 12/9/11: An earlier version of this article incorrectly noted in the headline that Avastin improves breast cancer survival.

SAN ANTONIO – Bevacizumab improved progression-free survival when added to standard treatment in a study of more than 400 women with HER2-positive locally recurrent or metastatic breast cancer.

That finding, which emerged from the AVEREL trial, adds another wrinkle in the ongoing controversy regarding use of bevacizumab (Avastin) in breast cancer treatment.

For the primary end point of investigator-assessed progression-free survival (PFS), conducted at a median follow-up of 26 months, the addition of bevacizumab resulted in a hazard ratio of 0.82 (P = .0775), compared with treatment with trastuzumab and docetaxel alone. This difference was not statistically significant. Median investigator-assessed PFS was 16.5 months with bevacizumab, compared with 13.7 months without it.

In an assessment by an independent review committee (IRC), however, a significant improvement in PFS was seen with the addition of bevacizumab (hazard ratio, 0.72; P = .0162). Median IRC-assessed PFS was 16.8 months with bevacizumab, compared with 13.9 months without it.

Lead investigator Dr. Luca Gianni reported the results at the San Antonio Breast Cancer Symposium. AVEREL is a randomized, placebo-controlled phase III trial designed to evaluate bevacizumab combined with trastuzumab (Herceptin) and docetaxel (Taxotere) as first-line therapy for HER2-positive, locally recurrent or metastatic breast cancer.

The findings add more data to support the effectiveness of the drug in particular subpopulations of patients with metastatic breast cancer.

In November 2011, the Food and Drug Administration announced it was revoking its approval of the metastatic breast cancer indication for bevacizumab after concluding the drug had not been shown safe and effective for that use.

Many in the breast cancer community consider the agency’s decision unwarranted. "Bevacizumab improves the response rate – about doubles it – which for my symptomatic patients is a clear benefit," said press conference moderator Dr. Lisa Carey, professor in the department of medicine at the University of North Carolina at Chapel Hill. "It improves the progression-free survival to a greater or lesser degree in every trial that it’s ever been studied."

She conceded that "it doesn’t do anything to overall survival." The FDA cited the lack of improvement in overall survival for metastatic breast cancer patients in its decision. Dr. Gianni noted, however, that "Survival is a very important end point, but it’s not the only end point in metastatic breast cancer."

Dr. Carey agreed. "I would love to have the availability of the drug routinely for my symptomatic patients, in whom I would like to have more than one agent given – particularly one that’s well-tolerated as [bevacizumab] is."

Patients were eligible for the AVEREL trial if they had measurable or evaluable HER2-positive locally recurrent or metastatic breast cancer with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. They could not have received prior chemotherapy for advanced disease. Patients with central nervous system metastases were excluded.

The researchers enrolled 424 women with previously untreated disease. The women were randomized to receive either trastuzumab plus docetaxel (n = 208) or the same regimen plus bevacizumab (n = 216). Intravenous trastuzumab was given with an 8-mg/kg loading dose that was followed by a dosage of 6 mg/kg given every 3 weeks. Docetaxel was given intravenously at a dosage of 100 mg/m² given every 3 weeks. Bevacizumab was given intravenously at a dosage of 15 mg/kg every 3 weeks.

Trastuzumab and bevacizumab were given until disease progression. Docetaxel was given for a planned minimum of six cycles or until progression or unacceptable toxicity occurred. The primary end point was investigator-assessed PFS. Secondary end points included overall survival (OS), overall response rate, duration of response, time to treatment failure, safety (including adverse events of special interest for bevacizumab), and quality of life. Exploratory analyses included PFS evaluated by an IRC (to comply with FDA recommendations) and biomarker assessment.

In terms of safety, "There were no new safety signals observed in this patient population with respect to what we really know from other patient populations exposed to Avastin," said Dr. Gianni, director of medical oncology at the San Raffaele Cancer Center in Milano, Italy.

The researchers also conducted an exploratory analyses of plasma vascular endothelial growth factor-alpha (VEGF-A). Their results suggest a potentially predictive effect – greater benefit with high VEGF-A levels – that are consistent with observations in HER2-negative locally recurrent or metastatic breast cancer.

The AVEREL trial was sponsored by Hoffman-La Roche. Dr. Gianni has disclosed that he is a consultant to Roche, Genentech, GSK, Wyeth, Novartis, Eisai, Pfizer, Millennium Takeda, Sanofi Aventis, Boehringer Ingelheim, Biogen Idec, AstraZeneca, Genomic Health, and Celgene. Dr. Carey reported that she has no relevant financial relationships to disclose.

*Correction, 12/9/11: An earlier version of this article incorrectly noted in the headline that Avastin improves breast cancer survival.

SAN ANTONIO – Immediate treatment with zoledronic acid in postmenopausal women with hormone receptor–positive breast cancer initiating letrozole therapy was associated with a 34% reduction in recurrence risk and 31% improvement in overall survival, compared with women of similar status who received the bisphosphonate later, according to new data from the ZO-FAST trial.

This study assessed the impact of zoledronic acid (Zometa) on aromatase inhibitor-associated bone loss after surgery for early breast cancer.

Additional disease-free and overall survival benefits were observed among the subgroup of patients who had been postmenopausal for at least 5 years, Dr. Richard de Boer reported yesterday at the San Antonio Breast Cancer Symposium.

The findings update those previously reported by Dr. de Boer of the Royal Melbourne Hospital and colleagues in the ZO-FAST (Zometa-Femara Adjuvant Synergy Trial), demonstrating that early zoledronic acid significantly improved bone mineral density and improved breast cancer disease-free survival.

The new, long-term data confirm the overall survival benefits, and the results of an exploratory subgroup analysis based on menopausal status indicates that the addition of zoledronic acid confers the most benefit to women who are truly menopausal at diagnosis, Dr. de Boer reported.

The study involved 1,065 postmenopausal women with hormone receptor–positive early breast cancer with a bone mineral density T-score of –2. In addition to receiving adjuvant endocrine therapy with 2.5 mg of letrozole (Femara) four times daily for 5 years, the women were randomized to receive 4 mg of zoledronic acid every 6 months either immediately or when their post-baseline T score dipped below –2 or they suffered a nontraumatic/asymptomatic fracture. Patients were included in the analysis if they had established menopause at the time of diagnosis or if they became menopausal as a consequence of chemotherapy or ovarian suppression, Dr. de Boer explained.

At 60 months follow-up, the hazard ratios for recurrence and mortality in the immediate treatment group were 0.66 and 0.69 respectively, with only the former representing a statistically significant improvement over the delayed treatment patients, Dr. de Boer reported. Exploratory analyses of the 670 women who were postmenopausal for more than 5 years or older than 60 years at study entry showed that immediate zoledronic acid treatment significantly improved disease-free survival, with a hazard ratio of 0.63, and significantly prolonged overall survival, with a hazard ratio of 0.50, compared with the delayed treatment group.

With respect to lumbar spine bone mineral density, "the benefits observed in the immediate therapy group early on, when bone loss is at it greatest, continued out over 5 years, with a net difference of 10% favoring the immediate zoledronic acid group," Dr. de Boer said, noting that similar results were observed in total hip bone mineral density, "with an overall change of close to 6% in the immediate group at the 5-year time point."

In a subset analysis comparing the immediate treatment group with the 27% of patients who initiated zoledronic acid, "we observed a hazard ratio 0.62 for recurrence in favor of the up-front zoledronic acid group," Dr. de Boer said. "Bone was the most common site of recurrence, and this favored the immediate group, with 14 events compared with 24 in the delayed group."

In a comparison of patients who did and did not initiate therapy, "the hazard ratio for disease-free survival was in favor of those who did initiate treatment, suggesting a delay in bisphosphonate initiation could still have an impact on disease outcomes," Dr. de Boer said.

In terms of safety, there were three confirmed cases of osteonecrosis of the jaw in the trial, all in the immediate group. "This compares favorably with published results of studies in which zoledronic acid was administered on a 6-month schedule," according to Dr. de Boer. "The AZURE [Adjuvant Zoledronic Acid to Reduce Recurrence] study had a more intensive administration schedule, and thus had more cases of jaw osteonecrosis."

The findings of this study, together with those of other recent studies including the AZURE trial, "support the hypothesis that the anticancer benefits of zoledronic acid may best be realized in a low-estrogen environment," Dr. de Boer concluded.

The additional anticancer benefit observed in the truly vs. recently postmenopausal women in this study warrants additional investigation, according to Dr. James Ingle of the Mayo Clinic in Rochester, Minn., the discussant for the session. "The study met its primary analysis endpoint, which was bone mineral density improvement, but it was not powered nor designed to detect a difference in breast events," he said. "Although the findings demonstrate the value of zoledronic acid, they are based on an unplanned analysis and thus insufficient on their own to support zoledronic acid as standard of care in postmenopausal women."

Dr. de Boer is on the speakers’ bureau for Novartis. Dr. Ingle said he had no financial conflicts to disclose.

SAN ANTONIO – Immediate treatment with zoledronic acid in postmenopausal women with hormone receptor–positive breast cancer initiating letrozole therapy was associated with a 34% reduction in recurrence risk and 31% improvement in overall survival, compared with women of similar status who received the bisphosphonate later, according to new data from the ZO-FAST trial.

This study assessed the impact of zoledronic acid (Zometa) on aromatase inhibitor-associated bone loss after surgery for early breast cancer.

Additional disease-free and overall survival benefits were observed among the subgroup of patients who had been postmenopausal for at least 5 years, Dr. Richard de Boer reported yesterday at the San Antonio Breast Cancer Symposium.

The findings update those previously reported by Dr. de Boer of the Royal Melbourne Hospital and colleagues in the ZO-FAST (Zometa-Femara Adjuvant Synergy Trial), demonstrating that early zoledronic acid significantly improved bone mineral density and improved breast cancer disease-free survival.

The new, long-term data confirm the overall survival benefits, and the results of an exploratory subgroup analysis based on menopausal status indicates that the addition of zoledronic acid confers the most benefit to women who are truly menopausal at diagnosis, Dr. de Boer reported.

The study involved 1,065 postmenopausal women with hormone receptor–positive early breast cancer with a bone mineral density T-score of –2. In addition to receiving adjuvant endocrine therapy with 2.5 mg of letrozole (Femara) four times daily for 5 years, the women were randomized to receive 4 mg of zoledronic acid every 6 months either immediately or when their post-baseline T score dipped below –2 or they suffered a nontraumatic/asymptomatic fracture. Patients were included in the analysis if they had established menopause at the time of diagnosis or if they became menopausal as a consequence of chemotherapy or ovarian suppression, Dr. de Boer explained.

At 60 months follow-up, the hazard ratios for recurrence and mortality in the immediate treatment group were 0.66 and 0.69 respectively, with only the former representing a statistically significant improvement over the delayed treatment patients, Dr. de Boer reported. Exploratory analyses of the 670 women who were postmenopausal for more than 5 years or older than 60 years at study entry showed that immediate zoledronic acid treatment significantly improved disease-free survival, with a hazard ratio of 0.63, and significantly prolonged overall survival, with a hazard ratio of 0.50, compared with the delayed treatment group.

With respect to lumbar spine bone mineral density, "the benefits observed in the immediate therapy group early on, when bone loss is at it greatest, continued out over 5 years, with a net difference of 10% favoring the immediate zoledronic acid group," Dr. de Boer said, noting that similar results were observed in total hip bone mineral density, "with an overall change of close to 6% in the immediate group at the 5-year time point."

In a subset analysis comparing the immediate treatment group with the 27% of patients who initiated zoledronic acid, "we observed a hazard ratio 0.62 for recurrence in favor of the up-front zoledronic acid group," Dr. de Boer said. "Bone was the most common site of recurrence, and this favored the immediate group, with 14 events compared with 24 in the delayed group."

In a comparison of patients who did and did not initiate therapy, "the hazard ratio for disease-free survival was in favor of those who did initiate treatment, suggesting a delay in bisphosphonate initiation could still have an impact on disease outcomes," Dr. de Boer said.

In terms of safety, there were three confirmed cases of osteonecrosis of the jaw in the trial, all in the immediate group. "This compares favorably with published results of studies in which zoledronic acid was administered on a 6-month schedule," according to Dr. de Boer. "The AZURE [Adjuvant Zoledronic Acid to Reduce Recurrence] study had a more intensive administration schedule, and thus had more cases of jaw osteonecrosis."

The findings of this study, together with those of other recent studies including the AZURE trial, "support the hypothesis that the anticancer benefits of zoledronic acid may best be realized in a low-estrogen environment," Dr. de Boer concluded.

The additional anticancer benefit observed in the truly vs. recently postmenopausal women in this study warrants additional investigation, according to Dr. James Ingle of the Mayo Clinic in Rochester, Minn., the discussant for the session. "The study met its primary analysis endpoint, which was bone mineral density improvement, but it was not powered nor designed to detect a difference in breast events," he said. "Although the findings demonstrate the value of zoledronic acid, they are based on an unplanned analysis and thus insufficient on their own to support zoledronic acid as standard of care in postmenopausal women."

Dr. de Boer is on the speakers’ bureau for Novartis. Dr. Ingle said he had no financial conflicts to disclose.

SAN ANTONIO – Immediate treatment with zoledronic acid in postmenopausal women with hormone receptor–positive breast cancer initiating letrozole therapy was associated with a 34% reduction in recurrence risk and 31% improvement in overall survival, compared with women of similar status who received the bisphosphonate later, according to new data from the ZO-FAST trial.

This study assessed the impact of zoledronic acid (Zometa) on aromatase inhibitor-associated bone loss after surgery for early breast cancer.

Additional disease-free and overall survival benefits were observed among the subgroup of patients who had been postmenopausal for at least 5 years, Dr. Richard de Boer reported yesterday at the San Antonio Breast Cancer Symposium.

The findings update those previously reported by Dr. de Boer of the Royal Melbourne Hospital and colleagues in the ZO-FAST (Zometa-Femara Adjuvant Synergy Trial), demonstrating that early zoledronic acid significantly improved bone mineral density and improved breast cancer disease-free survival.

The new, long-term data confirm the overall survival benefits, and the results of an exploratory subgroup analysis based on menopausal status indicates that the addition of zoledronic acid confers the most benefit to women who are truly menopausal at diagnosis, Dr. de Boer reported.

The study involved 1,065 postmenopausal women with hormone receptor–positive early breast cancer with a bone mineral density T-score of –2. In addition to receiving adjuvant endocrine therapy with 2.5 mg of letrozole (Femara) four times daily for 5 years, the women were randomized to receive 4 mg of zoledronic acid every 6 months either immediately or when their post-baseline T score dipped below –2 or they suffered a nontraumatic/asymptomatic fracture. Patients were included in the analysis if they had established menopause at the time of diagnosis or if they became menopausal as a consequence of chemotherapy or ovarian suppression, Dr. de Boer explained.

At 60 months follow-up, the hazard ratios for recurrence and mortality in the immediate treatment group were 0.66 and 0.69 respectively, with only the former representing a statistically significant improvement over the delayed treatment patients, Dr. de Boer reported. Exploratory analyses of the 670 women who were postmenopausal for more than 5 years or older than 60 years at study entry showed that immediate zoledronic acid treatment significantly improved disease-free survival, with a hazard ratio of 0.63, and significantly prolonged overall survival, with a hazard ratio of 0.50, compared with the delayed treatment group.

With respect to lumbar spine bone mineral density, "the benefits observed in the immediate therapy group early on, when bone loss is at it greatest, continued out over 5 years, with a net difference of 10% favoring the immediate zoledronic acid group," Dr. de Boer said, noting that similar results were observed in total hip bone mineral density, "with an overall change of close to 6% in the immediate group at the 5-year time point."

In a subset analysis comparing the immediate treatment group with the 27% of patients who initiated zoledronic acid, "we observed a hazard ratio 0.62 for recurrence in favor of the up-front zoledronic acid group," Dr. de Boer said. "Bone was the most common site of recurrence, and this favored the immediate group, with 14 events compared with 24 in the delayed group."

In a comparison of patients who did and did not initiate therapy, "the hazard ratio for disease-free survival was in favor of those who did initiate treatment, suggesting a delay in bisphosphonate initiation could still have an impact on disease outcomes," Dr. de Boer said.

In terms of safety, there were three confirmed cases of osteonecrosis of the jaw in the trial, all in the immediate group. "This compares favorably with published results of studies in which zoledronic acid was administered on a 6-month schedule," according to Dr. de Boer. "The AZURE [Adjuvant Zoledronic Acid to Reduce Recurrence] study had a more intensive administration schedule, and thus had more cases of jaw osteonecrosis."

The findings of this study, together with those of other recent studies including the AZURE trial, "support the hypothesis that the anticancer benefits of zoledronic acid may best be realized in a low-estrogen environment," Dr. de Boer concluded.

The additional anticancer benefit observed in the truly vs. recently postmenopausal women in this study warrants additional investigation, according to Dr. James Ingle of the Mayo Clinic in Rochester, Minn., the discussant for the session. "The study met its primary analysis endpoint, which was bone mineral density improvement, but it was not powered nor designed to detect a difference in breast events," he said. "Although the findings demonstrate the value of zoledronic acid, they are based on an unplanned analysis and thus insufficient on their own to support zoledronic acid as standard of care in postmenopausal women."

Dr. de Boer is on the speakers’ bureau for Novartis. Dr. Ingle said he had no financial conflicts to disclose.

CHICAGO – A mismatch between breast size and detector size during mammography resulted in significantly higher doses of radiation for women with large breasts in a study of 886 patients.

On average, women with large breasts screened on a small detector received almost 5 milligray (mGy) of radiation, which exceeds the American College of Radiology guidelines of 3-4 mGy or less for a standard two-view mammogram.

Photo courtesy Rhoda Baer/National Cancer Institute

When a mismatch occurs, women with large breasts receive significantly higher doses of radiation than women with small breasts or their counterparts with large breasts correctly matched to a large detector, Dr. Cathy Wells said when presenting the award-winning study at the annual meeting of the Radiological Society of North America.

"Women with large breasts should be imaged with a large detector to avoid an unnecessary increase in radiation dose," she urged.

The quality assurance study involved 886 women who presented for screening or diagnostic mammography during a 6-week period in late 2009. The exams were performed with a phosphor charge-coupled device detector, which is available in pre-set sizes (large or small) due to manufacturing constraints, she said. Insufficient data for 22 patients left 426 screening and 438 diagnostic patients evaluable for analysis.

A sizeable number, or almost 20% of patients, were affected by a mismatch between breast and detector size, said Dr. Wells, who completed the study at Beth Israel Deaconess Medical Center and is now a breast imaging fellow at Massachusetts General Hospital, both in Boston.

The percentage of mismatches varied from 10% of screening patients with large breasts, defined as a "C" cup or larger, to 27% of screening patients with small breasts imaged with a large detector.

A mismatch occurred in 22% of diagnostic mammography patients with large breasts and 17% of diagnostic patients with small breasts.

Despite the sizeable number of mismatches in the study, not all women will be faced with this problem when they arrive for their mammogram, Dr. Wells said in an interview. The phosphor charge-coupled device detector is one of four types of digital detectors currently available in the United States, and to her knowledge the only type that has such size constraints. In addition, not all imaging centers use this detector type.

Some centers, including her own, have both large- and small-size detectors available, although there can be a wait for the proper size, she noted. Women can choose to wait or be imaged with a different detector after a discussion with the technologist.

"The best option for women to ensure a correct match between breast size and detector size would be to talk with the technologist who performs the actual mammogram, [as] the scheduler or person at the check-in desk will likely not know the answer," Dr. Wells said.

"Women could ask the technologist whether the detector comes in different sizes, since not all do, and if so, whether they are correctly matched."

Screening mammogram patients with correctly matched breast and detector sizes received an average mean glandular dose per breast of 3.3 mGy, compared with 4.9 mGy for mismatched patients with large breasts (P value less than .05).

This was due to significantly more views obtained in mismatched patients with large breasts, compared with both the large-breast patients imaged on a large detector and small-breast patients imaged on a small detector (mean 5.9 views vs. 4.6 views vs. 4.7 views, P less than .05), Dr. Wells said. Interestingly, small-breast patients mismatched to a large detector underwent a similar number of views at a mean of 4.6, but actually received slightly less radiation at mean dose of 2.9 mGy (P less than .05).

During diagnostic mammograms, the radiation dose was again significantly higher among mismatched patients with large breasts, compared with the correctly matched large- and small-breast groups (8.2 mGy vs. 6.7 mGy, P less than .05), but it did not appear to be related to the number of views obtained, she said, adding that other factors must be at work. Several variables contribute to radiation dose, but in this case, the most likely culprit is compression thickness, Dr. Wells said.

"It may be more difficult to adequately compress a large breast with a small detector, resulting in a larger radiation dose," she said. "We hope to analyze the data again, to answer this question."

Dr. Wells and her coauthors reported having no conflicts of interest.

CHICAGO – A mismatch between breast size and detector size during mammography resulted in significantly higher doses of radiation for women with large breasts in a study of 886 patients.

On average, women with large breasts screened on a small detector received almost 5 milligray (mGy) of radiation, which exceeds the American College of Radiology guidelines of 3-4 mGy or less for a standard two-view mammogram.

Photo courtesy Rhoda Baer/National Cancer Institute

When a mismatch occurs, women with large breasts receive significantly higher doses of radiation than women with small breasts or their counterparts with large breasts correctly matched to a large detector, Dr. Cathy Wells said when presenting the award-winning study at the annual meeting of the Radiological Society of North America.

"Women with large breasts should be imaged with a large detector to avoid an unnecessary increase in radiation dose," she urged.

The quality assurance study involved 886 women who presented for screening or diagnostic mammography during a 6-week period in late 2009. The exams were performed with a phosphor charge-coupled device detector, which is available in pre-set sizes (large or small) due to manufacturing constraints, she said. Insufficient data for 22 patients left 426 screening and 438 diagnostic patients evaluable for analysis.

A sizeable number, or almost 20% of patients, were affected by a mismatch between breast and detector size, said Dr. Wells, who completed the study at Beth Israel Deaconess Medical Center and is now a breast imaging fellow at Massachusetts General Hospital, both in Boston.

The percentage of mismatches varied from 10% of screening patients with large breasts, defined as a "C" cup or larger, to 27% of screening patients with small breasts imaged with a large detector.

A mismatch occurred in 22% of diagnostic mammography patients with large breasts and 17% of diagnostic patients with small breasts.

Despite the sizeable number of mismatches in the study, not all women will be faced with this problem when they arrive for their mammogram, Dr. Wells said in an interview. The phosphor charge-coupled device detector is one of four types of digital detectors currently available in the United States, and to her knowledge the only type that has such size constraints. In addition, not all imaging centers use this detector type.

Some centers, including her own, have both large- and small-size detectors available, although there can be a wait for the proper size, she noted. Women can choose to wait or be imaged with a different detector after a discussion with the technologist.

"The best option for women to ensure a correct match between breast size and detector size would be to talk with the technologist who performs the actual mammogram, [as] the scheduler or person at the check-in desk will likely not know the answer," Dr. Wells said.

"Women could ask the technologist whether the detector comes in different sizes, since not all do, and if so, whether they are correctly matched."

Screening mammogram patients with correctly matched breast and detector sizes received an average mean glandular dose per breast of 3.3 mGy, compared with 4.9 mGy for mismatched patients with large breasts (P value less than .05).

This was due to significantly more views obtained in mismatched patients with large breasts, compared with both the large-breast patients imaged on a large detector and small-breast patients imaged on a small detector (mean 5.9 views vs. 4.6 views vs. 4.7 views, P less than .05), Dr. Wells said. Interestingly, small-breast patients mismatched to a large detector underwent a similar number of views at a mean of 4.6, but actually received slightly less radiation at mean dose of 2.9 mGy (P less than .05).

During diagnostic mammograms, the radiation dose was again significantly higher among mismatched patients with large breasts, compared with the correctly matched large- and small-breast groups (8.2 mGy vs. 6.7 mGy, P less than .05), but it did not appear to be related to the number of views obtained, she said, adding that other factors must be at work. Several variables contribute to radiation dose, but in this case, the most likely culprit is compression thickness, Dr. Wells said.

"It may be more difficult to adequately compress a large breast with a small detector, resulting in a larger radiation dose," she said. "We hope to analyze the data again, to answer this question."

Dr. Wells and her coauthors reported having no conflicts of interest.

CHICAGO – A mismatch between breast size and detector size during mammography resulted in significantly higher doses of radiation for women with large breasts in a study of 886 patients.

On average, women with large breasts screened on a small detector received almost 5 milligray (mGy) of radiation, which exceeds the American College of Radiology guidelines of 3-4 mGy or less for a standard two-view mammogram.

Photo courtesy Rhoda Baer/National Cancer Institute

When a mismatch occurs, women with large breasts receive significantly higher doses of radiation than women with small breasts or their counterparts with large breasts correctly matched to a large detector, Dr. Cathy Wells said when presenting the award-winning study at the annual meeting of the Radiological Society of North America.

"Women with large breasts should be imaged with a large detector to avoid an unnecessary increase in radiation dose," she urged.

The quality assurance study involved 886 women who presented for screening or diagnostic mammography during a 6-week period in late 2009. The exams were performed with a phosphor charge-coupled device detector, which is available in pre-set sizes (large or small) due to manufacturing constraints, she said. Insufficient data for 22 patients left 426 screening and 438 diagnostic patients evaluable for analysis.

A sizeable number, or almost 20% of patients, were affected by a mismatch between breast and detector size, said Dr. Wells, who completed the study at Beth Israel Deaconess Medical Center and is now a breast imaging fellow at Massachusetts General Hospital, both in Boston.

The percentage of mismatches varied from 10% of screening patients with large breasts, defined as a "C" cup or larger, to 27% of screening patients with small breasts imaged with a large detector.

A mismatch occurred in 22% of diagnostic mammography patients with large breasts and 17% of diagnostic patients with small breasts.

Despite the sizeable number of mismatches in the study, not all women will be faced with this problem when they arrive for their mammogram, Dr. Wells said in an interview. The phosphor charge-coupled device detector is one of four types of digital detectors currently available in the United States, and to her knowledge the only type that has such size constraints. In addition, not all imaging centers use this detector type.

Some centers, including her own, have both large- and small-size detectors available, although there can be a wait for the proper size, she noted. Women can choose to wait or be imaged with a different detector after a discussion with the technologist.

"The best option for women to ensure a correct match between breast size and detector size would be to talk with the technologist who performs the actual mammogram, [as] the scheduler or person at the check-in desk will likely not know the answer," Dr. Wells said.

"Women could ask the technologist whether the detector comes in different sizes, since not all do, and if so, whether they are correctly matched."

Screening mammogram patients with correctly matched breast and detector sizes received an average mean glandular dose per breast of 3.3 mGy, compared with 4.9 mGy for mismatched patients with large breasts (P value less than .05).

This was due to significantly more views obtained in mismatched patients with large breasts, compared with both the large-breast patients imaged on a large detector and small-breast patients imaged on a small detector (mean 5.9 views vs. 4.6 views vs. 4.7 views, P less than .05), Dr. Wells said. Interestingly, small-breast patients mismatched to a large detector underwent a similar number of views at a mean of 4.6, but actually received slightly less radiation at mean dose of 2.9 mGy (P less than .05).

During diagnostic mammograms, the radiation dose was again significantly higher among mismatched patients with large breasts, compared with the correctly matched large- and small-breast groups (8.2 mGy vs. 6.7 mGy, P less than .05), but it did not appear to be related to the number of views obtained, she said, adding that other factors must be at work. Several variables contribute to radiation dose, but in this case, the most likely culprit is compression thickness, Dr. Wells said.

"It may be more difficult to adequately compress a large breast with a small detector, resulting in a larger radiation dose," she said. "We hope to analyze the data again, to answer this question."

Dr. Wells and her coauthors reported having no conflicts of interest.

 San Antonio – While treatment with the clodronate does not appear to affect disease-free survival among women with stages I-III breast cancer, the drug does appear to improve certain outcomes for women aged 50 years and older, according to the results of a phase III trial of more than 3,000 patients.

Disease-free survival (DFS) did not differ between women treated with clodronate and those given placebo (hazard ratio, 0.91; P = .27). However, women at least 50 years of age saw benefits in secondary protocol predefined end points, Dr. Alexander H.G. Paterson said at the San Antonio Breast Cancer Symposium.

"This is an easy treatment and it’s oral. It seems to have an effect in older women and low toxicity. We’ve now got four trials [pointing in] the same direction ... that is of a benefit in older patients," said Dr. Paterson, a professor in the departments of medicine and oncology at the University of Calgary in Canada.

In the double-blind, phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34 clinical trial, patients with stage I-III breast cancer were randomized to receive oral clodronate 1,600 mg daily for 3 years or placebo, given alone or in addition to adjuvant chemotherapy or hormone therapy. Patients also underwent surgery (lumpectomies or mastectomies) and received radiation therapy and chemotherapy or hormonal therapy.

The groups were stratified by age (younger than 50 years or at least 50 years), number of positive nodes and estrogen receptor/progesterone receptor (ER/PR) status. The primary end point was disease-free survival, which was defined to include all recurrences, deaths, and second primary cancers. Secondary end points are the incidence of skeletal metastases, overall survival, recurrence-free interval, bone metastasis–free interval, and nonbone metastasis–free interval.

The researchers reported on 3,311 patients (1,656 on placebo and 1,655 on clodronate) with a median of 8 years in the study. Of note, almost two-thirds of patients (64%) were at least 50 years old at the time of enrollment. Three-quarters had pathologically-negative axillary nodes and almost a quarter (22%) had ER-negative or PR-negative breast cancer.

"Compliance was an issue. The drop in compliance really occurred in the first 6 months, when patients were also receiving intravenous chemotherapy," said Dr. Paterson. A total of 40% of patients did not complete 3 years of study therapy.

Patients on clodronate had a slightly lower rate of treatment failure at distant sites (5.4% vs. 6.6%). The researchers suspect that the disease-free survival benefit was attenuated due to the equivalent event rates for second primary cancers, contralateral cancers and local/regional relapses.

Overall toxicity was low and comparable for the two groups. There was one case of osteonecrosis of the jaw in the clodronate group.

However, clodronate showed benefit regarding distant metastases in all protocol predefined secondary end points. Hazard reductions ranged from 15% for overall survival to 26% for nonbone metastasis–free interval.

Dr. Paterson noted that secondary protocol predefined end point reductions were even greater among women at least 50 years of age. For these women, there was a 24% reduction in breast cancer recurrence–free interval (P = .05), a 39% reduction in bone metastasis–free interval (P = .024), and a 37% reduction in nonbone metastasis–free interval (P = .015). In addition, women 50 years and older had a 20% reduction in overall survival, though this was not statistically significant (P = 0.1).

"Similar beneficial results in older postmenopausal women are seen in other studies involving bisphosphonates," he said.

Bisphosponates are thought to inhibit the growth of bone metastases by inhibiting osteoclast function and subsequent bone turnover. However, the role of bisphosphonates in preventing or delaying the development of bone (or other) metastases in patients with early breast cancer remains unclear.

The trial received support from the National Cancer Institute and Bayer Schering Pharma Oy. Dr. Paterson disclosed that he is a consultant for GlaxoSmithKline, Amgen, Roche Diagnostics, and Nicomed.

 San Antonio – While treatment with the clodronate does not appear to affect disease-free survival among women with stages I-III breast cancer, the drug does appear to improve certain outcomes for women aged 50 years and older, according to the results of a phase III trial of more than 3,000 patients.

Disease-free survival (DFS) did not differ between women treated with clodronate and those given placebo (hazard ratio, 0.91; P = .27). However, women at least 50 years of age saw benefits in secondary protocol predefined end points, Dr. Alexander H.G. Paterson said at the San Antonio Breast Cancer Symposium.

"This is an easy treatment and it’s oral. It seems to have an effect in older women and low toxicity. We’ve now got four trials [pointing in] the same direction ... that is of a benefit in older patients," said Dr. Paterson, a professor in the departments of medicine and oncology at the University of Calgary in Canada.

In the double-blind, phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34 clinical trial, patients with stage I-III breast cancer were randomized to receive oral clodronate 1,600 mg daily for 3 years or placebo, given alone or in addition to adjuvant chemotherapy or hormone therapy. Patients also underwent surgery (lumpectomies or mastectomies) and received radiation therapy and chemotherapy or hormonal therapy.

The groups were stratified by age (younger than 50 years or at least 50 years), number of positive nodes and estrogen receptor/progesterone receptor (ER/PR) status. The primary end point was disease-free survival, which was defined to include all recurrences, deaths, and second primary cancers. Secondary end points are the incidence of skeletal metastases, overall survival, recurrence-free interval, bone metastasis–free interval, and nonbone metastasis–free interval.

The researchers reported on 3,311 patients (1,656 on placebo and 1,655 on clodronate) with a median of 8 years in the study. Of note, almost two-thirds of patients (64%) were at least 50 years old at the time of enrollment. Three-quarters had pathologically-negative axillary nodes and almost a quarter (22%) had ER-negative or PR-negative breast cancer.

"Compliance was an issue. The drop in compliance really occurred in the first 6 months, when patients were also receiving intravenous chemotherapy," said Dr. Paterson. A total of 40% of patients did not complete 3 years of study therapy.

Patients on clodronate had a slightly lower rate of treatment failure at distant sites (5.4% vs. 6.6%). The researchers suspect that the disease-free survival benefit was attenuated due to the equivalent event rates for second primary cancers, contralateral cancers and local/regional relapses.

Overall toxicity was low and comparable for the two groups. There was one case of osteonecrosis of the jaw in the clodronate group.

However, clodronate showed benefit regarding distant metastases in all protocol predefined secondary end points. Hazard reductions ranged from 15% for overall survival to 26% for nonbone metastasis–free interval.

Dr. Paterson noted that secondary protocol predefined end point reductions were even greater among women at least 50 years of age. For these women, there was a 24% reduction in breast cancer recurrence–free interval (P = .05), a 39% reduction in bone metastasis–free interval (P = .024), and a 37% reduction in nonbone metastasis–free interval (P = .015). In addition, women 50 years and older had a 20% reduction in overall survival, though this was not statistically significant (P = 0.1).

"Similar beneficial results in older postmenopausal women are seen in other studies involving bisphosphonates," he said.

Bisphosponates are thought to inhibit the growth of bone metastases by inhibiting osteoclast function and subsequent bone turnover. However, the role of bisphosphonates in preventing or delaying the development of bone (or other) metastases in patients with early breast cancer remains unclear.

The trial received support from the National Cancer Institute and Bayer Schering Pharma Oy. Dr. Paterson disclosed that he is a consultant for GlaxoSmithKline, Amgen, Roche Diagnostics, and Nicomed.

 San Antonio – While treatment with the clodronate does not appear to affect disease-free survival among women with stages I-III breast cancer, the drug does appear to improve certain outcomes for women aged 50 years and older, according to the results of a phase III trial of more than 3,000 patients.

Disease-free survival (DFS) did not differ between women treated with clodronate and those given placebo (hazard ratio, 0.91; P = .27). However, women at least 50 years of age saw benefits in secondary protocol predefined end points, Dr. Alexander H.G. Paterson said at the San Antonio Breast Cancer Symposium.

"This is an easy treatment and it’s oral. It seems to have an effect in older women and low toxicity. We’ve now got four trials [pointing in] the same direction ... that is of a benefit in older patients," said Dr. Paterson, a professor in the departments of medicine and oncology at the University of Calgary in Canada.

In the double-blind, phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34 clinical trial, patients with stage I-III breast cancer were randomized to receive oral clodronate 1,600 mg daily for 3 years or placebo, given alone or in addition to adjuvant chemotherapy or hormone therapy. Patients also underwent surgery (lumpectomies or mastectomies) and received radiation therapy and chemotherapy or hormonal therapy.

The groups were stratified by age (younger than 50 years or at least 50 years), number of positive nodes and estrogen receptor/progesterone receptor (ER/PR) status. The primary end point was disease-free survival, which was defined to include all recurrences, deaths, and second primary cancers. Secondary end points are the incidence of skeletal metastases, overall survival, recurrence-free interval, bone metastasis–free interval, and nonbone metastasis–free interval.

The researchers reported on 3,311 patients (1,656 on placebo and 1,655 on clodronate) with a median of 8 years in the study. Of note, almost two-thirds of patients (64%) were at least 50 years old at the time of enrollment. Three-quarters had pathologically-negative axillary nodes and almost a quarter (22%) had ER-negative or PR-negative breast cancer.

"Compliance was an issue. The drop in compliance really occurred in the first 6 months, when patients were also receiving intravenous chemotherapy," said Dr. Paterson. A total of 40% of patients did not complete 3 years of study therapy.

Patients on clodronate had a slightly lower rate of treatment failure at distant sites (5.4% vs. 6.6%). The researchers suspect that the disease-free survival benefit was attenuated due to the equivalent event rates for second primary cancers, contralateral cancers and local/regional relapses.

Overall toxicity was low and comparable for the two groups. There was one case of osteonecrosis of the jaw in the clodronate group.

However, clodronate showed benefit regarding distant metastases in all protocol predefined secondary end points. Hazard reductions ranged from 15% for overall survival to 26% for nonbone metastasis–free interval.

Dr. Paterson noted that secondary protocol predefined end point reductions were even greater among women at least 50 years of age. For these women, there was a 24% reduction in breast cancer recurrence–free interval (P = .05), a 39% reduction in bone metastasis–free interval (P = .024), and a 37% reduction in nonbone metastasis–free interval (P = .015). In addition, women 50 years and older had a 20% reduction in overall survival, though this was not statistically significant (P = 0.1).

"Similar beneficial results in older postmenopausal women are seen in other studies involving bisphosphonates," he said.

Bisphosponates are thought to inhibit the growth of bone metastases by inhibiting osteoclast function and subsequent bone turnover. However, the role of bisphosphonates in preventing or delaying the development of bone (or other) metastases in patients with early breast cancer remains unclear.

The trial received support from the National Cancer Institute and Bayer Schering Pharma Oy. Dr. Paterson disclosed that he is a consultant for GlaxoSmithKline, Amgen, Roche Diagnostics, and Nicomed.

SAN ANTONIO – A risk score based on a 12-gene assay is expected to help physicians determine whether postsurgical radiation for ductal carcinoma in situ would improve an individual patient’s outcome, Dr. Lawrence J. Solin reported at the San Antonio Breast Cancer Symposium.

In a biomarker validation study, investigators demonstrated that a prespecified score on the Oncotype DX DCIS measure developed by Genomic Health Inc. can predict the risk of an ipsilateral breast event – either the development of a new invasive breast cancer or the recurrence of DCIS in the same breast – in women who have undergone breast-conservation surgery.

The 12-gene assay is a subset of the Oncotype DX 21 gene assay for invasive breast cancer. Dr. Solin, chair of radiation oncology at Albert Einstein Medical Center in Philadelphia, and colleagues in the Eastern Cooperative Oncology Group (ECOG) evaluated its predictive value in 327 patients drawn from the prospective multicenter ECOG E5194 study in which the more extensive assay had been performed, he explained. All of the patients had low/intermediate grade DCIS, defined as 2.5 cm or smaller or high-grade DCIS, defined as 1 cm or smaller, he said (J. Clin. Oncol. 2009;27:5319-24).

Based on the 21-gene assay, central pathology review, and a recurrence algorithm, the investigators calculated a DCIS score from 0-100, with scores less than 39, 39-54, and 55 and higher, respectively, classified as low, intermediate, and high risk for recurrence, Dr. Solin said. During nearly 9 years of follow-up, recurrent DCIS developed in 20 patients and invasive cancer in the ipsilateral breast in 26 patients, he reported. Among patients with low/intermediate DCIS and high-grade DCIS, respectively, the 10-year breast event rates were 15.4% and 15.1%, and the invasive breast event rates were 5.6% and 9.8%, he reported.

By DCIS score, "75% of the patients were in the low-risk category, compared with 14% classified as intermediate risk and 11% as high risk," said Dr. Solin. The rates of both any ipsilateral breast event and invasive breast cancer were directly related to DCIS risk score, with 12.0%, 24.5%, and 27.3% of patients in the low, intermediate, and high DCIS score groups experiencing any ipsilateral breast event and 5.1%, 8.9%, and 19.1% developing invasive breast cancer, he said. In multivariate analysis, DCIS score, menopausal status, and tumor size were all significantly associated with recurrence.

The DCIS score is "groundbreaking," according to Dr. Solin, because it is the first validated molecular marker that clearly differentiates low-risk from high-risk disease in DCIS, Dr. Solin stressed. The tool "will help physicians understand the underlying biology of [DCIS] for the individual patient, accurately gauging the risk for that patient and helping guide treatment," he said. Clinical and pathologic factors are not reliable enough on their own to determine whether radiation following breast-conservation surgery will confer any survival benefit, he explained.

Genomic Health has announced the Oncotype DX DCIS tool will be available by the end of December 2011. In response to questions about the price of the test and insurance coverage, Dr. Solin noted that, in aggregate, the savings associated with avoiding unnecessary additional treatment in patients with a low-risk DCIS score would more than compensate for the price of the test in individual patients.

Dr. Solin reported having no relevant financial disclosures. The study team included employees of Genomic Health.

SAN ANTONIO – A risk score based on a 12-gene assay is expected to help physicians determine whether postsurgical radiation for ductal carcinoma in situ would improve an individual patient’s outcome, Dr. Lawrence J. Solin reported at the San Antonio Breast Cancer Symposium.

In a biomarker validation study, investigators demonstrated that a prespecified score on the Oncotype DX DCIS measure developed by Genomic Health Inc. can predict the risk of an ipsilateral breast event – either the development of a new invasive breast cancer or the recurrence of DCIS in the same breast – in women who have undergone breast-conservation surgery.

The 12-gene assay is a subset of the Oncotype DX 21 gene assay for invasive breast cancer. Dr. Solin, chair of radiation oncology at Albert Einstein Medical Center in Philadelphia, and colleagues in the Eastern Cooperative Oncology Group (ECOG) evaluated its predictive value in 327 patients drawn from the prospective multicenter ECOG E5194 study in which the more extensive assay had been performed, he explained. All of the patients had low/intermediate grade DCIS, defined as 2.5 cm or smaller or high-grade DCIS, defined as 1 cm or smaller, he said (J. Clin. Oncol. 2009;27:5319-24).

Based on the 21-gene assay, central pathology review, and a recurrence algorithm, the investigators calculated a DCIS score from 0-100, with scores less than 39, 39-54, and 55 and higher, respectively, classified as low, intermediate, and high risk for recurrence, Dr. Solin said. During nearly 9 years of follow-up, recurrent DCIS developed in 20 patients and invasive cancer in the ipsilateral breast in 26 patients, he reported. Among patients with low/intermediate DCIS and high-grade DCIS, respectively, the 10-year breast event rates were 15.4% and 15.1%, and the invasive breast event rates were 5.6% and 9.8%, he reported.

By DCIS score, "75% of the patients were in the low-risk category, compared with 14% classified as intermediate risk and 11% as high risk," said Dr. Solin. The rates of both any ipsilateral breast event and invasive breast cancer were directly related to DCIS risk score, with 12.0%, 24.5%, and 27.3% of patients in the low, intermediate, and high DCIS score groups experiencing any ipsilateral breast event and 5.1%, 8.9%, and 19.1% developing invasive breast cancer, he said. In multivariate analysis, DCIS score, menopausal status, and tumor size were all significantly associated with recurrence.

The DCIS score is "groundbreaking," according to Dr. Solin, because it is the first validated molecular marker that clearly differentiates low-risk from high-risk disease in DCIS, Dr. Solin stressed. The tool "will help physicians understand the underlying biology of [DCIS] for the individual patient, accurately gauging the risk for that patient and helping guide treatment," he said. Clinical and pathologic factors are not reliable enough on their own to determine whether radiation following breast-conservation surgery will confer any survival benefit, he explained.

Genomic Health has announced the Oncotype DX DCIS tool will be available by the end of December 2011. In response to questions about the price of the test and insurance coverage, Dr. Solin noted that, in aggregate, the savings associated with avoiding unnecessary additional treatment in patients with a low-risk DCIS score would more than compensate for the price of the test in individual patients.

Dr. Solin reported having no relevant financial disclosures. The study team included employees of Genomic Health.

SAN ANTONIO – A risk score based on a 12-gene assay is expected to help physicians determine whether postsurgical radiation for ductal carcinoma in situ would improve an individual patient’s outcome, Dr. Lawrence J. Solin reported at the San Antonio Breast Cancer Symposium.

In a biomarker validation study, investigators demonstrated that a prespecified score on the Oncotype DX DCIS measure developed by Genomic Health Inc. can predict the risk of an ipsilateral breast event – either the development of a new invasive breast cancer or the recurrence of DCIS in the same breast – in women who have undergone breast-conservation surgery.

The 12-gene assay is a subset of the Oncotype DX 21 gene assay for invasive breast cancer. Dr. Solin, chair of radiation oncology at Albert Einstein Medical Center in Philadelphia, and colleagues in the Eastern Cooperative Oncology Group (ECOG) evaluated its predictive value in 327 patients drawn from the prospective multicenter ECOG E5194 study in which the more extensive assay had been performed, he explained. All of the patients had low/intermediate grade DCIS, defined as 2.5 cm or smaller or high-grade DCIS, defined as 1 cm or smaller, he said (J. Clin. Oncol. 2009;27:5319-24).

Based on the 21-gene assay, central pathology review, and a recurrence algorithm, the investigators calculated a DCIS score from 0-100, with scores less than 39, 39-54, and 55 and higher, respectively, classified as low, intermediate, and high risk for recurrence, Dr. Solin said. During nearly 9 years of follow-up, recurrent DCIS developed in 20 patients and invasive cancer in the ipsilateral breast in 26 patients, he reported. Among patients with low/intermediate DCIS and high-grade DCIS, respectively, the 10-year breast event rates were 15.4% and 15.1%, and the invasive breast event rates were 5.6% and 9.8%, he reported.

By DCIS score, "75% of the patients were in the low-risk category, compared with 14% classified as intermediate risk and 11% as high risk," said Dr. Solin. The rates of both any ipsilateral breast event and invasive breast cancer were directly related to DCIS risk score, with 12.0%, 24.5%, and 27.3% of patients in the low, intermediate, and high DCIS score groups experiencing any ipsilateral breast event and 5.1%, 8.9%, and 19.1% developing invasive breast cancer, he said. In multivariate analysis, DCIS score, menopausal status, and tumor size were all significantly associated with recurrence.

The DCIS score is "groundbreaking," according to Dr. Solin, because it is the first validated molecular marker that clearly differentiates low-risk from high-risk disease in DCIS, Dr. Solin stressed. The tool "will help physicians understand the underlying biology of [DCIS] for the individual patient, accurately gauging the risk for that patient and helping guide treatment," he said. Clinical and pathologic factors are not reliable enough on their own to determine whether radiation following breast-conservation surgery will confer any survival benefit, he explained.

Genomic Health has announced the Oncotype DX DCIS tool will be available by the end of December 2011. In response to questions about the price of the test and insurance coverage, Dr. Solin noted that, in aggregate, the savings associated with avoiding unnecessary additional treatment in patients with a low-risk DCIS score would more than compensate for the price of the test in individual patients.

Dr. Solin reported having no relevant financial disclosures. The study team included employees of Genomic Health.

The addition of pertuzumab to a standard chemotherapy combination of trastuzumab and docetaxel led to an additional 6 months of progression-free survival in patients with HER2-positive metastatic breast cancer, CLEOPATRA trial investigators reported in the New England Journal of Medicine.

Adding pertuzumab drove median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in the pertuzumab group, they wrote. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival.

The results support dual blockade of the HER2 growth factor, which is targeted in different locations by pertuzumab and trastuzumab (Herceptin). In a prepared statement, lead investigator Dr. José Baselga, chief of hematology/oncology at Massachusetts General Hospital in Boston, characterized the improvement as "huge."

"Most metastatic patients with HER2-positive breast cancer eventually stop responding to trastuzumab, so the fact that we now have an agent that can be added to current treatment to delay progression is very exciting," he said of the research, which was published online Dec. 7 and is being presented at the San Antonio Breast Cancer Symposium.

"With the advent of trastuzumab and now pertuzumab, we have come a very long way in treating a type of breast cancer that once had a very poor prognosis."

For the double-blind phase III trial, known as CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized from February 2008 through July 2010 either to a control group that received placebo plus trastuzumab and docetaxel (Taxotere) or the pertuzumab group, which received pertuzumab plus trastuzumab* and docetaxel.

To be eligible for the trial, patients had to have a baseline left ventricular ejection fraction of 50% or greater and no history of declines to less than 50% during or after prior trastuzumab therapy (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1113216]). Patients could have received one prior hormonal treatment for metastatic breast cancer and/or prior systemic neoadjuvant or adjuvant therapy, including prior trastuzumab and docetaxel. The median age of patients was 54 years, and 59% were white.

Study medication consisted of an 840-mg loading dose of pertuzumab followed by 420-mg three times weekly; an 8-mg/kg loading dose of trastuzumab followed by 6 mg/kg three times weekly, and a 75 mg/m² dose of docetaxel every three weeks with subsequent dose escalation to 100 mg/m² if 75 mg/m² was well tolerated. At least six cycles of docetaxel were recommended. The primary study end point was progression-free survival as determined by independent review.

The researchers noted that the survival data are not complete, "since the interim analysis of overall survival was performed after 165 events had occurred (43% of the prespecified total number of events for the final analysis). Although there is a strong trend toward prolonged survival with pertuzumab plus trastuzumab plus docetaxel, the result is exploratory ... The final analysis of overall survival is event-driven and is estimated to be performed in 2013," they wrote.

The objective response rate was 69.3% in the control group vs. 80.2% in the pertuzumab group. While the difference favored the pertuzumab group statistically, the researchers consider the finding exploratory until the final analysis is conducted.

No increased rates of symptomatic or asymptomatic cardiac dysfunction were observed in the pertuzumab group, compared with the control group. However, diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin were reported more frequently in the pertuzumab group, compared with the control group.

"The events were mostly grade 1 or 2 and occurred during the period of concomitant docetaxel administration," the researchers wrote. "Grade 3 or higher febrile neutropenia and diarrhea were also increased in the pertuzumab group."

Dr. Baselga and his associates went on to state that the study findings "suggest that targeting HER2-positive tumors with two anti-HER2 monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of HER2 and highlights the clinical importance of preventing the ligand-dependent formation of HER2 dimers in order to silence HER2 signaling to the greatest extent possible."

The study was funded by F. Hoffmann-LaRoche and Genentech. Dr. Baselga disclosed that he is a member of the scientific advisory board for F. Hoffmann-LaRoche and for numerous other pharmaceutical companies. He is also a paid consultant for F. Hoffmann-LaRoche, Genentech, and for numerous other pharmaceutical companies.

* Correction 12/8/11: An earlier version of this story incorrectly described the regimen in the pertuzumab group. The error has been corrected.

The addition of pertuzumab to a standard chemotherapy combination of trastuzumab and docetaxel led to an additional 6 months of progression-free survival in patients with HER2-positive metastatic breast cancer, CLEOPATRA trial investigators reported in the New England Journal of Medicine.

Adding pertuzumab drove median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in the pertuzumab group, they wrote. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival.

The results support dual blockade of the HER2 growth factor, which is targeted in different locations by pertuzumab and trastuzumab (Herceptin). In a prepared statement, lead investigator Dr. José Baselga, chief of hematology/oncology at Massachusetts General Hospital in Boston, characterized the improvement as "huge."

"Most metastatic patients with HER2-positive breast cancer eventually stop responding to trastuzumab, so the fact that we now have an agent that can be added to current treatment to delay progression is very exciting," he said of the research, which was published online Dec. 7 and is being presented at the San Antonio Breast Cancer Symposium.

"With the advent of trastuzumab and now pertuzumab, we have come a very long way in treating a type of breast cancer that once had a very poor prognosis."

For the double-blind phase III trial, known as CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized from February 2008 through July 2010 either to a control group that received placebo plus trastuzumab and docetaxel (Taxotere) or the pertuzumab group, which received pertuzumab plus trastuzumab* and docetaxel.

To be eligible for the trial, patients had to have a baseline left ventricular ejection fraction of 50% or greater and no history of declines to less than 50% during or after prior trastuzumab therapy (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1113216]). Patients could have received one prior hormonal treatment for metastatic breast cancer and/or prior systemic neoadjuvant or adjuvant therapy, including prior trastuzumab and docetaxel. The median age of patients was 54 years, and 59% were white.

Study medication consisted of an 840-mg loading dose of pertuzumab followed by 420-mg three times weekly; an 8-mg/kg loading dose of trastuzumab followed by 6 mg/kg three times weekly, and a 75 mg/m² dose of docetaxel every three weeks with subsequent dose escalation to 100 mg/m² if 75 mg/m² was well tolerated. At least six cycles of docetaxel were recommended. The primary study end point was progression-free survival as determined by independent review.

The researchers noted that the survival data are not complete, "since the interim analysis of overall survival was performed after 165 events had occurred (43% of the prespecified total number of events for the final analysis). Although there is a strong trend toward prolonged survival with pertuzumab plus trastuzumab plus docetaxel, the result is exploratory ... The final analysis of overall survival is event-driven and is estimated to be performed in 2013," they wrote.

The objective response rate was 69.3% in the control group vs. 80.2% in the pertuzumab group. While the difference favored the pertuzumab group statistically, the researchers consider the finding exploratory until the final analysis is conducted.

No increased rates of symptomatic or asymptomatic cardiac dysfunction were observed in the pertuzumab group, compared with the control group. However, diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin were reported more frequently in the pertuzumab group, compared with the control group.

"The events were mostly grade 1 or 2 and occurred during the period of concomitant docetaxel administration," the researchers wrote. "Grade 3 or higher febrile neutropenia and diarrhea were also increased in the pertuzumab group."

Dr. Baselga and his associates went on to state that the study findings "suggest that targeting HER2-positive tumors with two anti-HER2 monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of HER2 and highlights the clinical importance of preventing the ligand-dependent formation of HER2 dimers in order to silence HER2 signaling to the greatest extent possible."

The study was funded by F. Hoffmann-LaRoche and Genentech. Dr. Baselga disclosed that he is a member of the scientific advisory board for F. Hoffmann-LaRoche and for numerous other pharmaceutical companies. He is also a paid consultant for F. Hoffmann-LaRoche, Genentech, and for numerous other pharmaceutical companies.

* Correction 12/8/11: An earlier version of this story incorrectly described the regimen in the pertuzumab group. The error has been corrected.

The addition of pertuzumab to a standard chemotherapy combination of trastuzumab and docetaxel led to an additional 6 months of progression-free survival in patients with HER2-positive metastatic breast cancer, CLEOPATRA trial investigators reported in the New England Journal of Medicine.

Adding pertuzumab drove median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in the pertuzumab group, they wrote. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival.

The results support dual blockade of the HER2 growth factor, which is targeted in different locations by pertuzumab and trastuzumab (Herceptin). In a prepared statement, lead investigator Dr. José Baselga, chief of hematology/oncology at Massachusetts General Hospital in Boston, characterized the improvement as "huge."

"Most metastatic patients with HER2-positive breast cancer eventually stop responding to trastuzumab, so the fact that we now have an agent that can be added to current treatment to delay progression is very exciting," he said of the research, which was published online Dec. 7 and is being presented at the San Antonio Breast Cancer Symposium.

"With the advent of trastuzumab and now pertuzumab, we have come a very long way in treating a type of breast cancer that once had a very poor prognosis."

For the double-blind phase III trial, known as CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized from February 2008 through July 2010 either to a control group that received placebo plus trastuzumab and docetaxel (Taxotere) or the pertuzumab group, which received pertuzumab plus trastuzumab* and docetaxel.

To be eligible for the trial, patients had to have a baseline left ventricular ejection fraction of 50% or greater and no history of declines to less than 50% during or after prior trastuzumab therapy (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1113216]). Patients could have received one prior hormonal treatment for metastatic breast cancer and/or prior systemic neoadjuvant or adjuvant therapy, including prior trastuzumab and docetaxel. The median age of patients was 54 years, and 59% were white.

Study medication consisted of an 840-mg loading dose of pertuzumab followed by 420-mg three times weekly; an 8-mg/kg loading dose of trastuzumab followed by 6 mg/kg three times weekly, and a 75 mg/m² dose of docetaxel every three weeks with subsequent dose escalation to 100 mg/m² if 75 mg/m² was well tolerated. At least six cycles of docetaxel were recommended. The primary study end point was progression-free survival as determined by independent review.

The researchers noted that the survival data are not complete, "since the interim analysis of overall survival was performed after 165 events had occurred (43% of the prespecified total number of events for the final analysis). Although there is a strong trend toward prolonged survival with pertuzumab plus trastuzumab plus docetaxel, the result is exploratory ... The final analysis of overall survival is event-driven and is estimated to be performed in 2013," they wrote.

The objective response rate was 69.3% in the control group vs. 80.2% in the pertuzumab group. While the difference favored the pertuzumab group statistically, the researchers consider the finding exploratory until the final analysis is conducted.

No increased rates of symptomatic or asymptomatic cardiac dysfunction were observed in the pertuzumab group, compared with the control group. However, diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin were reported more frequently in the pertuzumab group, compared with the control group.

"The events were mostly grade 1 or 2 and occurred during the period of concomitant docetaxel administration," the researchers wrote. "Grade 3 or higher febrile neutropenia and diarrhea were also increased in the pertuzumab group."

Dr. Baselga and his associates went on to state that the study findings "suggest that targeting HER2-positive tumors with two anti-HER2 monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of HER2 and highlights the clinical importance of preventing the ligand-dependent formation of HER2 dimers in order to silence HER2 signaling to the greatest extent possible."

The study was funded by F. Hoffmann-LaRoche and Genentech. Dr. Baselga disclosed that he is a member of the scientific advisory board for F. Hoffmann-LaRoche and for numerous other pharmaceutical companies. He is also a paid consultant for F. Hoffmann-LaRoche, Genentech, and for numerous other pharmaceutical companies.

* Correction 12/8/11: An earlier version of this story incorrectly described the regimen in the pertuzumab group. The error has been corrected.

Combined treatment with everolimus and exemestane more than doubled median progression-free survival in postmenopausal women with hormone receptor–positive breast cancer that had advanced previously after hormone therapy.

Compared with exemestane (Aromasin) and placebo, the everolimus (Afinitor) and exemestane combination increased the median progression-free interval from 3.2 months to 7.4 months, according to Dr. Gabriel N. Hortobagyi, who will present new data from the phase III BOLERO-2 trial at the San Antonio Breast Cancer Symposium.

Moreover, the clinical benefit rate doubled from 25.5% to 50.5%, as twice as many women had either a complete or partial response or stable disease exceeding 6 months, Dr. Hortobagyi, professor and chair of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center, will report.

The BOLERO-2 findings could shift standard treatment of therapy-resistant patients from sequential use of aromatase inhibitors to simultaneous inhibition of the estrogen-signaling pathway with an aromatase inhibitor such as exemestane and of the PI3-kinase/AKT/mTOR pathway with everolimus.

"For the first time in a large phase III trial, we have demonstrated that this dual-attack is more effective than a single endocrine treatment for patients who have received prior endocrine therapy," Dr. Hortobagyi said in a press statement.

The gain from addition of an mTOR inhibitor comes with a higher incidence of adverse events such as stomatitis, anemia, and dyspnea in patients taking the combination. "In the current study, a high percentage of patients discontinued everolimus because of lack of tolerability," the BOLERO-2 researchers wrote in a report published online Dec. 7 in the New England Journal of Medicine.

"The longer treatment duration in the combination therapy group might have contributed to the high discontinuation rate. Careful monitoring of patients and increased physician awareness of the safety profile of everolimus are warranted," wrote lead author José Baselga, MD, PhD, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, and his co-authors.

Between June 2009 and January 2011, Dr. Baselga and his associates at 189 centers in 24 countries randomized 485 women with HR-positive breast cancer refractory to nonsteroidal aromatase inhibitors to receive a combination of everolimus and exemestane (combination therapy group), and 239 women to receive exemestane plus placebo (exemestane-alone group) in the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2). The mean age of patients was 62 years, 56% had visceral involvement, and 76% had bone metastasis. The primary end point was progression-free survival (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1109653]).

Dr. Baselga and his associates reported that previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse event was stomatitis (8% in the combination therapy group vs. 1% in the exemestane-alone group), followed by anemia (6% vs. less than 1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. less than 1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).

"Our positive results are consistent with the outcomes of two other studies of everolimus and antiestrogen therapy in patients with HR-positive breast cancer ... [and] the magnitude of the observed benefit compares favorably with that of the limited options available to this group of patients," the researchers wrote.

Nearly twice as many adverse events were reported among patients in the combination therapy group compared with the exemestane-alone group (23% vs. 12%). Dr. Baselga and his associates observed that "a higher percentage of patients discontinued everolimus in the combination therapy group than discontinued placebo in the control group because of adverse events (19% vs. 4%), and withdrawal of consent (5% vs. 2%). For exemestane discontinuation, the corresponding numbers were 7% versus 3% and 7% versus 2%."

The researchers went on to note that the adverse events seen in the combination therapy group "are consistent with those reported with everolimus and other rapamycin analogues and include stomatitis, fatigue and asthenia, diarrhea, cough, pyrexia, and hyperglycemia."

The study was sponsored by Novartis. Dr. Baselga disclosed that he is a member of the scientific advisory board for Novartis and numerous other companies including Merck and Bayer. He also has accepted consulting fees from numerous pharmaceutical companies. Dr. Hortobagyi reported receiving research funds from and serving as a consultant for Novartis. Some of the other researchers have ties to a variety of pharmaceutical companies.

Combined treatment with everolimus and exemestane more than doubled median progression-free survival in postmenopausal women with hormone receptor–positive breast cancer that had advanced previously after hormone therapy.

Compared with exemestane (Aromasin) and placebo, the everolimus (Afinitor) and exemestane combination increased the median progression-free interval from 3.2 months to 7.4 months, according to Dr. Gabriel N. Hortobagyi, who will present new data from the phase III BOLERO-2 trial at the San Antonio Breast Cancer Symposium.

Moreover, the clinical benefit rate doubled from 25.5% to 50.5%, as twice as many women had either a complete or partial response or stable disease exceeding 6 months, Dr. Hortobagyi, professor and chair of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center, will report.

The BOLERO-2 findings could shift standard treatment of therapy-resistant patients from sequential use of aromatase inhibitors to simultaneous inhibition of the estrogen-signaling pathway with an aromatase inhibitor such as exemestane and of the PI3-kinase/AKT/mTOR pathway with everolimus.

"For the first time in a large phase III trial, we have demonstrated that this dual-attack is more effective than a single endocrine treatment for patients who have received prior endocrine therapy," Dr. Hortobagyi said in a press statement.

The gain from addition of an mTOR inhibitor comes with a higher incidence of adverse events such as stomatitis, anemia, and dyspnea in patients taking the combination. "In the current study, a high percentage of patients discontinued everolimus because of lack of tolerability," the BOLERO-2 researchers wrote in a report published online Dec. 7 in the New England Journal of Medicine.

"The longer treatment duration in the combination therapy group might have contributed to the high discontinuation rate. Careful monitoring of patients and increased physician awareness of the safety profile of everolimus are warranted," wrote lead author José Baselga, MD, PhD, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, and his co-authors.

Between June 2009 and January 2011, Dr. Baselga and his associates at 189 centers in 24 countries randomized 485 women with HR-positive breast cancer refractory to nonsteroidal aromatase inhibitors to receive a combination of everolimus and exemestane (combination therapy group), and 239 women to receive exemestane plus placebo (exemestane-alone group) in the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2). The mean age of patients was 62 years, 56% had visceral involvement, and 76% had bone metastasis. The primary end point was progression-free survival (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1109653]).

Dr. Baselga and his associates reported that previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse event was stomatitis (8% in the combination therapy group vs. 1% in the exemestane-alone group), followed by anemia (6% vs. less than 1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. less than 1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).

"Our positive results are consistent with the outcomes of two other studies of everolimus and antiestrogen therapy in patients with HR-positive breast cancer ... [and] the magnitude of the observed benefit compares favorably with that of the limited options available to this group of patients," the researchers wrote.

Nearly twice as many adverse events were reported among patients in the combination therapy group compared with the exemestane-alone group (23% vs. 12%). Dr. Baselga and his associates observed that "a higher percentage of patients discontinued everolimus in the combination therapy group than discontinued placebo in the control group because of adverse events (19% vs. 4%), and withdrawal of consent (5% vs. 2%). For exemestane discontinuation, the corresponding numbers were 7% versus 3% and 7% versus 2%."

The researchers went on to note that the adverse events seen in the combination therapy group "are consistent with those reported with everolimus and other rapamycin analogues and include stomatitis, fatigue and asthenia, diarrhea, cough, pyrexia, and hyperglycemia."

The study was sponsored by Novartis. Dr. Baselga disclosed that he is a member of the scientific advisory board for Novartis and numerous other companies including Merck and Bayer. He also has accepted consulting fees from numerous pharmaceutical companies. Dr. Hortobagyi reported receiving research funds from and serving as a consultant for Novartis. Some of the other researchers have ties to a variety of pharmaceutical companies.

Combined treatment with everolimus and exemestane more than doubled median progression-free survival in postmenopausal women with hormone receptor–positive breast cancer that had advanced previously after hormone therapy.

Compared with exemestane (Aromasin) and placebo, the everolimus (Afinitor) and exemestane combination increased the median progression-free interval from 3.2 months to 7.4 months, according to Dr. Gabriel N. Hortobagyi, who will present new data from the phase III BOLERO-2 trial at the San Antonio Breast Cancer Symposium.

Moreover, the clinical benefit rate doubled from 25.5% to 50.5%, as twice as many women had either a complete or partial response or stable disease exceeding 6 months, Dr. Hortobagyi, professor and chair of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center, will report.

The BOLERO-2 findings could shift standard treatment of therapy-resistant patients from sequential use of aromatase inhibitors to simultaneous inhibition of the estrogen-signaling pathway with an aromatase inhibitor such as exemestane and of the PI3-kinase/AKT/mTOR pathway with everolimus.

"For the first time in a large phase III trial, we have demonstrated that this dual-attack is more effective than a single endocrine treatment for patients who have received prior endocrine therapy," Dr. Hortobagyi said in a press statement.

The gain from addition of an mTOR inhibitor comes with a higher incidence of adverse events such as stomatitis, anemia, and dyspnea in patients taking the combination. "In the current study, a high percentage of patients discontinued everolimus because of lack of tolerability," the BOLERO-2 researchers wrote in a report published online Dec. 7 in the New England Journal of Medicine.

"The longer treatment duration in the combination therapy group might have contributed to the high discontinuation rate. Careful monitoring of patients and increased physician awareness of the safety profile of everolimus are warranted," wrote lead author José Baselga, MD, PhD, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, and his co-authors.

Between June 2009 and January 2011, Dr. Baselga and his associates at 189 centers in 24 countries randomized 485 women with HR-positive breast cancer refractory to nonsteroidal aromatase inhibitors to receive a combination of everolimus and exemestane (combination therapy group), and 239 women to receive exemestane plus placebo (exemestane-alone group) in the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2). The mean age of patients was 62 years, 56% had visceral involvement, and 76% had bone metastasis. The primary end point was progression-free survival (N. Engl. J. Med. 2011 Dec. 7 [doi: 10.1056/NEJMoa1109653]).

Dr. Baselga and his associates reported that previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse event was stomatitis (8% in the combination therapy group vs. 1% in the exemestane-alone group), followed by anemia (6% vs. less than 1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. less than 1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).

"Our positive results are consistent with the outcomes of two other studies of everolimus and antiestrogen therapy in patients with HR-positive breast cancer ... [and] the magnitude of the observed benefit compares favorably with that of the limited options available to this group of patients," the researchers wrote.

Nearly twice as many adverse events were reported among patients in the combination therapy group compared with the exemestane-alone group (23% vs. 12%). Dr. Baselga and his associates observed that "a higher percentage of patients discontinued everolimus in the combination therapy group than discontinued placebo in the control group because of adverse events (19% vs. 4%), and withdrawal of consent (5% vs. 2%). For exemestane discontinuation, the corresponding numbers were 7% versus 3% and 7% versus 2%."

The researchers went on to note that the adverse events seen in the combination therapy group "are consistent with those reported with everolimus and other rapamycin analogues and include stomatitis, fatigue and asthenia, diarrhea, cough, pyrexia, and hyperglycemia."

The study was sponsored by Novartis. Dr. Baselga disclosed that he is a member of the scientific advisory board for Novartis and numerous other companies including Merck and Bayer. He also has accepted consulting fees from numerous pharmaceutical companies. Dr. Hortobagyi reported receiving research funds from and serving as a consultant for Novartis. Some of the other researchers have ties to a variety of pharmaceutical companies.

SAN ANTONIO – Women may reduce their risk of breast cancer by avoiding unnecessary medical radiation throughout life, avoiding the use of combined estrogen-progestin hormone therapy after menopause, avoiding smoking, limiting alcohol intake, and increasing physical activity level, according to a report by the Institute of Medicine’s Committee on Breast Cancer and the Environment.

The committee was convened in response to a request by Susan G. Komen for the Cure to review evidence on the contribution of environmental exposures to the development of breast cancer. "Environment" was broadly interpreted to include all nongenetic contributors to breast cancer development, from growth patterns to chemical and microbial exposures to social and cultural practices across the lifespan.

The most consistent evidence backs a link between breast cancer and combined hormone therapy, exposure to ionizing radiation, excess weight after menopause, and alcohol consumption. The evidence regarding smoking and breast cancer is less consistent, with some studies showing a causal relationship and others showing limited evidence of a relationship, according to the findings, which were reported during a press briefing held in conjunction with the San Antonio Breast Cancer Symposium.

Evidence is particularly conflicting with regard to physical activity, personal use of hair dyes, and exposure to non-ionizing radiation such as that emitted by microwave ovens and other electrical devices.

Possible associations with even less persuasive evidence include secondhand smoke exposure, nighttime shift work (possibly through disruptions to circadian rhythm), and exposures to benzene, ethylene oxide, and 1,3-butadiene. Exposure to bisphenol A (BPA) presents a "plausible hazard" for which little data exist.

In general, environmental factors found to have any possible link with breast cancer development were associated with less than a doubling of risk.

For an individual woman, the potential risk reduction from avoiding environmental factors would vary, and "may be small or may be moderate," committee chair, Irva Hertz-Picciotto, Ph.D., a professor at the school of medicine at the University of California, Davis, said during the press briefing.

Nonetheless, the impact of risk factor avoidance could be important at a population level, according to the report.

The IOM committee focused on initial breast cancer occurrence, taking into account changes in the breast over a woman’s lifetime, as well as the potential influence of the timing of certain exposures. Diagnosis, treatment, and screening practices were not addressed.

The committee analyzed evidence amassed by the International Agency for Research on Cancer, the World Cancer Research Fund International, and other authoritative organizations. Those data were supplemented by reviews and original research reports from the peer-reviewed literature.

Evidence reviewed primarily focused on exposure during adulthood so the committee was unable to address the effects of various exposures across the life course. Also, many chemical exposures have never been studied in regard to their association with breast cancer.

Furthermore, the contribution of genetic factors and potential gene-environment associations are difficult to assess, the committee conceded.

Topics considered high priority for further research include the role of shift work, endocrine activity, and genotoxicity. Furthermore, research is needed on the "biologic significance of life stages at which environmental risk factors are encountered, what steps may counter their effects, when preventive actions can be most effective, and whether opportunities for prevention can be found for the variety of forms of breast cancer," according to the report.

The report provides a number of strategies for counseling women about how to best prevent breast cancer, according to Dr. Robert Hiatt, a committee member and deputy director of the Comprehensive Cancer Center at the University of California, San Francisco. For example, doctors need to address with their patients the issue of ionizing radiation exposure.

The IOM report was supported by a contract between the National Academy of Sciences and Susan G. Komen for the Cure. Individual authors had no conflicts of interest, according to NAS protocols.

SAN ANTONIO – Women may reduce their risk of breast cancer by avoiding unnecessary medical radiation throughout life, avoiding the use of combined estrogen-progestin hormone therapy after menopause, avoiding smoking, limiting alcohol intake, and increasing physical activity level, according to a report by the Institute of Medicine’s Committee on Breast Cancer and the Environment.

The committee was convened in response to a request by Susan G. Komen for the Cure to review evidence on the contribution of environmental exposures to the development of breast cancer. "Environment" was broadly interpreted to include all nongenetic contributors to breast cancer development, from growth patterns to chemical and microbial exposures to social and cultural practices across the lifespan.

The most consistent evidence backs a link between breast cancer and combined hormone therapy, exposure to ionizing radiation, excess weight after menopause, and alcohol consumption. The evidence regarding smoking and breast cancer is less consistent, with some studies showing a causal relationship and others showing limited evidence of a relationship, according to the findings, which were reported during a press briefing held in conjunction with the San Antonio Breast Cancer Symposium.

Evidence is particularly conflicting with regard to physical activity, personal use of hair dyes, and exposure to non-ionizing radiation such as that emitted by microwave ovens and other electrical devices.

Possible associations with even less persuasive evidence include secondhand smoke exposure, nighttime shift work (possibly through disruptions to circadian rhythm), and exposures to benzene, ethylene oxide, and 1,3-butadiene. Exposure to bisphenol A (BPA) presents a "plausible hazard" for which little data exist.

In general, environmental factors found to have any possible link with breast cancer development were associated with less than a doubling of risk.

For an individual woman, the potential risk reduction from avoiding environmental factors would vary, and "may be small or may be moderate," committee chair, Irva Hertz-Picciotto, Ph.D., a professor at the school of medicine at the University of California, Davis, said during the press briefing.

Nonetheless, the impact of risk factor avoidance could be important at a population level, according to the report.

The IOM committee focused on initial breast cancer occurrence, taking into account changes in the breast over a woman’s lifetime, as well as the potential influence of the timing of certain exposures. Diagnosis, treatment, and screening practices were not addressed.

The committee analyzed evidence amassed by the International Agency for Research on Cancer, the World Cancer Research Fund International, and other authoritative organizations. Those data were supplemented by reviews and original research reports from the peer-reviewed literature.

Evidence reviewed primarily focused on exposure during adulthood so the committee was unable to address the effects of various exposures across the life course. Also, many chemical exposures have never been studied in regard to their association with breast cancer.

Furthermore, the contribution of genetic factors and potential gene-environment associations are difficult to assess, the committee conceded.

Topics considered high priority for further research include the role of shift work, endocrine activity, and genotoxicity. Furthermore, research is needed on the "biologic significance of life stages at which environmental risk factors are encountered, what steps may counter their effects, when preventive actions can be most effective, and whether opportunities for prevention can be found for the variety of forms of breast cancer," according to the report.

The report provides a number of strategies for counseling women about how to best prevent breast cancer, according to Dr. Robert Hiatt, a committee member and deputy director of the Comprehensive Cancer Center at the University of California, San Francisco. For example, doctors need to address with their patients the issue of ionizing radiation exposure.

The IOM report was supported by a contract between the National Academy of Sciences and Susan G. Komen for the Cure. Individual authors had no conflicts of interest, according to NAS protocols.

SAN ANTONIO – Women may reduce their risk of breast cancer by avoiding unnecessary medical radiation throughout life, avoiding the use of combined estrogen-progestin hormone therapy after menopause, avoiding smoking, limiting alcohol intake, and increasing physical activity level, according to a report by the Institute of Medicine’s Committee on Breast Cancer and the Environment.

The committee was convened in response to a request by Susan G. Komen for the Cure to review evidence on the contribution of environmental exposures to the development of breast cancer. "Environment" was broadly interpreted to include all nongenetic contributors to breast cancer development, from growth patterns to chemical and microbial exposures to social and cultural practices across the lifespan.

The most consistent evidence backs a link between breast cancer and combined hormone therapy, exposure to ionizing radiation, excess weight after menopause, and alcohol consumption. The evidence regarding smoking and breast cancer is less consistent, with some studies showing a causal relationship and others showing limited evidence of a relationship, according to the findings, which were reported during a press briefing held in conjunction with the San Antonio Breast Cancer Symposium.

Evidence is particularly conflicting with regard to physical activity, personal use of hair dyes, and exposure to non-ionizing radiation such as that emitted by microwave ovens and other electrical devices.

Possible associations with even less persuasive evidence include secondhand smoke exposure, nighttime shift work (possibly through disruptions to circadian rhythm), and exposures to benzene, ethylene oxide, and 1,3-butadiene. Exposure to bisphenol A (BPA) presents a "plausible hazard" for which little data exist.

In general, environmental factors found to have any possible link with breast cancer development were associated with less than a doubling of risk.

For an individual woman, the potential risk reduction from avoiding environmental factors would vary, and "may be small or may be moderate," committee chair, Irva Hertz-Picciotto, Ph.D., a professor at the school of medicine at the University of California, Davis, said during the press briefing.

Nonetheless, the impact of risk factor avoidance could be important at a population level, according to the report.

The IOM committee focused on initial breast cancer occurrence, taking into account changes in the breast over a woman’s lifetime, as well as the potential influence of the timing of certain exposures. Diagnosis, treatment, and screening practices were not addressed.

The committee analyzed evidence amassed by the International Agency for Research on Cancer, the World Cancer Research Fund International, and other authoritative organizations. Those data were supplemented by reviews and original research reports from the peer-reviewed literature.

Evidence reviewed primarily focused on exposure during adulthood so the committee was unable to address the effects of various exposures across the life course. Also, many chemical exposures have never been studied in regard to their association with breast cancer.

Furthermore, the contribution of genetic factors and potential gene-environment associations are difficult to assess, the committee conceded.

Topics considered high priority for further research include the role of shift work, endocrine activity, and genotoxicity. Furthermore, research is needed on the "biologic significance of life stages at which environmental risk factors are encountered, what steps may counter their effects, when preventive actions can be most effective, and whether opportunities for prevention can be found for the variety of forms of breast cancer," according to the report.

The report provides a number of strategies for counseling women about how to best prevent breast cancer, according to Dr. Robert Hiatt, a committee member and deputy director of the Comprehensive Cancer Center at the University of California, San Francisco. For example, doctors need to address with their patients the issue of ionizing radiation exposure.

The IOM report was supported by a contract between the National Academy of Sciences and Susan G. Komen for the Cure. Individual authors had no conflicts of interest, according to NAS protocols.

SAN ANTONIO – Adding zoledronic acid to adjuvant endocrine therapy significantly improves disease-free and overall survival in premenopausal women with endocrine-receptor–positive early breast cancer at 7 years’ follow-up, Dr. Michael Gnant reported today at the San Antonio Breast Cancer Symposium.

Women in the ABCSG (Austrian Breast and Colorectal Cancer Study Group)-12 trial randomized to receive zoledronic acid in addition to ovarian function suppression and endocrine therapy had a 28% reduction in risk of recurrence and 37% reduction in mortality risk at 84 months, compared with women randomized to adjuvant endocrine therapy alone, according to Dr. Gnant, professor of surgery at the Medical University of Vienna.

The findings confirm data previously reported by the ABCSG-12 investigators demonstrating disease-free and overall survival benefits associated with the treatment regimen at 48 and 62 months of follow up (Lancet Oncol. 2011;12:631-41). "The continued success of this treatment means we can intervene early and still observe persistence of the benefit of treatment," said Dr. Gnant, president of the ABSCG.

The four-arm open-label trial randomly assigned 1,803 women to ovarian suppression and endocrine therapy plus or minus zoledronic acid for 3 years. Investigators used log-rank tests and Cox models to evaluate disease-free survival and overall survival, Dr. Gnant explained.

All of the patients, mean age 44.5 years, were premenopausal and had undergone surgery for stage I or II hormone receptor–positive breast cancer. They were treated for 3 years with 3.6 mg subcutaneous goserelin every 28 days, and randomized to 20 mg of oral tamoxifen daily plus placebo, 1 mg of oral anastrozole daily plus placebo, or either of the latter with 4 mg intravenous zoledronic acid every 6 months.

At a median 84 months’ follow-up, the hazard ratios for breast cancer recurrence and death, respectively, for women receiving adjuvant zoledronic acid were .72 and .63, Dr. Gnant reported, noting that the reductions remained significant in univariate and multivariate analyses. Further, in multivariate analysis, "there was no interaction between zoledronic acid and tumor parameters or endocrine therapy," he said. "The hazard ratios were identical for small and large tumors, node-positive and node-negative tumors, and for patients receiving anastrozole and tamoxifen."

There was a strong interaction between zoledronic acid and age in terms of survival benefit, however, with patients older than 40 years experiencing a 34% reduction in recurrence risk and a 44% reduction in mortality, according to Dr. Gnant. No similarly significant survival benefits were observed among patients younger than 40 years, he said.

As expected, patients receiving zoledronic acid experienced more arthralgia, Dr. Gnant stated, "but, importantly, there were no cases of osteonecrosis of the jaw and no renal failure in the treatment population."

The findings, which are consistent with those seen in the postmenopausal cohort of the AZURE trial, "suggest that estrogen deprivation and reduction of bone turnover-derived growth factors in the bone marrow microenvironment are needed to sufficiently suppress dormant micrometastases," Dr. Gnant explained. Together with the known bone-protective benefits of zoledronic acid, the new data provide sufficient support for adding the bisphosphonate to adjuvant endocrine therapy in premenopausal women with early endocrine-receptor–positive breast cancer, he said.

Dr. James N. Ingle of the Mayo Clinic in Rochester, Minn., the discussant for the session, concluded that the ABCSG-12 findings provide level-one evidence for the value of adding zoledronic acid to goserelin and tamoxifen or anastrozole in this patient population. "Zoledronic acid as standard of care [in these patients] will be more widely accepted when the results of the ongoing SOFT [Suppression of Ovarian Function trial] are reported," which will clarify the value of tamoxifen vs. exemestane (Aromasin) in conjunction with ovarian suppression, he said.

Dr. Gnant and Dr. Ingle reported having no relevant financial disclosures.

SAN ANTONIO – Adding zoledronic acid to adjuvant endocrine therapy significantly improves disease-free and overall survival in premenopausal women with endocrine-receptor–positive early breast cancer at 7 years’ follow-up, Dr. Michael Gnant reported today at the San Antonio Breast Cancer Symposium.

Women in the ABCSG (Austrian Breast and Colorectal Cancer Study Group)-12 trial randomized to receive zoledronic acid in addition to ovarian function suppression and endocrine therapy had a 28% reduction in risk of recurrence and 37% reduction in mortality risk at 84 months, compared with women randomized to adjuvant endocrine therapy alone, according to Dr. Gnant, professor of surgery at the Medical University of Vienna.

The findings confirm data previously reported by the ABCSG-12 investigators demonstrating disease-free and overall survival benefits associated with the treatment regimen at 48 and 62 months of follow up (Lancet Oncol. 2011;12:631-41). "The continued success of this treatment means we can intervene early and still observe persistence of the benefit of treatment," said Dr. Gnant, president of the ABSCG.

The four-arm open-label trial randomly assigned 1,803 women to ovarian suppression and endocrine therapy plus or minus zoledronic acid for 3 years. Investigators used log-rank tests and Cox models to evaluate disease-free survival and overall survival, Dr. Gnant explained.

All of the patients, mean age 44.5 years, were premenopausal and had undergone surgery for stage I or II hormone receptor–positive breast cancer. They were treated for 3 years with 3.6 mg subcutaneous goserelin every 28 days, and randomized to 20 mg of oral tamoxifen daily plus placebo, 1 mg of oral anastrozole daily plus placebo, or either of the latter with 4 mg intravenous zoledronic acid every 6 months.

At a median 84 months’ follow-up, the hazard ratios for breast cancer recurrence and death, respectively, for women receiving adjuvant zoledronic acid were .72 and .63, Dr. Gnant reported, noting that the reductions remained significant in univariate and multivariate analyses. Further, in multivariate analysis, "there was no interaction between zoledronic acid and tumor parameters or endocrine therapy," he said. "The hazard ratios were identical for small and large tumors, node-positive and node-negative tumors, and for patients receiving anastrozole and tamoxifen."

There was a strong interaction between zoledronic acid and age in terms of survival benefit, however, with patients older than 40 years experiencing a 34% reduction in recurrence risk and a 44% reduction in mortality, according to Dr. Gnant. No similarly significant survival benefits were observed among patients younger than 40 years, he said.

As expected, patients receiving zoledronic acid experienced more arthralgia, Dr. Gnant stated, "but, importantly, there were no cases of osteonecrosis of the jaw and no renal failure in the treatment population."

The findings, which are consistent with those seen in the postmenopausal cohort of the AZURE trial, "suggest that estrogen deprivation and reduction of bone turnover-derived growth factors in the bone marrow microenvironment are needed to sufficiently suppress dormant micrometastases," Dr. Gnant explained. Together with the known bone-protective benefits of zoledronic acid, the new data provide sufficient support for adding the bisphosphonate to adjuvant endocrine therapy in premenopausal women with early endocrine-receptor–positive breast cancer, he said.

Dr. James N. Ingle of the Mayo Clinic in Rochester, Minn., the discussant for the session, concluded that the ABCSG-12 findings provide level-one evidence for the value of adding zoledronic acid to goserelin and tamoxifen or anastrozole in this patient population. "Zoledronic acid as standard of care [in these patients] will be more widely accepted when the results of the ongoing SOFT [Suppression of Ovarian Function trial] are reported," which will clarify the value of tamoxifen vs. exemestane (Aromasin) in conjunction with ovarian suppression, he said.

Dr. Gnant and Dr. Ingle reported having no relevant financial disclosures.

SAN ANTONIO – Adding zoledronic acid to adjuvant endocrine therapy significantly improves disease-free and overall survival in premenopausal women with endocrine-receptor–positive early breast cancer at 7 years’ follow-up, Dr. Michael Gnant reported today at the San Antonio Breast Cancer Symposium.

Women in the ABCSG (Austrian Breast and Colorectal Cancer Study Group)-12 trial randomized to receive zoledronic acid in addition to ovarian function suppression and endocrine therapy had a 28% reduction in risk of recurrence and 37% reduction in mortality risk at 84 months, compared with women randomized to adjuvant endocrine therapy alone, according to Dr. Gnant, professor of surgery at the Medical University of Vienna.

The findings confirm data previously reported by the ABCSG-12 investigators demonstrating disease-free and overall survival benefits associated with the treatment regimen at 48 and 62 months of follow up (Lancet Oncol. 2011;12:631-41). "The continued success of this treatment means we can intervene early and still observe persistence of the benefit of treatment," said Dr. Gnant, president of the ABSCG.

The four-arm open-label trial randomly assigned 1,803 women to ovarian suppression and endocrine therapy plus or minus zoledronic acid for 3 years. Investigators used log-rank tests and Cox models to evaluate disease-free survival and overall survival, Dr. Gnant explained.

All of the patients, mean age 44.5 years, were premenopausal and had undergone surgery for stage I or II hormone receptor–positive breast cancer. They were treated for 3 years with 3.6 mg subcutaneous goserelin every 28 days, and randomized to 20 mg of oral tamoxifen daily plus placebo, 1 mg of oral anastrozole daily plus placebo, or either of the latter with 4 mg intravenous zoledronic acid every 6 months.

At a median 84 months’ follow-up, the hazard ratios for breast cancer recurrence and death, respectively, for women receiving adjuvant zoledronic acid were .72 and .63, Dr. Gnant reported, noting that the reductions remained significant in univariate and multivariate analyses. Further, in multivariate analysis, "there was no interaction between zoledronic acid and tumor parameters or endocrine therapy," he said. "The hazard ratios were identical for small and large tumors, node-positive and node-negative tumors, and for patients receiving anastrozole and tamoxifen."

There was a strong interaction between zoledronic acid and age in terms of survival benefit, however, with patients older than 40 years experiencing a 34% reduction in recurrence risk and a 44% reduction in mortality, according to Dr. Gnant. No similarly significant survival benefits were observed among patients younger than 40 years, he said.

As expected, patients receiving zoledronic acid experienced more arthralgia, Dr. Gnant stated, "but, importantly, there were no cases of osteonecrosis of the jaw and no renal failure in the treatment population."

The findings, which are consistent with those seen in the postmenopausal cohort of the AZURE trial, "suggest that estrogen deprivation and reduction of bone turnover-derived growth factors in the bone marrow microenvironment are needed to sufficiently suppress dormant micrometastases," Dr. Gnant explained. Together with the known bone-protective benefits of zoledronic acid, the new data provide sufficient support for adding the bisphosphonate to adjuvant endocrine therapy in premenopausal women with early endocrine-receptor–positive breast cancer, he said.

Dr. James N. Ingle of the Mayo Clinic in Rochester, Minn., the discussant for the session, concluded that the ABCSG-12 findings provide level-one evidence for the value of adding zoledronic acid to goserelin and tamoxifen or anastrozole in this patient population. "Zoledronic acid as standard of care [in these patients] will be more widely accepted when the results of the ongoing SOFT [Suppression of Ovarian Function trial] are reported," which will clarify the value of tamoxifen vs. exemestane (Aromasin) in conjunction with ovarian suppression, he said.

Dr. Gnant and Dr. Ingle reported having no relevant financial disclosures.

SAN ANTONIO – An investigational genetic test may not only be able to differentiate women likely to have early recurrence of estrogen receptor–positive breast cancer but also could lead to novel combinations of existing drugs to treat these patients earlier in the disease process, according to Dr. Minetta C. Liu.

Researchers developed a 91-gene classifier "that essentially separated those patients who were going to recur early [within 3 years] vs. those who were going to recur late [beyond 10 years]," Dr. Liu announced at a press briefing held during the San Antonio Breast Cancer Symposium.

"Our work is very much hypothesis generating. To be able to identify early vs. late recurrences at the time of diagnosis would be useful, but we actually need to be able to know what to do about it once we identify it," said Dr. Liu, director of translational breast cancer research at Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

The ability to reliably predict early treatment failure may help to identify patients who require agents beyond endocrine therapy to prevent the early onset of distant metastases, she said. "We hope to exploit these molecular differences of early vs. later recurrences to help us guide novel drug combinations in ER–positive early-stage disease," Dr. Liu added.

Session moderator Dr. Jennifer A. Ligibel of Dana-Farber Cancer Institute, Boston, agreed: This type of analysis "will help us to give chemotherapy to fewer patients potentially, if they do not have tumors that are consistent with early relapse and to know which patients really require extended therapy beyond the initial 5 years of treatment of endocrine therapy for patients who are potentially destined for late relapse."

The researchers acquired snap-frozen, pretreatment tumor biopsies collected at the Edinburgh Breakthrough Research Unit in Scotland between 1982 and 1990. The samples were from patients with stages I-III estrogen receptor–positive breast cancer, starting tamoxifen-alone adjuvant treatment. These patients had to have at least a 10-year follow-up in the absence of distant release.

A histology review was performed of the samples and those that contained at least 50% tumor were cleared for RNA extraction for gene expression profiling.

This training data set included 111 samples, with 57 relapses. Tumors from patients with relapse were subdivided into early recurrence (within 3 years of diagnosis) and late recurrence (more than 10 years). A total of 25 patients had early recurrences and 22 had late recurrences. Median follow-up was 13 years.

The investigators selected a validation data set from the literature that met certain criteria, such as quality of data and follow-up (BMC Genomics 2008;9:239). This previously published data set included 255 samples from patients with stages I-II estrogen receptor–positive breast cancer with tamoxifen-alone adjuvant treatment. Of these, 67 had distant relapse – 25 patients had early recurrences and 7 had late recurrences. The median follow-up was 9 years.

Using this training data set, the researchers developed a 91-gene classifier "that essentially separated those patients, who were going to recur early vs. those who were going to recur late," Dr. Liu said. They optimized the classifier and applied it to a validation data set.

"We had very high accuracy, sensitivity, specificity, positive predictive value, and negative predictive value," said Dr. Liu. However, "we didn’t stop at developing a classifier. We wanted to understand what these genes are trying to tell us within the classifier. ... A novel computational method allowed us to look at [estrogen receptor]network topology – to create a map basically."

The investigators identified several genes that were overexpressed in patients with early recurrences: CALM1, CALM2, CALM3, SRC, CDK1, and MAPK1. They also identified genes that had increased expression in patients with late recurrences: ESR1, ESR2, EGFR, BCL2, and AR.

"Clearly there are robust molecular differences between those tumors that recur early versus those that recur much later despite adjuvant tamoxifen. The majority of the genes in our classifier relate to apoptosis and proliferation," said Dr. Liu.

"I want to emphasize that we’re not just about developing a score and identifying these patients. We actually want to do something about it and understand what the underlying mechanisms are behind these genetic differences."

Dr. Liu reported that she has no relevant financial disclosures.

SAN ANTONIO – An investigational genetic test may not only be able to differentiate women likely to have early recurrence of estrogen receptor–positive breast cancer but also could lead to novel combinations of existing drugs to treat these patients earlier in the disease process, according to Dr. Minetta C. Liu.

Researchers developed a 91-gene classifier "that essentially separated those patients who were going to recur early [within 3 years] vs. those who were going to recur late [beyond 10 years]," Dr. Liu announced at a press briefing held during the San Antonio Breast Cancer Symposium.

"Our work is very much hypothesis generating. To be able to identify early vs. late recurrences at the time of diagnosis would be useful, but we actually need to be able to know what to do about it once we identify it," said Dr. Liu, director of translational breast cancer research at Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

The ability to reliably predict early treatment failure may help to identify patients who require agents beyond endocrine therapy to prevent the early onset of distant metastases, she said. "We hope to exploit these molecular differences of early vs. later recurrences to help us guide novel drug combinations in ER–positive early-stage disease," Dr. Liu added.

Session moderator Dr. Jennifer A. Ligibel of Dana-Farber Cancer Institute, Boston, agreed: This type of analysis "will help us to give chemotherapy to fewer patients potentially, if they do not have tumors that are consistent with early relapse and to know which patients really require extended therapy beyond the initial 5 years of treatment of endocrine therapy for patients who are potentially destined for late relapse."

The researchers acquired snap-frozen, pretreatment tumor biopsies collected at the Edinburgh Breakthrough Research Unit in Scotland between 1982 and 1990. The samples were from patients with stages I-III estrogen receptor–positive breast cancer, starting tamoxifen-alone adjuvant treatment. These patients had to have at least a 10-year follow-up in the absence of distant release.

A histology review was performed of the samples and those that contained at least 50% tumor were cleared for RNA extraction for gene expression profiling.

This training data set included 111 samples, with 57 relapses. Tumors from patients with relapse were subdivided into early recurrence (within 3 years of diagnosis) and late recurrence (more than 10 years). A total of 25 patients had early recurrences and 22 had late recurrences. Median follow-up was 13 years.

The investigators selected a validation data set from the literature that met certain criteria, such as quality of data and follow-up (BMC Genomics 2008;9:239). This previously published data set included 255 samples from patients with stages I-II estrogen receptor–positive breast cancer with tamoxifen-alone adjuvant treatment. Of these, 67 had distant relapse – 25 patients had early recurrences and 7 had late recurrences. The median follow-up was 9 years.

Using this training data set, the researchers developed a 91-gene classifier "that essentially separated those patients, who were going to recur early vs. those who were going to recur late," Dr. Liu said. They optimized the classifier and applied it to a validation data set.

"We had very high accuracy, sensitivity, specificity, positive predictive value, and negative predictive value," said Dr. Liu. However, "we didn’t stop at developing a classifier. We wanted to understand what these genes are trying to tell us within the classifier. ... A novel computational method allowed us to look at [estrogen receptor]network topology – to create a map basically."

The investigators identified several genes that were overexpressed in patients with early recurrences: CALM1, CALM2, CALM3, SRC, CDK1, and MAPK1. They also identified genes that had increased expression in patients with late recurrences: ESR1, ESR2, EGFR, BCL2, and AR.

"Clearly there are robust molecular differences between those tumors that recur early versus those that recur much later despite adjuvant tamoxifen. The majority of the genes in our classifier relate to apoptosis and proliferation," said Dr. Liu.

"I want to emphasize that we’re not just about developing a score and identifying these patients. We actually want to do something about it and understand what the underlying mechanisms are behind these genetic differences."

Dr. Liu reported that she has no relevant financial disclosures.

SAN ANTONIO – An investigational genetic test may not only be able to differentiate women likely to have early recurrence of estrogen receptor–positive breast cancer but also could lead to novel combinations of existing drugs to treat these patients earlier in the disease process, according to Dr. Minetta C. Liu.

Researchers developed a 91-gene classifier "that essentially separated those patients who were going to recur early [within 3 years] vs. those who were going to recur late [beyond 10 years]," Dr. Liu announced at a press briefing held during the San Antonio Breast Cancer Symposium.

"Our work is very much hypothesis generating. To be able to identify early vs. late recurrences at the time of diagnosis would be useful, but we actually need to be able to know what to do about it once we identify it," said Dr. Liu, director of translational breast cancer research at Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

The ability to reliably predict early treatment failure may help to identify patients who require agents beyond endocrine therapy to prevent the early onset of distant metastases, she said. "We hope to exploit these molecular differences of early vs. later recurrences to help us guide novel drug combinations in ER–positive early-stage disease," Dr. Liu added.

Session moderator Dr. Jennifer A. Ligibel of Dana-Farber Cancer Institute, Boston, agreed: This type of analysis "will help us to give chemotherapy to fewer patients potentially, if they do not have tumors that are consistent with early relapse and to know which patients really require extended therapy beyond the initial 5 years of treatment of endocrine therapy for patients who are potentially destined for late relapse."

The researchers acquired snap-frozen, pretreatment tumor biopsies collected at the Edinburgh Breakthrough Research Unit in Scotland between 1982 and 1990. The samples were from patients with stages I-III estrogen receptor–positive breast cancer, starting tamoxifen-alone adjuvant treatment. These patients had to have at least a 10-year follow-up in the absence of distant release.

A histology review was performed of the samples and those that contained at least 50% tumor were cleared for RNA extraction for gene expression profiling.

This training data set included 111 samples, with 57 relapses. Tumors from patients with relapse were subdivided into early recurrence (within 3 years of diagnosis) and late recurrence (more than 10 years). A total of 25 patients had early recurrences and 22 had late recurrences. Median follow-up was 13 years.

The investigators selected a validation data set from the literature that met certain criteria, such as quality of data and follow-up (BMC Genomics 2008;9:239). This previously published data set included 255 samples from patients with stages I-II estrogen receptor–positive breast cancer with tamoxifen-alone adjuvant treatment. Of these, 67 had distant relapse – 25 patients had early recurrences and 7 had late recurrences. The median follow-up was 9 years.

Using this training data set, the researchers developed a 91-gene classifier "that essentially separated those patients, who were going to recur early vs. those who were going to recur late," Dr. Liu said. They optimized the classifier and applied it to a validation data set.

"We had very high accuracy, sensitivity, specificity, positive predictive value, and negative predictive value," said Dr. Liu. However, "we didn’t stop at developing a classifier. We wanted to understand what these genes are trying to tell us within the classifier. ... A novel computational method allowed us to look at [estrogen receptor]network topology – to create a map basically."

The investigators identified several genes that were overexpressed in patients with early recurrences: CALM1, CALM2, CALM3, SRC, CDK1, and MAPK1. They also identified genes that had increased expression in patients with late recurrences: ESR1, ESR2, EGFR, BCL2, and AR.

"Clearly there are robust molecular differences between those tumors that recur early versus those that recur much later despite adjuvant tamoxifen. The majority of the genes in our classifier relate to apoptosis and proliferation," said Dr. Liu.

"I want to emphasize that we’re not just about developing a score and identifying these patients. We actually want to do something about it and understand what the underlying mechanisms are behind these genetic differences."

Dr. Liu reported that she has no relevant financial disclosures.