Breast Cancer

A telephone-based lifestyle intervention can have a significant effect on weight loss in overweight breast cancer survivors, according to a study that also highlights the dilemmas of funding large lifestyle trials with definitive mortality endpoints.

Mean weight loss at 6 months was greater in women who received telephone-based coaching and were mailed health information vs. women who received mailed information only (5.3% vs. 0.7%; P less than .001), investigators reported online June 16 in the Journal of Clinical Oncology. The study was part of the multicenter LISA(Lifestyle Intervention Study in Adjuvant Treatment of Early Breast Cancer) trial.

At 24 months the weight loss still compared favorably in the intervention group (3.6% loss vs. 0.4% in the mail-only group; P less than .001), reported Dr. Pamela J. Goodwin of the Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, and her associates (J. Clin. Oncol. 2014 June 16 [doi: 10.1200/JCO.2013.53.1517].

But will losing weight improve breast cancer outcomes?

The original aim of LISA was to examine the effect of weight loss on disease-free survival, but patient accrual was terminated early (at 338 of the 2,150 planned participants), because of a loss of funding from sponsor Novartis Pharmaceuticals, leaving that question unanswered.

Patients were eligible to participate in the study if they had been diagnosed in the last 36 months, had a body mass index of 24 kg/m² or higher, and were receiving letrozole for hormone receptor–positive breast cancer. Study participants were randomly assigned to receive general health information by mail, or to a lifestyle intervention where they received weight loss advice by telephone in addition to the health information by mail.

The telephone-based lifestyle intervention included a dietary goal (500-1,000 kcal per day deficit) and a physical activity goal (150-200 minutes of moderate-intensity physical activity per week) to achieve weight loss.

"Our results support the use of telephone-based delivery of weight-loss interventions in patients with breast cancer, and they suggest that our approach will be generally effective in postmenopausal patients receiving an aromatase inhibitor," the investigators concluded.

The results, combined with the recognition that obesity is associated with poor breast cancer outcomes, provide support for a randomized trial using a telephone-based weight-loss intervention that is adequately powered to detect clinically important effects on breast cancer outcomes, they said.

While the findings add to a growing body of evidence supporting the benefits of weight-loss interventions in overweight breast cancer survivors, questions remain regarding the effect of weight loss on breast cancer recurrence and mortality, said Melinda L. Irwin, Ph.D., M.P.H., in an accompanying editorial (J. Clin. Oncol. 2014 June 16 [doi: 10.1200/JCO.2014.56.4583]).

"How can important lifestyle trials with definitive mortality end points best be funded?" asked Dr. Irwin of Yale University, New Haven, Conn. She suggested that pharmaceutical companies be required to include a lifestyle intervention arm in drug trials.

"Given that pharmaceutical companies primarily fund therapeutic trials, with little incentive to fund lifestyle interventions, and given the scarcity of funding from government agencies for large-scale long-term trials of lifestyle interventions with disease-free survival endpoints, another option may be to require pharmaceutical companies to include lifestyle interventions as an active comparison arm to drug trials, especially in cases when drug options provide modest benefit, or uptake or adherence to particular medications [is] low," she said.

The study was funded by Novartis Pharmaceuticals. Dr. Goodwin and Dr. Irwin reported no disclosures. Two coauthors disclosed honoraria or research funding from Novartis and other companies.

A telephone-based lifestyle intervention can have a significant effect on weight loss in overweight breast cancer survivors, according to a study that also highlights the dilemmas of funding large lifestyle trials with definitive mortality endpoints.

Mean weight loss at 6 months was greater in women who received telephone-based coaching and were mailed health information vs. women who received mailed information only (5.3% vs. 0.7%; P less than .001), investigators reported online June 16 in the Journal of Clinical Oncology. The study was part of the multicenter LISA(Lifestyle Intervention Study in Adjuvant Treatment of Early Breast Cancer) trial.

At 24 months the weight loss still compared favorably in the intervention group (3.6% loss vs. 0.4% in the mail-only group; P less than .001), reported Dr. Pamela J. Goodwin of the Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, and her associates (J. Clin. Oncol. 2014 June 16 [doi: 10.1200/JCO.2013.53.1517].

But will losing weight improve breast cancer outcomes?

The original aim of LISA was to examine the effect of weight loss on disease-free survival, but patient accrual was terminated early (at 338 of the 2,150 planned participants), because of a loss of funding from sponsor Novartis Pharmaceuticals, leaving that question unanswered.

Patients were eligible to participate in the study if they had been diagnosed in the last 36 months, had a body mass index of 24 kg/m² or higher, and were receiving letrozole for hormone receptor–positive breast cancer. Study participants were randomly assigned to receive general health information by mail, or to a lifestyle intervention where they received weight loss advice by telephone in addition to the health information by mail.

The telephone-based lifestyle intervention included a dietary goal (500-1,000 kcal per day deficit) and a physical activity goal (150-200 minutes of moderate-intensity physical activity per week) to achieve weight loss.

"Our results support the use of telephone-based delivery of weight-loss interventions in patients with breast cancer, and they suggest that our approach will be generally effective in postmenopausal patients receiving an aromatase inhibitor," the investigators concluded.

The results, combined with the recognition that obesity is associated with poor breast cancer outcomes, provide support for a randomized trial using a telephone-based weight-loss intervention that is adequately powered to detect clinically important effects on breast cancer outcomes, they said.

While the findings add to a growing body of evidence supporting the benefits of weight-loss interventions in overweight breast cancer survivors, questions remain regarding the effect of weight loss on breast cancer recurrence and mortality, said Melinda L. Irwin, Ph.D., M.P.H., in an accompanying editorial (J. Clin. Oncol. 2014 June 16 [doi: 10.1200/JCO.2014.56.4583]).

"How can important lifestyle trials with definitive mortality end points best be funded?" asked Dr. Irwin of Yale University, New Haven, Conn. She suggested that pharmaceutical companies be required to include a lifestyle intervention arm in drug trials.

"Given that pharmaceutical companies primarily fund therapeutic trials, with little incentive to fund lifestyle interventions, and given the scarcity of funding from government agencies for large-scale long-term trials of lifestyle interventions with disease-free survival endpoints, another option may be to require pharmaceutical companies to include lifestyle interventions as an active comparison arm to drug trials, especially in cases when drug options provide modest benefit, or uptake or adherence to particular medications [is] low," she said.

The study was funded by Novartis Pharmaceuticals. Dr. Goodwin and Dr. Irwin reported no disclosures. Two coauthors disclosed honoraria or research funding from Novartis and other companies.

A telephone-based lifestyle intervention can have a significant effect on weight loss in overweight breast cancer survivors, according to a study that also highlights the dilemmas of funding large lifestyle trials with definitive mortality endpoints.

Mean weight loss at 6 months was greater in women who received telephone-based coaching and were mailed health information vs. women who received mailed information only (5.3% vs. 0.7%; P less than .001), investigators reported online June 16 in the Journal of Clinical Oncology. The study was part of the multicenter LISA(Lifestyle Intervention Study in Adjuvant Treatment of Early Breast Cancer) trial.

At 24 months the weight loss still compared favorably in the intervention group (3.6% loss vs. 0.4% in the mail-only group; P less than .001), reported Dr. Pamela J. Goodwin of the Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, and her associates (J. Clin. Oncol. 2014 June 16 [doi: 10.1200/JCO.2013.53.1517].

But will losing weight improve breast cancer outcomes?

The original aim of LISA was to examine the effect of weight loss on disease-free survival, but patient accrual was terminated early (at 338 of the 2,150 planned participants), because of a loss of funding from sponsor Novartis Pharmaceuticals, leaving that question unanswered.

Patients were eligible to participate in the study if they had been diagnosed in the last 36 months, had a body mass index of 24 kg/m² or higher, and were receiving letrozole for hormone receptor–positive breast cancer. Study participants were randomly assigned to receive general health information by mail, or to a lifestyle intervention where they received weight loss advice by telephone in addition to the health information by mail.

The telephone-based lifestyle intervention included a dietary goal (500-1,000 kcal per day deficit) and a physical activity goal (150-200 minutes of moderate-intensity physical activity per week) to achieve weight loss.

"Our results support the use of telephone-based delivery of weight-loss interventions in patients with breast cancer, and they suggest that our approach will be generally effective in postmenopausal patients receiving an aromatase inhibitor," the investigators concluded.

The results, combined with the recognition that obesity is associated with poor breast cancer outcomes, provide support for a randomized trial using a telephone-based weight-loss intervention that is adequately powered to detect clinically important effects on breast cancer outcomes, they said.

While the findings add to a growing body of evidence supporting the benefits of weight-loss interventions in overweight breast cancer survivors, questions remain regarding the effect of weight loss on breast cancer recurrence and mortality, said Melinda L. Irwin, Ph.D., M.P.H., in an accompanying editorial (J. Clin. Oncol. 2014 June 16 [doi: 10.1200/JCO.2014.56.4583]).

"How can important lifestyle trials with definitive mortality end points best be funded?" asked Dr. Irwin of Yale University, New Haven, Conn. She suggested that pharmaceutical companies be required to include a lifestyle intervention arm in drug trials.

"Given that pharmaceutical companies primarily fund therapeutic trials, with little incentive to fund lifestyle interventions, and given the scarcity of funding from government agencies for large-scale long-term trials of lifestyle interventions with disease-free survival endpoints, another option may be to require pharmaceutical companies to include lifestyle interventions as an active comparison arm to drug trials, especially in cases when drug options provide modest benefit, or uptake or adherence to particular medications [is] low," she said.

The study was funded by Novartis Pharmaceuticals. Dr. Goodwin and Dr. Irwin reported no disclosures. Two coauthors disclosed honoraria or research funding from Novartis and other companies.

Older women with breast cancer are less likely to initiate adjuvant hormonal therapy if they are frail, according to researchers.

In a prospective cohort study of women aged 65 and older diagnosed with invasive, nonmetastatic estrogen receptor–positive breast cancers (n = 1,062), about a quarter of the women were frail or prefrail (4.9% and 18.7%, respectively) based on a validated frailty score determined at baseline, reported Vanessa Sheppard, Ph.D., of Georgetown University Medical Center, Washington (J. Clin. Oncol. 2014 June 16 [doi:10.1200/JCO.2013.51.7367]).

Overall, 14% of the women in the study did not initiate hormonal therapy. Women considered prefrail or frail were significantly less likely to initiate therapy than were those considered "robust" or nonfrail (odds ratio, 1.63; 95% CI, 1.11-2.40; P =.013). Nonwhite race was also significantly associated with noninitiation of therapy (OR, 1.71; CI, 1.04-2.80; P = 0.33).

Baseline frailty was not predictive of discontinuation of therapy after a median follow-up of 3 years, Dr. Sheppard and colleagues reported.

The findings suggest "women and/or their providers are making informed judgments about the risks and benefits," the researchers wrote. "An alternative explanation is that women with greater frailty may have been concerned about adverse effects based on interactions of hormonal therapy and specific comorbidities, such as cardio- and/or cerebrovascular disease and risk of thromboembolic events," they added.

Limitations of the study include a potential for bias associated with self-reporting (discontinuation of therapy was measured only through self-report) and measurement of frailty only at baseline, the investigators said.

The National Institutes of Health, Amgen, and the Cancer and Leukemia Group B (CALGB) Foundation funded the study. Four of Dr. Sheppard’s coauthors, Dr. Gretchen Kimmick, Dr. Eric Winer, Dr. Arti Hurria, and Dr. Claudine Isaacs reported ties with pharmaceutical manufacturers.

Older women with breast cancer are less likely to initiate adjuvant hormonal therapy if they are frail, according to researchers.

In a prospective cohort study of women aged 65 and older diagnosed with invasive, nonmetastatic estrogen receptor–positive breast cancers (n = 1,062), about a quarter of the women were frail or prefrail (4.9% and 18.7%, respectively) based on a validated frailty score determined at baseline, reported Vanessa Sheppard, Ph.D., of Georgetown University Medical Center, Washington (J. Clin. Oncol. 2014 June 16 [doi:10.1200/JCO.2013.51.7367]).

Overall, 14% of the women in the study did not initiate hormonal therapy. Women considered prefrail or frail were significantly less likely to initiate therapy than were those considered "robust" or nonfrail (odds ratio, 1.63; 95% CI, 1.11-2.40; P =.013). Nonwhite race was also significantly associated with noninitiation of therapy (OR, 1.71; CI, 1.04-2.80; P = 0.33).

Baseline frailty was not predictive of discontinuation of therapy after a median follow-up of 3 years, Dr. Sheppard and colleagues reported.

The findings suggest "women and/or their providers are making informed judgments about the risks and benefits," the researchers wrote. "An alternative explanation is that women with greater frailty may have been concerned about adverse effects based on interactions of hormonal therapy and specific comorbidities, such as cardio- and/or cerebrovascular disease and risk of thromboembolic events," they added.

Limitations of the study include a potential for bias associated with self-reporting (discontinuation of therapy was measured only through self-report) and measurement of frailty only at baseline, the investigators said.

The National Institutes of Health, Amgen, and the Cancer and Leukemia Group B (CALGB) Foundation funded the study. Four of Dr. Sheppard’s coauthors, Dr. Gretchen Kimmick, Dr. Eric Winer, Dr. Arti Hurria, and Dr. Claudine Isaacs reported ties with pharmaceutical manufacturers.

Older women with breast cancer are less likely to initiate adjuvant hormonal therapy if they are frail, according to researchers.

In a prospective cohort study of women aged 65 and older diagnosed with invasive, nonmetastatic estrogen receptor–positive breast cancers (n = 1,062), about a quarter of the women were frail or prefrail (4.9% and 18.7%, respectively) based on a validated frailty score determined at baseline, reported Vanessa Sheppard, Ph.D., of Georgetown University Medical Center, Washington (J. Clin. Oncol. 2014 June 16 [doi:10.1200/JCO.2013.51.7367]).

Overall, 14% of the women in the study did not initiate hormonal therapy. Women considered prefrail or frail were significantly less likely to initiate therapy than were those considered "robust" or nonfrail (odds ratio, 1.63; 95% CI, 1.11-2.40; P =.013). Nonwhite race was also significantly associated with noninitiation of therapy (OR, 1.71; CI, 1.04-2.80; P = 0.33).

Baseline frailty was not predictive of discontinuation of therapy after a median follow-up of 3 years, Dr. Sheppard and colleagues reported.

The findings suggest "women and/or their providers are making informed judgments about the risks and benefits," the researchers wrote. "An alternative explanation is that women with greater frailty may have been concerned about adverse effects based on interactions of hormonal therapy and specific comorbidities, such as cardio- and/or cerebrovascular disease and risk of thromboembolic events," they added.

Limitations of the study include a potential for bias associated with self-reporting (discontinuation of therapy was measured only through self-report) and measurement of frailty only at baseline, the investigators said.

The National Institutes of Health, Amgen, and the Cancer and Leukemia Group B (CALGB) Foundation funded the study. Four of Dr. Sheppard’s coauthors, Dr. Gretchen Kimmick, Dr. Eric Winer, Dr. Arti Hurria, and Dr. Claudine Isaacs reported ties with pharmaceutical manufacturers.

An expert review panel from the American Society for Clinical Oncology largely endorsed new guidelines for "no ink on tumor" margins in early breast conservation surgery, while emphasizing the role of post-lumpectomy imaging in patients with microcalcifications and adding several other "minor qualifications."

Published earlier this year, the guidelines from the Society of Surgical Oncology (SSO) and the American Society of Radiation Oncology (ASTRO) focus on stage I and II breast cancer patients who are undergoing lumpectomy with whole-breast radiation. In these patients, a "no ink on tumor" margin "is associated with low rates of [ipsilateral breast tumor recurrence] and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs," the guideline’s authors wrote (Ann. Surg. Oncol. 2014;21:704-16). The guidelines mark a step toward consensus on a historically controversial topic. "Widespread adoption of this guideline, which defines a margin as being adequate as long as there is no cancer at the inked lumpectomy surface by microscopic pathology evaluation, will result in fewer re-excision lumpectomies and enhanced cosmesis with breast conserving surgery," said Dr. Lisa Newman.

The recommended margin reflects the current era of treatment, in which better systemic therapies and earlier diagnosis of breast cancer mean that patients may no longer derive extra benefit from thicker or "widely negative" lumpectomy margins, Dr. Newman added in an interview.

Two staff members at ASCO reviewed the guidelines for developmental rigor. The guidelines "scored high (77%) in terms of methodologic quality, with only minor deviations from the ideal," members of the separate ad hoc panel of ASCO experts wrote (J. Clin. Onc. 2014 [doi:10.1200/JCO.2014.55.1572]). But panel members also called for flexibility in applying the guideline, citing the "inherent weaknesses" and "selection bias" of the retrospective, observational studies on which the recommendations were based.

The guidelines provide a framework, but clinical judgment remains important in managing breast-conserving surgery patients, emphasized Dr. Newman, who served as cochair on the ASCO panel that reviewed the guideline and who is a surgical oncologist, professor of surgery, and director of the Breast Care Center for the University of Michigan, Ann Arbor. She said clinicians should carefully evaluate lumpectomy margins, which "can provide important clues regarding the burden of disease in the breast, and the likelihood of successful treatment with lumpectomy and breast radiation."

ASCO panel members also stressed the importance of postsurgical imaging in cases involving microcalcifications. Imaging is important to minimize the risk of leaving pockets of disease in the breast despite achieving microscopically negative margins, Dr. Newman said. Surgeons can work with their colleagues in breast imaging to review microcalcifications and correlate them with pathology findings, she added.

In particular, a lumpectomy specimen that has several close margins and evidence of diffuse disease "may well represent a different category of risk regarding local recurrence, compared to a well defined, unifocal cancer that has a single microscopic focus of cancer abutting one margin," Dr. Newman added. Ideally, surgeons and radiation oncologists should discuss these aspects of cases, and should consider them when counseling patients about outcomes from lumpectomy surgery, she said.

Both ASCO and SSO/ASTRO recommended monitoring outcomes as institutions implement the new margin guidelines. Authors of the ASCO opinion reported having no conflicts of interest.

An expert review panel from the American Society for Clinical Oncology largely endorsed new guidelines for "no ink on tumor" margins in early breast conservation surgery, while emphasizing the role of post-lumpectomy imaging in patients with microcalcifications and adding several other "minor qualifications."

Published earlier this year, the guidelines from the Society of Surgical Oncology (SSO) and the American Society of Radiation Oncology (ASTRO) focus on stage I and II breast cancer patients who are undergoing lumpectomy with whole-breast radiation. In these patients, a "no ink on tumor" margin "is associated with low rates of [ipsilateral breast tumor recurrence] and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs," the guideline’s authors wrote (Ann. Surg. Oncol. 2014;21:704-16). The guidelines mark a step toward consensus on a historically controversial topic. "Widespread adoption of this guideline, which defines a margin as being adequate as long as there is no cancer at the inked lumpectomy surface by microscopic pathology evaluation, will result in fewer re-excision lumpectomies and enhanced cosmesis with breast conserving surgery," said Dr. Lisa Newman.

The recommended margin reflects the current era of treatment, in which better systemic therapies and earlier diagnosis of breast cancer mean that patients may no longer derive extra benefit from thicker or "widely negative" lumpectomy margins, Dr. Newman added in an interview.

Two staff members at ASCO reviewed the guidelines for developmental rigor. The guidelines "scored high (77%) in terms of methodologic quality, with only minor deviations from the ideal," members of the separate ad hoc panel of ASCO experts wrote (J. Clin. Onc. 2014 [doi:10.1200/JCO.2014.55.1572]). But panel members also called for flexibility in applying the guideline, citing the "inherent weaknesses" and "selection bias" of the retrospective, observational studies on which the recommendations were based.

The guidelines provide a framework, but clinical judgment remains important in managing breast-conserving surgery patients, emphasized Dr. Newman, who served as cochair on the ASCO panel that reviewed the guideline and who is a surgical oncologist, professor of surgery, and director of the Breast Care Center for the University of Michigan, Ann Arbor. She said clinicians should carefully evaluate lumpectomy margins, which "can provide important clues regarding the burden of disease in the breast, and the likelihood of successful treatment with lumpectomy and breast radiation."

ASCO panel members also stressed the importance of postsurgical imaging in cases involving microcalcifications. Imaging is important to minimize the risk of leaving pockets of disease in the breast despite achieving microscopically negative margins, Dr. Newman said. Surgeons can work with their colleagues in breast imaging to review microcalcifications and correlate them with pathology findings, she added.

In particular, a lumpectomy specimen that has several close margins and evidence of diffuse disease "may well represent a different category of risk regarding local recurrence, compared to a well defined, unifocal cancer that has a single microscopic focus of cancer abutting one margin," Dr. Newman added. Ideally, surgeons and radiation oncologists should discuss these aspects of cases, and should consider them when counseling patients about outcomes from lumpectomy surgery, she said.

Both ASCO and SSO/ASTRO recommended monitoring outcomes as institutions implement the new margin guidelines. Authors of the ASCO opinion reported having no conflicts of interest.

An expert review panel from the American Society for Clinical Oncology largely endorsed new guidelines for "no ink on tumor" margins in early breast conservation surgery, while emphasizing the role of post-lumpectomy imaging in patients with microcalcifications and adding several other "minor qualifications."

Published earlier this year, the guidelines from the Society of Surgical Oncology (SSO) and the American Society of Radiation Oncology (ASTRO) focus on stage I and II breast cancer patients who are undergoing lumpectomy with whole-breast radiation. In these patients, a "no ink on tumor" margin "is associated with low rates of [ipsilateral breast tumor recurrence] and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs," the guideline’s authors wrote (Ann. Surg. Oncol. 2014;21:704-16). The guidelines mark a step toward consensus on a historically controversial topic. "Widespread adoption of this guideline, which defines a margin as being adequate as long as there is no cancer at the inked lumpectomy surface by microscopic pathology evaluation, will result in fewer re-excision lumpectomies and enhanced cosmesis with breast conserving surgery," said Dr. Lisa Newman.

The recommended margin reflects the current era of treatment, in which better systemic therapies and earlier diagnosis of breast cancer mean that patients may no longer derive extra benefit from thicker or "widely negative" lumpectomy margins, Dr. Newman added in an interview.

Two staff members at ASCO reviewed the guidelines for developmental rigor. The guidelines "scored high (77%) in terms of methodologic quality, with only minor deviations from the ideal," members of the separate ad hoc panel of ASCO experts wrote (J. Clin. Onc. 2014 [doi:10.1200/JCO.2014.55.1572]). But panel members also called for flexibility in applying the guideline, citing the "inherent weaknesses" and "selection bias" of the retrospective, observational studies on which the recommendations were based.

The guidelines provide a framework, but clinical judgment remains important in managing breast-conserving surgery patients, emphasized Dr. Newman, who served as cochair on the ASCO panel that reviewed the guideline and who is a surgical oncologist, professor of surgery, and director of the Breast Care Center for the University of Michigan, Ann Arbor. She said clinicians should carefully evaluate lumpectomy margins, which "can provide important clues regarding the burden of disease in the breast, and the likelihood of successful treatment with lumpectomy and breast radiation."

ASCO panel members also stressed the importance of postsurgical imaging in cases involving microcalcifications. Imaging is important to minimize the risk of leaving pockets of disease in the breast despite achieving microscopically negative margins, Dr. Newman said. Surgeons can work with their colleagues in breast imaging to review microcalcifications and correlate them with pathology findings, she added.

In particular, a lumpectomy specimen that has several close margins and evidence of diffuse disease "may well represent a different category of risk regarding local recurrence, compared to a well defined, unifocal cancer that has a single microscopic focus of cancer abutting one margin," Dr. Newman added. Ideally, surgeons and radiation oncologists should discuss these aspects of cases, and should consider them when counseling patients about outcomes from lumpectomy surgery, she said.

Both ASCO and SSO/ASTRO recommended monitoring outcomes as institutions implement the new margin guidelines. Authors of the ASCO opinion reported having no conflicts of interest.

Single-agent paclitaxel has failed to demonstrate noninferiority, compared with doxorubicin and cyclophosphamide in patients with early-stage, operable breast cancer, although it did show significantly less toxicity.

The trial in 3,871 women, followed for a median of 6.1 years and treated with four or six cycles of each treatment, recorded a hazard ratio (HR) for relapse-free survival of 1.26, favoring the combination of doxorubicin and cyclophosphamide, with an upper-bound confidence interval of 1.48, which exceeded the upper confidence bound of 1.3.

Combination therapy was associated with an HR of 1.27 for overall survival, while the estimated absolute advantage of the doxorubicin and cyclophosphamide combination at 5 years was 3% for relapse-free survival (RFS) and 1% for overall survival (OS), investigators reported online June 16 in the Journal of Clinical Oncology.

"Because we were not able to demonstrate noninferiority for either RFS or OS, single-agent T [paclitaxel] cannot be recommended as a standard regimen for women with primary breast cancer and zero to three positive axillary nodes," wrote Dr. Lawrence N. Shulman of the Dana-Farber Cancer Institute, Boston, and colleagues (J. Clin. Oncol. 2014 June 16 [doi:10.1200/JCO.2013.53.7142]).

An accompanying editorial noted that the results of the trial provided potentially useful biologic information on adjuvant chemotherapy for breast cancer although the results had limited application in current practice as many women are now treated with both taxanes and anthracyclines.

"The observation that single-agent T [paclitaxel] is potentially worse than AC [doxorubicin and cyclophosphamide] does provide some push back against those who want to abandon anthracyclines in early-stage breast cancer," wrote Dr. Pamela J. Goodwin of the University of Toronto and colleagues, in the editorial (J. Clin. Oncol. 2014 June 16 [doi: 10.1200/JCO.2014.55.9344]).

The study was partly supported by grants from the National Cancer Institute. Authors declared a range of consultancy, honoraria and funding from the pharmaceutical industry.

Single-agent paclitaxel has failed to demonstrate noninferiority, compared with doxorubicin and cyclophosphamide in patients with early-stage, operable breast cancer, although it did show significantly less toxicity.

The trial in 3,871 women, followed for a median of 6.1 years and treated with four or six cycles of each treatment, recorded a hazard ratio (HR) for relapse-free survival of 1.26, favoring the combination of doxorubicin and cyclophosphamide, with an upper-bound confidence interval of 1.48, which exceeded the upper confidence bound of 1.3.

Combination therapy was associated with an HR of 1.27 for overall survival, while the estimated absolute advantage of the doxorubicin and cyclophosphamide combination at 5 years was 3% for relapse-free survival (RFS) and 1% for overall survival (OS), investigators reported online June 16 in the Journal of Clinical Oncology.

"Because we were not able to demonstrate noninferiority for either RFS or OS, single-agent T [paclitaxel] cannot be recommended as a standard regimen for women with primary breast cancer and zero to three positive axillary nodes," wrote Dr. Lawrence N. Shulman of the Dana-Farber Cancer Institute, Boston, and colleagues (J. Clin. Oncol. 2014 June 16 [doi:10.1200/JCO.2013.53.7142]).

An accompanying editorial noted that the results of the trial provided potentially useful biologic information on adjuvant chemotherapy for breast cancer although the results had limited application in current practice as many women are now treated with both taxanes and anthracyclines.

"The observation that single-agent T [paclitaxel] is potentially worse than AC [doxorubicin and cyclophosphamide] does provide some push back against those who want to abandon anthracyclines in early-stage breast cancer," wrote Dr. Pamela J. Goodwin of the University of Toronto and colleagues, in the editorial (J. Clin. Oncol. 2014 June 16 [doi: 10.1200/JCO.2014.55.9344]).

The study was partly supported by grants from the National Cancer Institute. Authors declared a range of consultancy, honoraria and funding from the pharmaceutical industry.

Single-agent paclitaxel has failed to demonstrate noninferiority, compared with doxorubicin and cyclophosphamide in patients with early-stage, operable breast cancer, although it did show significantly less toxicity.

The trial in 3,871 women, followed for a median of 6.1 years and treated with four or six cycles of each treatment, recorded a hazard ratio (HR) for relapse-free survival of 1.26, favoring the combination of doxorubicin and cyclophosphamide, with an upper-bound confidence interval of 1.48, which exceeded the upper confidence bound of 1.3.

Combination therapy was associated with an HR of 1.27 for overall survival, while the estimated absolute advantage of the doxorubicin and cyclophosphamide combination at 5 years was 3% for relapse-free survival (RFS) and 1% for overall survival (OS), investigators reported online June 16 in the Journal of Clinical Oncology.

"Because we were not able to demonstrate noninferiority for either RFS or OS, single-agent T [paclitaxel] cannot be recommended as a standard regimen for women with primary breast cancer and zero to three positive axillary nodes," wrote Dr. Lawrence N. Shulman of the Dana-Farber Cancer Institute, Boston, and colleagues (J. Clin. Oncol. 2014 June 16 [doi:10.1200/JCO.2013.53.7142]).

An accompanying editorial noted that the results of the trial provided potentially useful biologic information on adjuvant chemotherapy for breast cancer although the results had limited application in current practice as many women are now treated with both taxanes and anthracyclines.

"The observation that single-agent T [paclitaxel] is potentially worse than AC [doxorubicin and cyclophosphamide] does provide some push back against those who want to abandon anthracyclines in early-stage breast cancer," wrote Dr. Pamela J. Goodwin of the University of Toronto and colleagues, in the editorial (J. Clin. Oncol. 2014 June 16 [doi: 10.1200/JCO.2014.55.9344]).

The study was partly supported by grants from the National Cancer Institute. Authors declared a range of consultancy, honoraria and funding from the pharmaceutical industry.

CHICAGO – Dual HER2 blockade with lapatinib and trastuzumab provides no additional benefit in the adjuvant treatment of HER2-positive breast cancer, according to the long-awaited, first results from the phase III ALTTO trial.

At 4 years, the primary outcome of disease-free survival was 86% with trastuzumab alone, compared with 88% with concurrent lapatinib (Tykerb) and trastuzumab (Herceptin) (hazard ratio, 0.84; P = .048), and 87% with trastuzumab followed by lapatinib (HR, 0.96; P = .610), Dr. Martine Piccart-Gebhart reported during the plenary session at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

Median overall survival rates were 94%, 95%, and 95%, respectively.

ALTTO’s sister trial, NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization), demonstrated that neoadjuvant treatment with combination trastuzumab and lapatinib doubled the number of pathological complete responses (pCRs), compared with each single agent, and reduced the overall risk of death by two-thirds in women with a pCR.

"The doubling in pCR observed in NeoALTTO did not translate into improved survival outcomes in ALTTO at 4.5 years," said Dr. Piccart-Gebhart, head of the medicine department, Jules Bordet Institute, Brussels.

Invited discussant and past ASCO president Dr. George Sledge Jr., professor of medicine and chief of oncology at Stanford University Medical Center, Palo Alto, Calif., pointed out that ALTTO called for a stringent P value of .025 or less to demonstrate statistical significance, but that no one should be "fooled" by the disease-free survival P value of .048 into thinking this was a positive trial.

"This is a negative trial," he said.

He also noted that the 555 disease-free events seen in ALTTO fell far short of the 850 events planned for, and thus the trial was underpowered.

"Might this trial, with more events and further follow-up, turn statistically positive? Perhaps, but not very positive given the results we’ve seen today," Dr. Sledge commented. "HER2 has reverted to the incrementalism that we see so commonly in the adjuvant field. This is not, alas, 2005. This is not a great leap forward. This is a serious disappointment not just for investigators, but for the entire field."

Several previous trials (B-31, N9831, and HERA) presented at the same meeting in 2005 showed a striking disease-free survival advantage from the addition of 1 year of trastuzumab to adjuvant chemotherapy in women with HER2-positive breast cancer.

During a press briefing, ALTTO study cochair Dr. Edith Perez cast the low event rate of ALTTO in a slightly more positive light, saying that the "patients overall did pretty well."

Ripple effects

Neil Osterweil/For Frontline Medical News

Had the results of ALTTO been positive, it would have changed the design of future breast cancer trials by eliminating the need for large adjuvant trials, suggested Dr. Perez, deputy director at large, Mayo Clinic Cancer Center, Jacksonville, Fla. Novel targeted agents could have been reliably evaluated in the neoadjuvant setting if pCR had correlated with the findings in adjuvant trials.

As it stands now, the data call into question whether an improvement in pCR can be routinely used as a reliable surrogate for disease-free and overall survival, ASCO president Dr. Clifford Hudis, chief of breast cancer at Memorial Sloan Kettering Cancer Center, New York, said at the briefing.

"The answer from ALTTO right now is maybe not, and this, I think, is going to cause a tremendous amount of high-level technical scientific discussion in terms of drug development," he told reporters.

Dr. Hudis pointed out that last fall, the Food and Drug Administration for the first time ever approved a drug, pertuzumab (Perjeta), for use in the preoperative breast cancer setting based on an increased pCR rate alone. The hope is that this will ultimately save lives, although this question won’t be answered until 2016, when results from the APHINITY trial are expected, he said.

Based on the ALTTO data, "the simple link that improving the rate of shrinkage of the cancer will necessarily reduce the rate of distant recurrence is not established," Dr. Hudis said. "So our ability to go from big studies taking many years to small studies taking months is not established. That’s a fundamental observation, and it may have implications well beyond breast cancer."

ALTTO design

The open-label, multicenter ALTTO study randomized 8,381 women after surgery to concurrent trastuzumab and lapatinib, trastuzumab followed by lapatinib, or trastuzumab alone for 1 year. Patients received anti-HER2 therapy after completing all chemotherapy (design 1), concurrently with a taxane following anthracycline (design 2), or concurrently with a non-anthracycline, platinum-containing regimen (design 2B).

The lapatinib-alone vs. trastuzumab-alone arm was closed in early 2011 due to futility, and results from that arm will be presented later this year.

The current efficacy results were based on 6,281 women, with 4,613 receiving the anti-HER2 drugs after completing chemotherapy.

Lapatinib was associated with significant increases in diarrhea, hepatobiliary events, and skin rash or erythema. This may explain why only 60-78% of patients in the lapatinib-containing arms received at least 85% of protocol-specified dose, Dr. Piccart-Gebhart said during the formal presentation of the late-breaking abstract.

Importantly, cardiac toxicity was "remarkably low in all treatment arms" at less than 1%, she said. This was true despite 97% of women receiving anthracyclines.

A primary cardiac event, defined as cardiac death or severe congestive heart failure (New York Heart Association class III-IV), occurred in 0.97% of patients on lapatinib plus trastuzumab, 0.25% on trastuzumab followed by lapatinib, and 0.86% on trastuzumab alone. Any cardiac event was reported in 3.7%, 2.4%, and 4.5%, respectively.

Follow-up in ALTTO will continue, with a protocol-specified updated efficacy analysis planned in 2 years.

ALTTO was sponsored by the National Cancer Institute and GlaxoSmithKline, maker of lapatinib. Dr. Piccart-Gebhart reported employment or a leadership role with PharmaMar, and a consulting/advisory role and honoraria from several companies, but not GSK. Dr. Sledge reported serving as a board member for Syndax and as a consultant for Roche-Genentech, Symphogen, and Seattle Genetics. Dr. Perez reported having no financial disclosures.

pwendling@frontlinemedcom.com

CHICAGO – Dual HER2 blockade with lapatinib and trastuzumab provides no additional benefit in the adjuvant treatment of HER2-positive breast cancer, according to the long-awaited, first results from the phase III ALTTO trial.

At 4 years, the primary outcome of disease-free survival was 86% with trastuzumab alone, compared with 88% with concurrent lapatinib (Tykerb) and trastuzumab (Herceptin) (hazard ratio, 0.84; P = .048), and 87% with trastuzumab followed by lapatinib (HR, 0.96; P = .610), Dr. Martine Piccart-Gebhart reported during the plenary session at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

Median overall survival rates were 94%, 95%, and 95%, respectively.

ALTTO’s sister trial, NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization), demonstrated that neoadjuvant treatment with combination trastuzumab and lapatinib doubled the number of pathological complete responses (pCRs), compared with each single agent, and reduced the overall risk of death by two-thirds in women with a pCR.

"The doubling in pCR observed in NeoALTTO did not translate into improved survival outcomes in ALTTO at 4.5 years," said Dr. Piccart-Gebhart, head of the medicine department, Jules Bordet Institute, Brussels.

Invited discussant and past ASCO president Dr. George Sledge Jr., professor of medicine and chief of oncology at Stanford University Medical Center, Palo Alto, Calif., pointed out that ALTTO called for a stringent P value of .025 or less to demonstrate statistical significance, but that no one should be "fooled" by the disease-free survival P value of .048 into thinking this was a positive trial.

"This is a negative trial," he said.

He also noted that the 555 disease-free events seen in ALTTO fell far short of the 850 events planned for, and thus the trial was underpowered.

"Might this trial, with more events and further follow-up, turn statistically positive? Perhaps, but not very positive given the results we’ve seen today," Dr. Sledge commented. "HER2 has reverted to the incrementalism that we see so commonly in the adjuvant field. This is not, alas, 2005. This is not a great leap forward. This is a serious disappointment not just for investigators, but for the entire field."

Several previous trials (B-31, N9831, and HERA) presented at the same meeting in 2005 showed a striking disease-free survival advantage from the addition of 1 year of trastuzumab to adjuvant chemotherapy in women with HER2-positive breast cancer.

During a press briefing, ALTTO study cochair Dr. Edith Perez cast the low event rate of ALTTO in a slightly more positive light, saying that the "patients overall did pretty well."

Ripple effects

Neil Osterweil/For Frontline Medical News

Had the results of ALTTO been positive, it would have changed the design of future breast cancer trials by eliminating the need for large adjuvant trials, suggested Dr. Perez, deputy director at large, Mayo Clinic Cancer Center, Jacksonville, Fla. Novel targeted agents could have been reliably evaluated in the neoadjuvant setting if pCR had correlated with the findings in adjuvant trials.

As it stands now, the data call into question whether an improvement in pCR can be routinely used as a reliable surrogate for disease-free and overall survival, ASCO president Dr. Clifford Hudis, chief of breast cancer at Memorial Sloan Kettering Cancer Center, New York, said at the briefing.

"The answer from ALTTO right now is maybe not, and this, I think, is going to cause a tremendous amount of high-level technical scientific discussion in terms of drug development," he told reporters.

Dr. Hudis pointed out that last fall, the Food and Drug Administration for the first time ever approved a drug, pertuzumab (Perjeta), for use in the preoperative breast cancer setting based on an increased pCR rate alone. The hope is that this will ultimately save lives, although this question won’t be answered until 2016, when results from the APHINITY trial are expected, he said.

Based on the ALTTO data, "the simple link that improving the rate of shrinkage of the cancer will necessarily reduce the rate of distant recurrence is not established," Dr. Hudis said. "So our ability to go from big studies taking many years to small studies taking months is not established. That’s a fundamental observation, and it may have implications well beyond breast cancer."

ALTTO design

The open-label, multicenter ALTTO study randomized 8,381 women after surgery to concurrent trastuzumab and lapatinib, trastuzumab followed by lapatinib, or trastuzumab alone for 1 year. Patients received anti-HER2 therapy after completing all chemotherapy (design 1), concurrently with a taxane following anthracycline (design 2), or concurrently with a non-anthracycline, platinum-containing regimen (design 2B).

The lapatinib-alone vs. trastuzumab-alone arm was closed in early 2011 due to futility, and results from that arm will be presented later this year.

The current efficacy results were based on 6,281 women, with 4,613 receiving the anti-HER2 drugs after completing chemotherapy.

Lapatinib was associated with significant increases in diarrhea, hepatobiliary events, and skin rash or erythema. This may explain why only 60-78% of patients in the lapatinib-containing arms received at least 85% of protocol-specified dose, Dr. Piccart-Gebhart said during the formal presentation of the late-breaking abstract.

Importantly, cardiac toxicity was "remarkably low in all treatment arms" at less than 1%, she said. This was true despite 97% of women receiving anthracyclines.

A primary cardiac event, defined as cardiac death or severe congestive heart failure (New York Heart Association class III-IV), occurred in 0.97% of patients on lapatinib plus trastuzumab, 0.25% on trastuzumab followed by lapatinib, and 0.86% on trastuzumab alone. Any cardiac event was reported in 3.7%, 2.4%, and 4.5%, respectively.

Follow-up in ALTTO will continue, with a protocol-specified updated efficacy analysis planned in 2 years.

ALTTO was sponsored by the National Cancer Institute and GlaxoSmithKline, maker of lapatinib. Dr. Piccart-Gebhart reported employment or a leadership role with PharmaMar, and a consulting/advisory role and honoraria from several companies, but not GSK. Dr. Sledge reported serving as a board member for Syndax and as a consultant for Roche-Genentech, Symphogen, and Seattle Genetics. Dr. Perez reported having no financial disclosures.

pwendling@frontlinemedcom.com

CHICAGO – Dual HER2 blockade with lapatinib and trastuzumab provides no additional benefit in the adjuvant treatment of HER2-positive breast cancer, according to the long-awaited, first results from the phase III ALTTO trial.

At 4 years, the primary outcome of disease-free survival was 86% with trastuzumab alone, compared with 88% with concurrent lapatinib (Tykerb) and trastuzumab (Herceptin) (hazard ratio, 0.84; P = .048), and 87% with trastuzumab followed by lapatinib (HR, 0.96; P = .610), Dr. Martine Piccart-Gebhart reported during the plenary session at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/Frontline Medical News

Median overall survival rates were 94%, 95%, and 95%, respectively.

ALTTO’s sister trial, NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization), demonstrated that neoadjuvant treatment with combination trastuzumab and lapatinib doubled the number of pathological complete responses (pCRs), compared with each single agent, and reduced the overall risk of death by two-thirds in women with a pCR.

"The doubling in pCR observed in NeoALTTO did not translate into improved survival outcomes in ALTTO at 4.5 years," said Dr. Piccart-Gebhart, head of the medicine department, Jules Bordet Institute, Brussels.

Invited discussant and past ASCO president Dr. George Sledge Jr., professor of medicine and chief of oncology at Stanford University Medical Center, Palo Alto, Calif., pointed out that ALTTO called for a stringent P value of .025 or less to demonstrate statistical significance, but that no one should be "fooled" by the disease-free survival P value of .048 into thinking this was a positive trial.

"This is a negative trial," he said.

He also noted that the 555 disease-free events seen in ALTTO fell far short of the 850 events planned for, and thus the trial was underpowered.

"Might this trial, with more events and further follow-up, turn statistically positive? Perhaps, but not very positive given the results we’ve seen today," Dr. Sledge commented. "HER2 has reverted to the incrementalism that we see so commonly in the adjuvant field. This is not, alas, 2005. This is not a great leap forward. This is a serious disappointment not just for investigators, but for the entire field."

Several previous trials (B-31, N9831, and HERA) presented at the same meeting in 2005 showed a striking disease-free survival advantage from the addition of 1 year of trastuzumab to adjuvant chemotherapy in women with HER2-positive breast cancer.

During a press briefing, ALTTO study cochair Dr. Edith Perez cast the low event rate of ALTTO in a slightly more positive light, saying that the "patients overall did pretty well."

Ripple effects

Neil Osterweil/For Frontline Medical News

Had the results of ALTTO been positive, it would have changed the design of future breast cancer trials by eliminating the need for large adjuvant trials, suggested Dr. Perez, deputy director at large, Mayo Clinic Cancer Center, Jacksonville, Fla. Novel targeted agents could have been reliably evaluated in the neoadjuvant setting if pCR had correlated with the findings in adjuvant trials.

As it stands now, the data call into question whether an improvement in pCR can be routinely used as a reliable surrogate for disease-free and overall survival, ASCO president Dr. Clifford Hudis, chief of breast cancer at Memorial Sloan Kettering Cancer Center, New York, said at the briefing.

"The answer from ALTTO right now is maybe not, and this, I think, is going to cause a tremendous amount of high-level technical scientific discussion in terms of drug development," he told reporters.

Dr. Hudis pointed out that last fall, the Food and Drug Administration for the first time ever approved a drug, pertuzumab (Perjeta), for use in the preoperative breast cancer setting based on an increased pCR rate alone. The hope is that this will ultimately save lives, although this question won’t be answered until 2016, when results from the APHINITY trial are expected, he said.

Based on the ALTTO data, "the simple link that improving the rate of shrinkage of the cancer will necessarily reduce the rate of distant recurrence is not established," Dr. Hudis said. "So our ability to go from big studies taking many years to small studies taking months is not established. That’s a fundamental observation, and it may have implications well beyond breast cancer."

ALTTO design

The open-label, multicenter ALTTO study randomized 8,381 women after surgery to concurrent trastuzumab and lapatinib, trastuzumab followed by lapatinib, or trastuzumab alone for 1 year. Patients received anti-HER2 therapy after completing all chemotherapy (design 1), concurrently with a taxane following anthracycline (design 2), or concurrently with a non-anthracycline, platinum-containing regimen (design 2B).

The lapatinib-alone vs. trastuzumab-alone arm was closed in early 2011 due to futility, and results from that arm will be presented later this year.

The current efficacy results were based on 6,281 women, with 4,613 receiving the anti-HER2 drugs after completing chemotherapy.

Lapatinib was associated with significant increases in diarrhea, hepatobiliary events, and skin rash or erythema. This may explain why only 60-78% of patients in the lapatinib-containing arms received at least 85% of protocol-specified dose, Dr. Piccart-Gebhart said during the formal presentation of the late-breaking abstract.

Importantly, cardiac toxicity was "remarkably low in all treatment arms" at less than 1%, she said. This was true despite 97% of women receiving anthracyclines.

A primary cardiac event, defined as cardiac death or severe congestive heart failure (New York Heart Association class III-IV), occurred in 0.97% of patients on lapatinib plus trastuzumab, 0.25% on trastuzumab followed by lapatinib, and 0.86% on trastuzumab alone. Any cardiac event was reported in 3.7%, 2.4%, and 4.5%, respectively.

Follow-up in ALTTO will continue, with a protocol-specified updated efficacy analysis planned in 2 years.

ALTTO was sponsored by the National Cancer Institute and GlaxoSmithKline, maker of lapatinib. Dr. Piccart-Gebhart reported employment or a leadership role with PharmaMar, and a consulting/advisory role and honoraria from several companies, but not GSK. Dr. Sledge reported serving as a board member for Syndax and as a consultant for Roche-Genentech, Symphogen, and Seattle Genetics. Dr. Perez reported having no financial disclosures.

pwendling@frontlinemedcom.com

Trastuzumab therapy in women with metastatic HER2-positive breast cancer is associated with significant gains in progression-free and overall survival but at the expense of cardiac toxicities such as heart failure and reduced left ventricular ejection fraction, according to a Cochrane Review.

The review of seven randomized, controlled trials involving 1,497 HER2-positive patients treated with trastuzumab, alone or in combination with other therapies, found the drug extended the time to death between 5 and 8 months and extended time to disease progression by 2-12 months, as reported June 11 in Cochrane Database of Systematic Reviews.

Treatment with trastuzumab led to a statistically significant improvement in overall survival (hazard ratio, 0.82; 95% CI 0.71-0.94; P = .004), and in progression-free survival (HR, 0.61; 95% CI 0.54-0.70; P less than .00001), compared with the control groups.

Trastuzumab was significantly more effective at improving overall survival when used as a first-line treatment (HR, 0.79; 95% CI 0.67-0.94; P = .006) and failed to achieve statistical significance when used after disease progression.

Coadministration with taxanes such as paclitaxel also led to a statistically significant improvement in overall survival (HR, 0.80; 95% CI 0.65-0.99; P = .04) and in progression-free survival (HR, 0.53; 95% CI 0.42-0.68).

"The meta-analysis showed a significant improvement in overall survival and progression-free survival for trastuzumab-containing regimens, which is possibly greater when considering patients treated as first-line compared to its use beyond progression, or patients receiving taxane-based regimens," wrote Ms. Sara Balduzzi, a statistician with the Italian Cochrane Centre, and her colleagues.

The review was prompted by concerns about the risks vs. benefits of trastuzumab (Cochrane Database Syst. Rev. 2014 June 11 [doi:10.1002/14651858.CD006242.pub2]).

"The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and, although the efficacy results seem to support its use, other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system," the authors wrote.

The incidence of a severe cardiac event was 4.7% in the trastuzumab group, compared with 1.1% in the control group, reflecting a more than threefold increase in risk (relative risk, 3.49; 90% CI 1.88-6.47; P = .0009).

Coadministration with an anthracycline increased the risk of a severe cardiac event fivefold, compared with treatment with anthracycline alone (RR, 5.43; 90% CI 2.28-12.94; P = .001).

In five trials, there were also 28 cases (5.9%) of left ventricular ejection fraction (LVEF) decline in the 478 women treated with trastuzumab, compared with 9 cases out of 460 (2%) in the control group (RR, 2.65; 90% CI 1.48-4.74; P = .006).

One study reported information on brain metastases; There were 42 cases (17.9%) out of 235 in the trastuzumab-containing group and 21/234 (9.0%) in the control group (RR, 1.99; 95% CI 1.32-3.01). Another study, which allowed the accrual of patients with known brain metastases, reported that 9 (6.2%) out of the 146 patients treated with trastuzumab experienced central nervous system progression, whereas 15 patients (10.3) out of the 145 treated with lapatinib alone experienced progression while on the study (RR, 0.60; 90% CI 0.31-1.16), the authors reported.

Researchers also observed a nonsignificant increase in the risk of neutropenic fever among women treated with trastuzumab.

Overall, there were 752 women in the trastuzumab-containing arm and 745 controls.

One author declared speaking engagements, consultancies, and an institutional grant from the pharmaceutical industry. There were no other conflicts of interest declared.

Trastuzumab therapy in women with metastatic HER2-positive breast cancer is associated with significant gains in progression-free and overall survival but at the expense of cardiac toxicities such as heart failure and reduced left ventricular ejection fraction, according to a Cochrane Review.

The review of seven randomized, controlled trials involving 1,497 HER2-positive patients treated with trastuzumab, alone or in combination with other therapies, found the drug extended the time to death between 5 and 8 months and extended time to disease progression by 2-12 months, as reported June 11 in Cochrane Database of Systematic Reviews.

Treatment with trastuzumab led to a statistically significant improvement in overall survival (hazard ratio, 0.82; 95% CI 0.71-0.94; P = .004), and in progression-free survival (HR, 0.61; 95% CI 0.54-0.70; P less than .00001), compared with the control groups.

Trastuzumab was significantly more effective at improving overall survival when used as a first-line treatment (HR, 0.79; 95% CI 0.67-0.94; P = .006) and failed to achieve statistical significance when used after disease progression.

Coadministration with taxanes such as paclitaxel also led to a statistically significant improvement in overall survival (HR, 0.80; 95% CI 0.65-0.99; P = .04) and in progression-free survival (HR, 0.53; 95% CI 0.42-0.68).

"The meta-analysis showed a significant improvement in overall survival and progression-free survival for trastuzumab-containing regimens, which is possibly greater when considering patients treated as first-line compared to its use beyond progression, or patients receiving taxane-based regimens," wrote Ms. Sara Balduzzi, a statistician with the Italian Cochrane Centre, and her colleagues.

The review was prompted by concerns about the risks vs. benefits of trastuzumab (Cochrane Database Syst. Rev. 2014 June 11 [doi:10.1002/14651858.CD006242.pub2]).

"The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and, although the efficacy results seem to support its use, other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system," the authors wrote.

The incidence of a severe cardiac event was 4.7% in the trastuzumab group, compared with 1.1% in the control group, reflecting a more than threefold increase in risk (relative risk, 3.49; 90% CI 1.88-6.47; P = .0009).

Coadministration with an anthracycline increased the risk of a severe cardiac event fivefold, compared with treatment with anthracycline alone (RR, 5.43; 90% CI 2.28-12.94; P = .001).

In five trials, there were also 28 cases (5.9%) of left ventricular ejection fraction (LVEF) decline in the 478 women treated with trastuzumab, compared with 9 cases out of 460 (2%) in the control group (RR, 2.65; 90% CI 1.48-4.74; P = .006).

One study reported information on brain metastases; There were 42 cases (17.9%) out of 235 in the trastuzumab-containing group and 21/234 (9.0%) in the control group (RR, 1.99; 95% CI 1.32-3.01). Another study, which allowed the accrual of patients with known brain metastases, reported that 9 (6.2%) out of the 146 patients treated with trastuzumab experienced central nervous system progression, whereas 15 patients (10.3) out of the 145 treated with lapatinib alone experienced progression while on the study (RR, 0.60; 90% CI 0.31-1.16), the authors reported.

Researchers also observed a nonsignificant increase in the risk of neutropenic fever among women treated with trastuzumab.

Overall, there were 752 women in the trastuzumab-containing arm and 745 controls.

One author declared speaking engagements, consultancies, and an institutional grant from the pharmaceutical industry. There were no other conflicts of interest declared.

Trastuzumab therapy in women with metastatic HER2-positive breast cancer is associated with significant gains in progression-free and overall survival but at the expense of cardiac toxicities such as heart failure and reduced left ventricular ejection fraction, according to a Cochrane Review.

The review of seven randomized, controlled trials involving 1,497 HER2-positive patients treated with trastuzumab, alone or in combination with other therapies, found the drug extended the time to death between 5 and 8 months and extended time to disease progression by 2-12 months, as reported June 11 in Cochrane Database of Systematic Reviews.

Treatment with trastuzumab led to a statistically significant improvement in overall survival (hazard ratio, 0.82; 95% CI 0.71-0.94; P = .004), and in progression-free survival (HR, 0.61; 95% CI 0.54-0.70; P less than .00001), compared with the control groups.

Trastuzumab was significantly more effective at improving overall survival when used as a first-line treatment (HR, 0.79; 95% CI 0.67-0.94; P = .006) and failed to achieve statistical significance when used after disease progression.

Coadministration with taxanes such as paclitaxel also led to a statistically significant improvement in overall survival (HR, 0.80; 95% CI 0.65-0.99; P = .04) and in progression-free survival (HR, 0.53; 95% CI 0.42-0.68).

"The meta-analysis showed a significant improvement in overall survival and progression-free survival for trastuzumab-containing regimens, which is possibly greater when considering patients treated as first-line compared to its use beyond progression, or patients receiving taxane-based regimens," wrote Ms. Sara Balduzzi, a statistician with the Italian Cochrane Centre, and her colleagues.

The review was prompted by concerns about the risks vs. benefits of trastuzumab (Cochrane Database Syst. Rev. 2014 June 11 [doi:10.1002/14651858.CD006242.pub2]).

"The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and, although the efficacy results seem to support its use, other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system," the authors wrote.

The incidence of a severe cardiac event was 4.7% in the trastuzumab group, compared with 1.1% in the control group, reflecting a more than threefold increase in risk (relative risk, 3.49; 90% CI 1.88-6.47; P = .0009).

Coadministration with an anthracycline increased the risk of a severe cardiac event fivefold, compared with treatment with anthracycline alone (RR, 5.43; 90% CI 2.28-12.94; P = .001).

In five trials, there were also 28 cases (5.9%) of left ventricular ejection fraction (LVEF) decline in the 478 women treated with trastuzumab, compared with 9 cases out of 460 (2%) in the control group (RR, 2.65; 90% CI 1.48-4.74; P = .006).

One study reported information on brain metastases; There were 42 cases (17.9%) out of 235 in the trastuzumab-containing group and 21/234 (9.0%) in the control group (RR, 1.99; 95% CI 1.32-3.01). Another study, which allowed the accrual of patients with known brain metastases, reported that 9 (6.2%) out of the 146 patients treated with trastuzumab experienced central nervous system progression, whereas 15 patients (10.3) out of the 145 treated with lapatinib alone experienced progression while on the study (RR, 0.60; 90% CI 0.31-1.16), the authors reported.

Researchers also observed a nonsignificant increase in the risk of neutropenic fever among women treated with trastuzumab.

Overall, there were 752 women in the trastuzumab-containing arm and 745 controls.

One author declared speaking engagements, consultancies, and an institutional grant from the pharmaceutical industry. There were no other conflicts of interest declared.

CHICAGO – The Oncology Report associate editors Dr. William J. Gradishar and Dr. Hope S. Rugo discuss breast cancer research highlights presented at the 2014 annual meeting of the American Association of Clinical Oncology.

Studies discussed include the combined analysis of the SOFT and TEXT trials, looking at ovarian suppression in combination with either an aromatase inhibitor or tamoxifen; ALTTO, looking at the impact of a dual blockade against HER2, and the implications on the use of pCR in research and drug approval; ECOG 5103 adjuvant bevacizumab trial; and POEMS, looking at the possibility of preserving fertility during chemotherapy with the addition of goserelin. 

Dr. William J. Gradishar is the Betsy Bramsen Professor of Breast Oncology at the Northwestern University, Chicago. Dr. Hope S. Rugo is a professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center.

CHICAGO – The Oncology Report associate editors Dr. William J. Gradishar and Dr. Hope S. Rugo discuss breast cancer research highlights presented at the 2014 annual meeting of the American Association of Clinical Oncology.

Studies discussed include the combined analysis of the SOFT and TEXT trials, looking at ovarian suppression in combination with either an aromatase inhibitor or tamoxifen; ALTTO, looking at the impact of a dual blockade against HER2, and the implications on the use of pCR in research and drug approval; ECOG 5103 adjuvant bevacizumab trial; and POEMS, looking at the possibility of preserving fertility during chemotherapy with the addition of goserelin. 

Dr. William J. Gradishar is the Betsy Bramsen Professor of Breast Oncology at the Northwestern University, Chicago. Dr. Hope S. Rugo is a professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center.

CHICAGO – The Oncology Report associate editors Dr. William J. Gradishar and Dr. Hope S. Rugo discuss breast cancer research highlights presented at the 2014 annual meeting of the American Association of Clinical Oncology.

Studies discussed include the combined analysis of the SOFT and TEXT trials, looking at ovarian suppression in combination with either an aromatase inhibitor or tamoxifen; ALTTO, looking at the impact of a dual blockade against HER2, and the implications on the use of pCR in research and drug approval; ECOG 5103 adjuvant bevacizumab trial; and POEMS, looking at the possibility of preserving fertility during chemotherapy with the addition of goserelin. 

Dr. William J. Gradishar is the Betsy Bramsen Professor of Breast Oncology at the Northwestern University, Chicago. Dr. Hope S. Rugo is a professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center.

CHICAGO – The aromatase inhibitor exemestane is more effective than tamoxifen in preventing breast cancer recurrence in premenopausal women also receiving ovarian function suppression as adjuvant treatment for hormone-sensitive early breast cancer.

These results, taken from a combined analysis of the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) studies, were presented in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

Click here for our interview with study cochair Dr. Olivia Pagani, breast unit clinical director at the Oncology Institute of Southern Switzerland in Bellinzona.

The trials were supported by the International Breast Cancer Study Group, Pfizer, Ipsen, and the National Cancer Institute. Dr. Pagani reports research support from Ipsen and Pfizer.

pwendling@frontlinemedcom.com

CHICAGO – The aromatase inhibitor exemestane is more effective than tamoxifen in preventing breast cancer recurrence in premenopausal women also receiving ovarian function suppression as adjuvant treatment for hormone-sensitive early breast cancer.

These results, taken from a combined analysis of the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) studies, were presented in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

Click here for our interview with study cochair Dr. Olivia Pagani, breast unit clinical director at the Oncology Institute of Southern Switzerland in Bellinzona.

The trials were supported by the International Breast Cancer Study Group, Pfizer, Ipsen, and the National Cancer Institute. Dr. Pagani reports research support from Ipsen and Pfizer.

pwendling@frontlinemedcom.com

CHICAGO – The aromatase inhibitor exemestane is more effective than tamoxifen in preventing breast cancer recurrence in premenopausal women also receiving ovarian function suppression as adjuvant treatment for hormone-sensitive early breast cancer.

These results, taken from a combined analysis of the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) studies, were presented in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

Click here for our interview with study cochair Dr. Olivia Pagani, breast unit clinical director at the Oncology Institute of Southern Switzerland in Bellinzona.

The trials were supported by the International Breast Cancer Study Group, Pfizer, Ipsen, and the National Cancer Institute. Dr. Pagani reports research support from Ipsen and Pfizer.

pwendling@frontlinemedcom.com

CHICAGO – Use of the gonadotropin-releasing hormone agonist goserelin during chemotherapy for early hormone receptor–negative breast cancer was associated with lower rates of ovarian failure and more pregnancies in the phase III POEMS study.

At 2 years, 22% of women receiving standard neoadjuvant or adjuvant chemotherapy alone and 8% of those receiving chemotherapy plus goserelin (Zoladex) experienced ovarian failure, defined as amenorrhea for the prior 6 months and follicle-stimulating hormone (FSH) in the postmenopausal range.

Patrice Wendling/Frontline Medical News

In logistic regression analysis that accounted for age and chemotherapy regimen, the risk of ovarian failure was reduced 70% with goserelin (odds ratio, 0.30; two-sided P = .04), Dr. Halle Moore reported at the annual meeting of the American Society of Clinical Oncology.

Risk was further reduced using the less stringent definition of ovarian failure of amenorrhea for the prior 6 months or FSH in the postmenopausal range (45% vs. 20%; OR, 0.29; P = .006).

The 2-year ovarian dysfunction rate was 33% with standard chemotherapy and 14% with chemotherapy plus goserelin (OR, 0.35; P = .03). Dysfunction was defined as amenorrhea for the prior 3 months and FSH, estradiol, and/or inhibin B levels in the postmenopausal range.

"For the 25 percent or so of women with breast cancer who are diagnosed under the age of 50, the induction of early menopause is a common and potentially devastating side effect of treatment," said Dr. Moore of the Cleveland Clinic.

Small studies have shown high rates of ovarian preservation in women with hematologic malignancies with the use of a luteinizing hormone release hormone (LHRH) analogue. Results of randomized trials in breast cancer have been mixed; the studies commonly used only return of menses as an endpoint, and few provided data on pregnancy outcomes, she said.

The intergroup POEMS/S0230 (Prevention of Early Menopause Study) randomly assigned 257 premenopausal women, aged 18-49 years, with operable stage I-IIIA estrogen or progesterone receptor–negative breast cancer to curative-intent standard cyclophosphamide containing neoadjuvant or adjuvant chemotherapy alone or with subcutaneous injections of goserelin 3.6 mg every 4 weeks starting at least 1 week prior to the first chemotherapy dose and ending within 2 weeks of the final dose. The average age of the groups was 38.7 and 37.6 years, respectively.

The study was closed prior to full accrual of the target 416 patients, with 218 women evaluable for pregnancy and survival outcomes and 135 for ovarian failure.

In all, 18 of 113 evaluable controls and 25 of evaluable 105 women given goserelin reported attempting pregnancy, with 12 and 22 women, respectively, becoming pregnant over the 5-year study period (OR, 2.45; P = .03), Dr. Moore said.

Compared with controls, women given goserelin were twice as likely to have a successful delivery (8 vs. 16; OR, 2.51; P = .05) and to have a successful delivery or an ongoing pregnancy at the time of the analysis (10 vs. 19; OR, 2.45; P = .04).

Twelve babies were born to women on chemotherapy alone and 18 to those given goserelin, with 3 and 5 pregnancies, respectively, ongoing.

Importantly, there was no evidence goserelin increased adverse pregnancy events such as miscarriage (5 controls vs. 4 goserelin), elective termination (3 vs. 2), and delivery complications (2 vs. 2), she said.

Grade II-IV endocrine toxicity was reported in 24% of the chemotherapy-alone arm and 48% of the goserelin arm (P = .006). One grade IV thromboembolic event occurred with goserelin, Dr. Moore said. The most common added toxicities with goserelin were hot flashes, mood changes, vaginal dryness, and headache.

A planned exploratory analysis revealed that 89% of women on goserelin versus 78% on chemotherapy alone were disease-free at 4 years, with a hazard ratio of 0.47 after controlling for age and regimen (P = .04) and 0.49 after further adjusting for cancer stage (P = .04).

Overall survival at 4 years was 92% with goserelin and 82% with chemotherapy alone, with hazard ratios of 0.45 (P = .06) and 0.43 (P = .05), respectively.

The favorable survival outcomes with the addition of goserelin are intriguing and reassuring regarding the safety of the approach, Dr. Moore said. One possible explanation for the finding is that there are a high number of LHRH receptors on hormone receptor–negative breast cancers.

"Premenopausal women beginning curative-intent chemotherapy should consider this new option to prevent premature ovarian failure," she concluded.

Discussant Dr. Sharon Giordano, chair of health services research at the University of Texas MD Anderson Cancer Center in Houston, praised POEMS for providing pregnancy information and reassuring outcome data, but said there were several limitations. The most worrisome of these was missing endpoint data for 38% of participants. The study was also hampered by early close and low accrual, and excluded women with more than 10% estrogen or progesterone receptor positivity.

"I don’t think we can consider these results definitive," she said. "Having said that, and with these caveats and recognizing the uncertainty, I would be comfortable offering goserelin to my young patients with estrogen receptor–negative breast cancer who desire to preserve fertility or prevent premature menopause."

The study was supported by the National Institutes of Health. Dr. Moore reported no disclosures; three coauthors have financial ties with AstraZeneca, maker of goserelin. Dr. Giordano reported no relevant disclosures.

pwendling@frontlinemedcom.com

CHICAGO – Use of the gonadotropin-releasing hormone agonist goserelin during chemotherapy for early hormone receptor–negative breast cancer was associated with lower rates of ovarian failure and more pregnancies in the phase III POEMS study.

At 2 years, 22% of women receiving standard neoadjuvant or adjuvant chemotherapy alone and 8% of those receiving chemotherapy plus goserelin (Zoladex) experienced ovarian failure, defined as amenorrhea for the prior 6 months and follicle-stimulating hormone (FSH) in the postmenopausal range.

Patrice Wendling/Frontline Medical News

In logistic regression analysis that accounted for age and chemotherapy regimen, the risk of ovarian failure was reduced 70% with goserelin (odds ratio, 0.30; two-sided P = .04), Dr. Halle Moore reported at the annual meeting of the American Society of Clinical Oncology.

Risk was further reduced using the less stringent definition of ovarian failure of amenorrhea for the prior 6 months or FSH in the postmenopausal range (45% vs. 20%; OR, 0.29; P = .006).

The 2-year ovarian dysfunction rate was 33% with standard chemotherapy and 14% with chemotherapy plus goserelin (OR, 0.35; P = .03). Dysfunction was defined as amenorrhea for the prior 3 months and FSH, estradiol, and/or inhibin B levels in the postmenopausal range.

"For the 25 percent or so of women with breast cancer who are diagnosed under the age of 50, the induction of early menopause is a common and potentially devastating side effect of treatment," said Dr. Moore of the Cleveland Clinic.

Small studies have shown high rates of ovarian preservation in women with hematologic malignancies with the use of a luteinizing hormone release hormone (LHRH) analogue. Results of randomized trials in breast cancer have been mixed; the studies commonly used only return of menses as an endpoint, and few provided data on pregnancy outcomes, she said.

The intergroup POEMS/S0230 (Prevention of Early Menopause Study) randomly assigned 257 premenopausal women, aged 18-49 years, with operable stage I-IIIA estrogen or progesterone receptor–negative breast cancer to curative-intent standard cyclophosphamide containing neoadjuvant or adjuvant chemotherapy alone or with subcutaneous injections of goserelin 3.6 mg every 4 weeks starting at least 1 week prior to the first chemotherapy dose and ending within 2 weeks of the final dose. The average age of the groups was 38.7 and 37.6 years, respectively.

The study was closed prior to full accrual of the target 416 patients, with 218 women evaluable for pregnancy and survival outcomes and 135 for ovarian failure.

In all, 18 of 113 evaluable controls and 25 of evaluable 105 women given goserelin reported attempting pregnancy, with 12 and 22 women, respectively, becoming pregnant over the 5-year study period (OR, 2.45; P = .03), Dr. Moore said.

Compared with controls, women given goserelin were twice as likely to have a successful delivery (8 vs. 16; OR, 2.51; P = .05) and to have a successful delivery or an ongoing pregnancy at the time of the analysis (10 vs. 19; OR, 2.45; P = .04).

Twelve babies were born to women on chemotherapy alone and 18 to those given goserelin, with 3 and 5 pregnancies, respectively, ongoing.

Importantly, there was no evidence goserelin increased adverse pregnancy events such as miscarriage (5 controls vs. 4 goserelin), elective termination (3 vs. 2), and delivery complications (2 vs. 2), she said.

Grade II-IV endocrine toxicity was reported in 24% of the chemotherapy-alone arm and 48% of the goserelin arm (P = .006). One grade IV thromboembolic event occurred with goserelin, Dr. Moore said. The most common added toxicities with goserelin were hot flashes, mood changes, vaginal dryness, and headache.

A planned exploratory analysis revealed that 89% of women on goserelin versus 78% on chemotherapy alone were disease-free at 4 years, with a hazard ratio of 0.47 after controlling for age and regimen (P = .04) and 0.49 after further adjusting for cancer stage (P = .04).

Overall survival at 4 years was 92% with goserelin and 82% with chemotherapy alone, with hazard ratios of 0.45 (P = .06) and 0.43 (P = .05), respectively.

The favorable survival outcomes with the addition of goserelin are intriguing and reassuring regarding the safety of the approach, Dr. Moore said. One possible explanation for the finding is that there are a high number of LHRH receptors on hormone receptor–negative breast cancers.

"Premenopausal women beginning curative-intent chemotherapy should consider this new option to prevent premature ovarian failure," she concluded.

Discussant Dr. Sharon Giordano, chair of health services research at the University of Texas MD Anderson Cancer Center in Houston, praised POEMS for providing pregnancy information and reassuring outcome data, but said there were several limitations. The most worrisome of these was missing endpoint data for 38% of participants. The study was also hampered by early close and low accrual, and excluded women with more than 10% estrogen or progesterone receptor positivity.

"I don’t think we can consider these results definitive," she said. "Having said that, and with these caveats and recognizing the uncertainty, I would be comfortable offering goserelin to my young patients with estrogen receptor–negative breast cancer who desire to preserve fertility or prevent premature menopause."

The study was supported by the National Institutes of Health. Dr. Moore reported no disclosures; three coauthors have financial ties with AstraZeneca, maker of goserelin. Dr. Giordano reported no relevant disclosures.

pwendling@frontlinemedcom.com

CHICAGO – Use of the gonadotropin-releasing hormone agonist goserelin during chemotherapy for early hormone receptor–negative breast cancer was associated with lower rates of ovarian failure and more pregnancies in the phase III POEMS study.

At 2 years, 22% of women receiving standard neoadjuvant or adjuvant chemotherapy alone and 8% of those receiving chemotherapy plus goserelin (Zoladex) experienced ovarian failure, defined as amenorrhea for the prior 6 months and follicle-stimulating hormone (FSH) in the postmenopausal range.

Patrice Wendling/Frontline Medical News

In logistic regression analysis that accounted for age and chemotherapy regimen, the risk of ovarian failure was reduced 70% with goserelin (odds ratio, 0.30; two-sided P = .04), Dr. Halle Moore reported at the annual meeting of the American Society of Clinical Oncology.

Risk was further reduced using the less stringent definition of ovarian failure of amenorrhea for the prior 6 months or FSH in the postmenopausal range (45% vs. 20%; OR, 0.29; P = .006).

The 2-year ovarian dysfunction rate was 33% with standard chemotherapy and 14% with chemotherapy plus goserelin (OR, 0.35; P = .03). Dysfunction was defined as amenorrhea for the prior 3 months and FSH, estradiol, and/or inhibin B levels in the postmenopausal range.

"For the 25 percent or so of women with breast cancer who are diagnosed under the age of 50, the induction of early menopause is a common and potentially devastating side effect of treatment," said Dr. Moore of the Cleveland Clinic.

Small studies have shown high rates of ovarian preservation in women with hematologic malignancies with the use of a luteinizing hormone release hormone (LHRH) analogue. Results of randomized trials in breast cancer have been mixed; the studies commonly used only return of menses as an endpoint, and few provided data on pregnancy outcomes, she said.

The intergroup POEMS/S0230 (Prevention of Early Menopause Study) randomly assigned 257 premenopausal women, aged 18-49 years, with operable stage I-IIIA estrogen or progesterone receptor–negative breast cancer to curative-intent standard cyclophosphamide containing neoadjuvant or adjuvant chemotherapy alone or with subcutaneous injections of goserelin 3.6 mg every 4 weeks starting at least 1 week prior to the first chemotherapy dose and ending within 2 weeks of the final dose. The average age of the groups was 38.7 and 37.6 years, respectively.

The study was closed prior to full accrual of the target 416 patients, with 218 women evaluable for pregnancy and survival outcomes and 135 for ovarian failure.

In all, 18 of 113 evaluable controls and 25 of evaluable 105 women given goserelin reported attempting pregnancy, with 12 and 22 women, respectively, becoming pregnant over the 5-year study period (OR, 2.45; P = .03), Dr. Moore said.

Compared with controls, women given goserelin were twice as likely to have a successful delivery (8 vs. 16; OR, 2.51; P = .05) and to have a successful delivery or an ongoing pregnancy at the time of the analysis (10 vs. 19; OR, 2.45; P = .04).

Twelve babies were born to women on chemotherapy alone and 18 to those given goserelin, with 3 and 5 pregnancies, respectively, ongoing.

Importantly, there was no evidence goserelin increased adverse pregnancy events such as miscarriage (5 controls vs. 4 goserelin), elective termination (3 vs. 2), and delivery complications (2 vs. 2), she said.

Grade II-IV endocrine toxicity was reported in 24% of the chemotherapy-alone arm and 48% of the goserelin arm (P = .006). One grade IV thromboembolic event occurred with goserelin, Dr. Moore said. The most common added toxicities with goserelin were hot flashes, mood changes, vaginal dryness, and headache.

A planned exploratory analysis revealed that 89% of women on goserelin versus 78% on chemotherapy alone were disease-free at 4 years, with a hazard ratio of 0.47 after controlling for age and regimen (P = .04) and 0.49 after further adjusting for cancer stage (P = .04).

Overall survival at 4 years was 92% with goserelin and 82% with chemotherapy alone, with hazard ratios of 0.45 (P = .06) and 0.43 (P = .05), respectively.

The favorable survival outcomes with the addition of goserelin are intriguing and reassuring regarding the safety of the approach, Dr. Moore said. One possible explanation for the finding is that there are a high number of LHRH receptors on hormone receptor–negative breast cancers.

"Premenopausal women beginning curative-intent chemotherapy should consider this new option to prevent premature ovarian failure," she concluded.

Discussant Dr. Sharon Giordano, chair of health services research at the University of Texas MD Anderson Cancer Center in Houston, praised POEMS for providing pregnancy information and reassuring outcome data, but said there were several limitations. The most worrisome of these was missing endpoint data for 38% of participants. The study was also hampered by early close and low accrual, and excluded women with more than 10% estrogen or progesterone receptor positivity.

"I don’t think we can consider these results definitive," she said. "Having said that, and with these caveats and recognizing the uncertainty, I would be comfortable offering goserelin to my young patients with estrogen receptor–negative breast cancer who desire to preserve fertility or prevent premature menopause."

The study was supported by the National Institutes of Health. Dr. Moore reported no disclosures; three coauthors have financial ties with AstraZeneca, maker of goserelin. Dr. Giordano reported no relevant disclosures.

pwendling@frontlinemedcom.com

CHICAGO – Women with breast cancer and bone metastasis can safely scale back the frequency of their zoledronic acid infusions from every 4 weeks to every 12 weeks without a loss in efficacy*, according to results of the phase III OPTIMIZE 2 trial.

Notably, the dreaded bisphosphonate side effect of osteonecrosis of the jaw was seen in two patients in the monthly arm, but none of those in the every-3-month treatment arm.

The findings apply only to breast cancer patients who’ve completed at least 1 year of monthly zoledronic acid therapy, according to study author Dr. Gabriel N. Hortobagyi, a professor of medicine at the University of Texas M.D. Anderson Cancer Center, Houston.

In an interview with us at the 50th anniversary of the American Society of Clinical Oncology, this past ASCO president said that the findings from this late-breaking abstract study will have implications for the costs of cancer care and possibly for patients with other cancers.

Dr. Hortobagyi reported consultant or advisory roles and research funding with Novartis, the study sponsor. Several coauthors are employees of or have leadership positions with Novartis.

pwendling@frontlinemedcom.com

Correction, 5/31/2014: An earlier version of this article misstated the duration of their zoledronic acid infusion treatments.

CHICAGO – Women with breast cancer and bone metastasis can safely scale back the frequency of their zoledronic acid infusions from every 4 weeks to every 12 weeks without a loss in efficacy*, according to results of the phase III OPTIMIZE 2 trial.

Notably, the dreaded bisphosphonate side effect of osteonecrosis of the jaw was seen in two patients in the monthly arm, but none of those in the every-3-month treatment arm.

The findings apply only to breast cancer patients who’ve completed at least 1 year of monthly zoledronic acid therapy, according to study author Dr. Gabriel N. Hortobagyi, a professor of medicine at the University of Texas M.D. Anderson Cancer Center, Houston.

In an interview with us at the 50th anniversary of the American Society of Clinical Oncology, this past ASCO president said that the findings from this late-breaking abstract study will have implications for the costs of cancer care and possibly for patients with other cancers.

Dr. Hortobagyi reported consultant or advisory roles and research funding with Novartis, the study sponsor. Several coauthors are employees of or have leadership positions with Novartis.

pwendling@frontlinemedcom.com

Correction, 5/31/2014: An earlier version of this article misstated the duration of their zoledronic acid infusion treatments.

CHICAGO – Women with breast cancer and bone metastasis can safely scale back the frequency of their zoledronic acid infusions from every 4 weeks to every 12 weeks without a loss in efficacy*, according to results of the phase III OPTIMIZE 2 trial.

Notably, the dreaded bisphosphonate side effect of osteonecrosis of the jaw was seen in two patients in the monthly arm, but none of those in the every-3-month treatment arm.

The findings apply only to breast cancer patients who’ve completed at least 1 year of monthly zoledronic acid therapy, according to study author Dr. Gabriel N. Hortobagyi, a professor of medicine at the University of Texas M.D. Anderson Cancer Center, Houston.

In an interview with us at the 50th anniversary of the American Society of Clinical Oncology, this past ASCO president said that the findings from this late-breaking abstract study will have implications for the costs of cancer care and possibly for patients with other cancers.

Dr. Hortobagyi reported consultant or advisory roles and research funding with Novartis, the study sponsor. Several coauthors are employees of or have leadership positions with Novartis.

pwendling@frontlinemedcom.com

Correction, 5/31/2014: An earlier version of this article misstated the duration of their zoledronic acid infusion treatments.