Breast Cancer

SAN ANTONIO – Treatment with atorvastatin did not significantly change mammographic density after 1 year in a small randomized phase III study of premenopausal women at high risk for breast cancer.

While statins are widely used to prevent cardiovascular disease, it has been suggested that these drugs also may have a role in breast cancer prevention. Statin users are estimated to have a 30%-70% lower incidence of breast cancer, compared with nonusers, according to Dr. Marie E. Wood, professor of medicine and director of the familial cancer program at the University of Vermont, Burlington, and her coinvestigators.

A total of 63 premenopausal women were randomized to receive either 40 mg of atorvastatin (Lipitor) or placebo daily for a year. At the end of that time the investigators found no association between change in breast density and atorvastatin use in a multivariable linear regression analysis adjusted for age and body mass index. The data were presented in poster form at the San Antonio Breast Cancer Symposium.

The women had a mean age of 44 years and a mean body mass index (BMI) of 26.4 kg/m². Mammographic density was assessed using the Breast Imaging Reporting and Data System (BI-RADS), which is a standardized qualitative assessment of mammographic breast density with four categories.

Four percent of women had fatty-replaced breast tissue, 29% had scattered fibroglandular densities, 56% had heterogeneously dense breasts, and 11% had extremely dense breast tissue.

A total of 26% of women withdrew from the study – four because of side effects (headache, back pain, joint pain), six because of abnormal laboratory values, and the remainder for other reasons.

Baseline to 12-month changes in breast density were measured in all patients on a continuous scale using the visual analog scale method. Mean density at study entry was 31.6% and 32.4% at the end of treatment. Because of the skewed distribution of breast density change, a Wilcoxon signed-rank test was performed to determine if the change in breast density varied with treatment. No statistically significant difference was observed between the two treatment groups (P = .89).

Premenopausal women with regular menstrual cycles (four cycles in past 6 months) were eligible if they were at least 35 years of age and at increased risk of developing breast cancer. Increased risk was defined as having at least one of the following: a prior biopsy demonstrating atypical hyperplasia or lobular carcinoma in situ; BRCA1/2 mutation carrier (or mutation is in a family member); 5-year Gail Model Risk of greater than1.66%; a strong family history of breast and/or ovarian cancer; a prior history of breast cancer (ductal carcinoma in situ and stage 0-IIIb) and at least 1 year off of all therapy; and a history of chemoradiotherapy treatment for Hodgkin’s disease.

Women were excluded if they had a history of stage IV breast cancer or ovarian cancer; were already taking statins; were taking HRT, tamoxifen, raloxifene, an aromatase inhibitor; or were participating in another chemoprevention trial.

The researchers urged caution in interpreting the data, given the small sample size, slow accrual, wide variation in the mammographic density in this population, and the fact that mammograms were done during the transition to digital mammography.

"While the primary aim of this study was not met, we have shown that biomarker studies can be done in a multi-institutional setting ... Additional biomarker evaluation may prove informative," they wrote

Dr. Wood and her associates are currently analyzing the effect of a daily statin vs. placebo on markers of breast cancer risk, including mammographic density, serum markers (IGF-1), and tissue markers (atypia and Ki67).

This study is sponsored by the Breast Cancer Research Foundation and the Cancer and Leukemia Group B. The researchers reported that they have no relevant disclosures.

SAN ANTONIO – Treatment with atorvastatin did not significantly change mammographic density after 1 year in a small randomized phase III study of premenopausal women at high risk for breast cancer.

While statins are widely used to prevent cardiovascular disease, it has been suggested that these drugs also may have a role in breast cancer prevention. Statin users are estimated to have a 30%-70% lower incidence of breast cancer, compared with nonusers, according to Dr. Marie E. Wood, professor of medicine and director of the familial cancer program at the University of Vermont, Burlington, and her coinvestigators.

A total of 63 premenopausal women were randomized to receive either 40 mg of atorvastatin (Lipitor) or placebo daily for a year. At the end of that time the investigators found no association between change in breast density and atorvastatin use in a multivariable linear regression analysis adjusted for age and body mass index. The data were presented in poster form at the San Antonio Breast Cancer Symposium.

The women had a mean age of 44 years and a mean body mass index (BMI) of 26.4 kg/m². Mammographic density was assessed using the Breast Imaging Reporting and Data System (BI-RADS), which is a standardized qualitative assessment of mammographic breast density with four categories.

Four percent of women had fatty-replaced breast tissue, 29% had scattered fibroglandular densities, 56% had heterogeneously dense breasts, and 11% had extremely dense breast tissue.

A total of 26% of women withdrew from the study – four because of side effects (headache, back pain, joint pain), six because of abnormal laboratory values, and the remainder for other reasons.

Baseline to 12-month changes in breast density were measured in all patients on a continuous scale using the visual analog scale method. Mean density at study entry was 31.6% and 32.4% at the end of treatment. Because of the skewed distribution of breast density change, a Wilcoxon signed-rank test was performed to determine if the change in breast density varied with treatment. No statistically significant difference was observed between the two treatment groups (P = .89).

Premenopausal women with regular menstrual cycles (four cycles in past 6 months) were eligible if they were at least 35 years of age and at increased risk of developing breast cancer. Increased risk was defined as having at least one of the following: a prior biopsy demonstrating atypical hyperplasia or lobular carcinoma in situ; BRCA1/2 mutation carrier (or mutation is in a family member); 5-year Gail Model Risk of greater than1.66%; a strong family history of breast and/or ovarian cancer; a prior history of breast cancer (ductal carcinoma in situ and stage 0-IIIb) and at least 1 year off of all therapy; and a history of chemoradiotherapy treatment for Hodgkin’s disease.

Women were excluded if they had a history of stage IV breast cancer or ovarian cancer; were already taking statins; were taking HRT, tamoxifen, raloxifene, an aromatase inhibitor; or were participating in another chemoprevention trial.

The researchers urged caution in interpreting the data, given the small sample size, slow accrual, wide variation in the mammographic density in this population, and the fact that mammograms were done during the transition to digital mammography.

"While the primary aim of this study was not met, we have shown that biomarker studies can be done in a multi-institutional setting ... Additional biomarker evaluation may prove informative," they wrote

Dr. Wood and her associates are currently analyzing the effect of a daily statin vs. placebo on markers of breast cancer risk, including mammographic density, serum markers (IGF-1), and tissue markers (atypia and Ki67).

This study is sponsored by the Breast Cancer Research Foundation and the Cancer and Leukemia Group B. The researchers reported that they have no relevant disclosures.

SAN ANTONIO – Treatment with atorvastatin did not significantly change mammographic density after 1 year in a small randomized phase III study of premenopausal women at high risk for breast cancer.

While statins are widely used to prevent cardiovascular disease, it has been suggested that these drugs also may have a role in breast cancer prevention. Statin users are estimated to have a 30%-70% lower incidence of breast cancer, compared with nonusers, according to Dr. Marie E. Wood, professor of medicine and director of the familial cancer program at the University of Vermont, Burlington, and her coinvestigators.

A total of 63 premenopausal women were randomized to receive either 40 mg of atorvastatin (Lipitor) or placebo daily for a year. At the end of that time the investigators found no association between change in breast density and atorvastatin use in a multivariable linear regression analysis adjusted for age and body mass index. The data were presented in poster form at the San Antonio Breast Cancer Symposium.

The women had a mean age of 44 years and a mean body mass index (BMI) of 26.4 kg/m². Mammographic density was assessed using the Breast Imaging Reporting and Data System (BI-RADS), which is a standardized qualitative assessment of mammographic breast density with four categories.

Four percent of women had fatty-replaced breast tissue, 29% had scattered fibroglandular densities, 56% had heterogeneously dense breasts, and 11% had extremely dense breast tissue.

A total of 26% of women withdrew from the study – four because of side effects (headache, back pain, joint pain), six because of abnormal laboratory values, and the remainder for other reasons.

Baseline to 12-month changes in breast density were measured in all patients on a continuous scale using the visual analog scale method. Mean density at study entry was 31.6% and 32.4% at the end of treatment. Because of the skewed distribution of breast density change, a Wilcoxon signed-rank test was performed to determine if the change in breast density varied with treatment. No statistically significant difference was observed between the two treatment groups (P = .89).

Premenopausal women with regular menstrual cycles (four cycles in past 6 months) were eligible if they were at least 35 years of age and at increased risk of developing breast cancer. Increased risk was defined as having at least one of the following: a prior biopsy demonstrating atypical hyperplasia or lobular carcinoma in situ; BRCA1/2 mutation carrier (or mutation is in a family member); 5-year Gail Model Risk of greater than1.66%; a strong family history of breast and/or ovarian cancer; a prior history of breast cancer (ductal carcinoma in situ and stage 0-IIIb) and at least 1 year off of all therapy; and a history of chemoradiotherapy treatment for Hodgkin’s disease.

Women were excluded if they had a history of stage IV breast cancer or ovarian cancer; were already taking statins; were taking HRT, tamoxifen, raloxifene, an aromatase inhibitor; or were participating in another chemoprevention trial.

The researchers urged caution in interpreting the data, given the small sample size, slow accrual, wide variation in the mammographic density in this population, and the fact that mammograms were done during the transition to digital mammography.

"While the primary aim of this study was not met, we have shown that biomarker studies can be done in a multi-institutional setting ... Additional biomarker evaluation may prove informative," they wrote

Dr. Wood and her associates are currently analyzing the effect of a daily statin vs. placebo on markers of breast cancer risk, including mammographic density, serum markers (IGF-1), and tissue markers (atypia and Ki67).

This study is sponsored by the Breast Cancer Research Foundation and the Cancer and Leukemia Group B. The researchers reported that they have no relevant disclosures.

SAN ANTONIO – Contralateral prophylactic mastectomy – in comparison to unilateral mastectomy – was associated with a significantly increased rate of major postoperative surgical complications in a 470-patient study.

Physicians therefore must provide appropriate information about these risks to patients who are considering the contralateral procedure, according to lead investigator Allison C. Stover, M.P.H. Major complications often require numerous unplanned procedures, which increase patient burden and treatment costs.

To assess the impact of the contralateral procedure on surgical outcomes, Ms. Stover of the University of California, San Francisco, and her colleagues identified patients who underwent unilateral or bilateral mastectomy with immediate reconstruction at her institution between 2005 and 2010. A minimum of 1 year of follow-up data was available for each study participant. Patients with bilateral cancer or bilateral prophylactic surgery were excluded from the analysis.

The investigators grouped the patients by unilateral or contralateral mastectomy status. They also prospectively captured complications, including infection with use of oral or intravenous antibiotics; implant exposure, loss, or removal; seroma; hematoma; delayed wound healing; necrosis; readmission; and return to the operating room.

Among the 470 patients (665 breasts) who met the study criteria, the mean follow-up time was 22 months. There were no differences between the groups in tumor grade, stage, follow-up time, smoking history, or radiation, either prior to or post surgery, Ms. Stover said in a poster presentation at the San Antonio Breast Cancer Symposium.

Significant between-group differences were observed in age and the number of skin-sparing mastectomies, she said, noting that the contralateral group was younger than the unilateral group (mean age 46.04 years vs. 50.55 years, respectively), and had a larger proportion of skin-sparing mastectomies.

The rate of any major complication was 1.5 times higher in the contralateral group compared with the unilateral group, Ms. Stover stated. "There were significant between-group differences in the number of severe infections requiring IV antibiotics and return to the operating room, as well as the overall rate of any major complication," she said.

A comparison of the complication rate by index vs. prophylactic breast within the contralateral group showed a significantly higher rate of implant loss in the index breast, but no significant differences in any other measure, Ms. Stover noted.

Because many contralateral cases are not at sufficiently high risk for a second breast cancer to meet clinical criteria for prophylactic surgery, the increased complication rate should be taken into consideration when counseling women who are contemplating contralateral mastectomy, Ms. Stover said, adding that they should also be incorporated into guidelines and clinical recommendations.

The poster discussant, Dr. Ismail Jatoi of the University of Texas Health Sciences Center in San Antonio, pointed out that the study’s mean follow-up of 22 months may be insufficient to adequately compare the complication rates. "There are long-term implications that may increase the value [of the contralateral procedure]. For example, patients who undergo the procedure no longer undergo mammograms and thus are not subject to false-positive reports and the subsequent associated testing. They may have lower morbidity over time," he said. "The long-term impact may be less dire than the short-term impact."

It is also possible that the results could be attributed to a "multiplicity of testing," Dr. Jatoi said. "When you test for a lot of bad outcomes, you’re likely to find one."

Despite these concerns, "there clearly are some risks, which point to the need for proper, thorough informed consent," said Dr. Jatoi. "The possible increased complication risks are definitely points to be made when we provide informed consent."

Ms. Stover and Dr. Jatoi reported that they had no relevant financial conflicts.

SAN ANTONIO – Contralateral prophylactic mastectomy – in comparison to unilateral mastectomy – was associated with a significantly increased rate of major postoperative surgical complications in a 470-patient study.

Physicians therefore must provide appropriate information about these risks to patients who are considering the contralateral procedure, according to lead investigator Allison C. Stover, M.P.H. Major complications often require numerous unplanned procedures, which increase patient burden and treatment costs.

To assess the impact of the contralateral procedure on surgical outcomes, Ms. Stover of the University of California, San Francisco, and her colleagues identified patients who underwent unilateral or bilateral mastectomy with immediate reconstruction at her institution between 2005 and 2010. A minimum of 1 year of follow-up data was available for each study participant. Patients with bilateral cancer or bilateral prophylactic surgery were excluded from the analysis.

The investigators grouped the patients by unilateral or contralateral mastectomy status. They also prospectively captured complications, including infection with use of oral or intravenous antibiotics; implant exposure, loss, or removal; seroma; hematoma; delayed wound healing; necrosis; readmission; and return to the operating room.

Among the 470 patients (665 breasts) who met the study criteria, the mean follow-up time was 22 months. There were no differences between the groups in tumor grade, stage, follow-up time, smoking history, or radiation, either prior to or post surgery, Ms. Stover said in a poster presentation at the San Antonio Breast Cancer Symposium.

Significant between-group differences were observed in age and the number of skin-sparing mastectomies, she said, noting that the contralateral group was younger than the unilateral group (mean age 46.04 years vs. 50.55 years, respectively), and had a larger proportion of skin-sparing mastectomies.

The rate of any major complication was 1.5 times higher in the contralateral group compared with the unilateral group, Ms. Stover stated. "There were significant between-group differences in the number of severe infections requiring IV antibiotics and return to the operating room, as well as the overall rate of any major complication," she said.

A comparison of the complication rate by index vs. prophylactic breast within the contralateral group showed a significantly higher rate of implant loss in the index breast, but no significant differences in any other measure, Ms. Stover noted.

Because many contralateral cases are not at sufficiently high risk for a second breast cancer to meet clinical criteria for prophylactic surgery, the increased complication rate should be taken into consideration when counseling women who are contemplating contralateral mastectomy, Ms. Stover said, adding that they should also be incorporated into guidelines and clinical recommendations.

The poster discussant, Dr. Ismail Jatoi of the University of Texas Health Sciences Center in San Antonio, pointed out that the study’s mean follow-up of 22 months may be insufficient to adequately compare the complication rates. "There are long-term implications that may increase the value [of the contralateral procedure]. For example, patients who undergo the procedure no longer undergo mammograms and thus are not subject to false-positive reports and the subsequent associated testing. They may have lower morbidity over time," he said. "The long-term impact may be less dire than the short-term impact."

It is also possible that the results could be attributed to a "multiplicity of testing," Dr. Jatoi said. "When you test for a lot of bad outcomes, you’re likely to find one."

Despite these concerns, "there clearly are some risks, which point to the need for proper, thorough informed consent," said Dr. Jatoi. "The possible increased complication risks are definitely points to be made when we provide informed consent."

Ms. Stover and Dr. Jatoi reported that they had no relevant financial conflicts.

SAN ANTONIO – Contralateral prophylactic mastectomy – in comparison to unilateral mastectomy – was associated with a significantly increased rate of major postoperative surgical complications in a 470-patient study.

Physicians therefore must provide appropriate information about these risks to patients who are considering the contralateral procedure, according to lead investigator Allison C. Stover, M.P.H. Major complications often require numerous unplanned procedures, which increase patient burden and treatment costs.

To assess the impact of the contralateral procedure on surgical outcomes, Ms. Stover of the University of California, San Francisco, and her colleagues identified patients who underwent unilateral or bilateral mastectomy with immediate reconstruction at her institution between 2005 and 2010. A minimum of 1 year of follow-up data was available for each study participant. Patients with bilateral cancer or bilateral prophylactic surgery were excluded from the analysis.

The investigators grouped the patients by unilateral or contralateral mastectomy status. They also prospectively captured complications, including infection with use of oral or intravenous antibiotics; implant exposure, loss, or removal; seroma; hematoma; delayed wound healing; necrosis; readmission; and return to the operating room.

Among the 470 patients (665 breasts) who met the study criteria, the mean follow-up time was 22 months. There were no differences between the groups in tumor grade, stage, follow-up time, smoking history, or radiation, either prior to or post surgery, Ms. Stover said in a poster presentation at the San Antonio Breast Cancer Symposium.

Significant between-group differences were observed in age and the number of skin-sparing mastectomies, she said, noting that the contralateral group was younger than the unilateral group (mean age 46.04 years vs. 50.55 years, respectively), and had a larger proportion of skin-sparing mastectomies.

The rate of any major complication was 1.5 times higher in the contralateral group compared with the unilateral group, Ms. Stover stated. "There were significant between-group differences in the number of severe infections requiring IV antibiotics and return to the operating room, as well as the overall rate of any major complication," she said.

A comparison of the complication rate by index vs. prophylactic breast within the contralateral group showed a significantly higher rate of implant loss in the index breast, but no significant differences in any other measure, Ms. Stover noted.

Because many contralateral cases are not at sufficiently high risk for a second breast cancer to meet clinical criteria for prophylactic surgery, the increased complication rate should be taken into consideration when counseling women who are contemplating contralateral mastectomy, Ms. Stover said, adding that they should also be incorporated into guidelines and clinical recommendations.

The poster discussant, Dr. Ismail Jatoi of the University of Texas Health Sciences Center in San Antonio, pointed out that the study’s mean follow-up of 22 months may be insufficient to adequately compare the complication rates. "There are long-term implications that may increase the value [of the contralateral procedure]. For example, patients who undergo the procedure no longer undergo mammograms and thus are not subject to false-positive reports and the subsequent associated testing. They may have lower morbidity over time," he said. "The long-term impact may be less dire than the short-term impact."

It is also possible that the results could be attributed to a "multiplicity of testing," Dr. Jatoi said. "When you test for a lot of bad outcomes, you’re likely to find one."

Despite these concerns, "there clearly are some risks, which point to the need for proper, thorough informed consent," said Dr. Jatoi. "The possible increased complication risks are definitely points to be made when we provide informed consent."

Ms. Stover and Dr. Jatoi reported that they had no relevant financial conflicts.

SAN ANTONIO – A phase III trial of an adjuvant breast cancer vaccine will begin enrollment before the end of 2011 as a result of favorable 5-year efficacy and safety data in a phase II study.

In updated phase II results, disease-free survival at a median follow-up of 60 months was 95.9% in 53 patients who received the E75 vaccine with multiple booster inoculations, significantly better than the 79.7% figure in 79 controls (P = .016), Dr. Timothy J. Vreeland reported at the San Antonio Breast Cancer Symposium.

The vaccine, known as NeuVax, is composed of the E75 peptide, which is derived from human epidermal growth factor receptor 2 (HER2), mixed with granulocyte macrophage colony-stimulating factor (GM-CSF). The vaccine has previously been shown to stimulate cytotoxic T cells to specifically target cells expressing HER2.

As a result of lessons learned in the randomized phase II study, the phase III trial will be restricted to patients with lymph node–positive tumors who are clinically disease-free after completing standard therapy. Only patients with low levels of HER2 expression, meaning immunohistochemistry 1+ or 2+, will be eligible.

The E75 vaccine was initially given as an intradermal injection once a month for 6 months. Because of waning immunity noted during phase I and II testing, however, a booster immunization program was initiated. It consists of a booster injection once every 6 months. The booster program will be routine in the phase III trial.

The overall phase II study population consisted of 187 patients with node-positive or high-risk node-negative tumors expressing any level of HER2. The median 5-year disease-free survival in the 108 patients in the vaccine arm was 89.4%, compared with 79.7% in controls, a nonsignificant difference. But the vaccine arm included 55 women who didn’t receive booster immunizations. When they were excluded, the 5-year disease-free survival rate climbed to 95.9%, according to Dr. Vreeland, a U.S. Army captain at San Antonio Military Medical Center.

The E75 vaccine has been very well tolerated. A total of 70%-85% of local and systemic toxicities in both the primary vaccination series and the booster inoculations have been grade I, with the remainder grade II. Seven of 53 patients (13%) in the booster program developed grade II delayed urticarial reactions at a median of 9 days post inoculation.

The phase III trial is called PRESENT (Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer with Low to Intermediate HER2 Expression with NeuVax Treatment).

The NeuVax vaccine has been licensed by the U.S. military to Galena Biopharma. Dr. Vreeland declared having no relevant financial disclosures.

SAN ANTONIO – A phase III trial of an adjuvant breast cancer vaccine will begin enrollment before the end of 2011 as a result of favorable 5-year efficacy and safety data in a phase II study.

In updated phase II results, disease-free survival at a median follow-up of 60 months was 95.9% in 53 patients who received the E75 vaccine with multiple booster inoculations, significantly better than the 79.7% figure in 79 controls (P = .016), Dr. Timothy J. Vreeland reported at the San Antonio Breast Cancer Symposium.

The vaccine, known as NeuVax, is composed of the E75 peptide, which is derived from human epidermal growth factor receptor 2 (HER2), mixed with granulocyte macrophage colony-stimulating factor (GM-CSF). The vaccine has previously been shown to stimulate cytotoxic T cells to specifically target cells expressing HER2.

As a result of lessons learned in the randomized phase II study, the phase III trial will be restricted to patients with lymph node–positive tumors who are clinically disease-free after completing standard therapy. Only patients with low levels of HER2 expression, meaning immunohistochemistry 1+ or 2+, will be eligible.

The E75 vaccine was initially given as an intradermal injection once a month for 6 months. Because of waning immunity noted during phase I and II testing, however, a booster immunization program was initiated. It consists of a booster injection once every 6 months. The booster program will be routine in the phase III trial.

The overall phase II study population consisted of 187 patients with node-positive or high-risk node-negative tumors expressing any level of HER2. The median 5-year disease-free survival in the 108 patients in the vaccine arm was 89.4%, compared with 79.7% in controls, a nonsignificant difference. But the vaccine arm included 55 women who didn’t receive booster immunizations. When they were excluded, the 5-year disease-free survival rate climbed to 95.9%, according to Dr. Vreeland, a U.S. Army captain at San Antonio Military Medical Center.

The E75 vaccine has been very well tolerated. A total of 70%-85% of local and systemic toxicities in both the primary vaccination series and the booster inoculations have been grade I, with the remainder grade II. Seven of 53 patients (13%) in the booster program developed grade II delayed urticarial reactions at a median of 9 days post inoculation.

The phase III trial is called PRESENT (Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer with Low to Intermediate HER2 Expression with NeuVax Treatment).

The NeuVax vaccine has been licensed by the U.S. military to Galena Biopharma. Dr. Vreeland declared having no relevant financial disclosures.

SAN ANTONIO – A phase III trial of an adjuvant breast cancer vaccine will begin enrollment before the end of 2011 as a result of favorable 5-year efficacy and safety data in a phase II study.

In updated phase II results, disease-free survival at a median follow-up of 60 months was 95.9% in 53 patients who received the E75 vaccine with multiple booster inoculations, significantly better than the 79.7% figure in 79 controls (P = .016), Dr. Timothy J. Vreeland reported at the San Antonio Breast Cancer Symposium.

The vaccine, known as NeuVax, is composed of the E75 peptide, which is derived from human epidermal growth factor receptor 2 (HER2), mixed with granulocyte macrophage colony-stimulating factor (GM-CSF). The vaccine has previously been shown to stimulate cytotoxic T cells to specifically target cells expressing HER2.

As a result of lessons learned in the randomized phase II study, the phase III trial will be restricted to patients with lymph node–positive tumors who are clinically disease-free after completing standard therapy. Only patients with low levels of HER2 expression, meaning immunohistochemistry 1+ or 2+, will be eligible.

The E75 vaccine was initially given as an intradermal injection once a month for 6 months. Because of waning immunity noted during phase I and II testing, however, a booster immunization program was initiated. It consists of a booster injection once every 6 months. The booster program will be routine in the phase III trial.

The overall phase II study population consisted of 187 patients with node-positive or high-risk node-negative tumors expressing any level of HER2. The median 5-year disease-free survival in the 108 patients in the vaccine arm was 89.4%, compared with 79.7% in controls, a nonsignificant difference. But the vaccine arm included 55 women who didn’t receive booster immunizations. When they were excluded, the 5-year disease-free survival rate climbed to 95.9%, according to Dr. Vreeland, a U.S. Army captain at San Antonio Military Medical Center.

The E75 vaccine has been very well tolerated. A total of 70%-85% of local and systemic toxicities in both the primary vaccination series and the booster inoculations have been grade I, with the remainder grade II. Seven of 53 patients (13%) in the booster program developed grade II delayed urticarial reactions at a median of 9 days post inoculation.

The phase III trial is called PRESENT (Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer with Low to Intermediate HER2 Expression with NeuVax Treatment).

The NeuVax vaccine has been licensed by the U.S. military to Galena Biopharma. Dr. Vreeland declared having no relevant financial disclosures.

SAN ANTONIO – Axillary lymph node dissection is not warranted in patients with clinically node-negative breast cancer and micrometastases in the sentinel node, another randomized phase III clinical trial has found.

New 57-month follow-up data from the International Breast Cancer Study Group (IBCSG) trial 23-01 in breast cancer patients with minimal sentinel node involvement show no disease-free or overall survival differences between patients who underwent axillary dissection and those who did not, Dr. Viviana Galimberti reported at the San Antonio Breast Cancer Symposium.

This is consistent with the results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, which reported in February that it found no survival difference between early-stage breast cancer patients who underwent axillary lymph node dissection and those who did not after being found sentinel node positive on biopsy (JAMA 2011;305:569-75).

The IBCSG trial 23-01 randomized 934 patients from 27 centers to axillary dissection or no further axillary surgery. All of the patients had tumors no larger than 5 cm and minimal sentinel node involvement, defined as one or more micrometastatic (less than 2 mm) sentinel node were included in the analysis, said Dr. Galimberti of the European Institute of Oncology in Milan. Disease-free survival was the study’s primary end point, while overall survival and systemic disease-free survival were secondary end points, she said.

Of the 934 patients, 3 were excluded, including 2 patients in whom no tumor was found in the sentinel node and 1 patient who withdrew consent, Dr. Galimberti said. Of the remaining 931 patients in the intent to treat population, 17 of the 464 assigned to axial dissection did not receive it and 14 of the 467 assigned to no dissection did receive it, she said.

At study entry, mean patient age was 54 years, and more than half (56%) of the patients were postmenopausal. Regarding disease characteristics, 67% of the patients had tumors less than 2 cm, 7% had tumors 3 cm or larger, and 26% had grade 3 disease "Most of the tumors [89%] were estrogen receptor–positive and 75% were progesterone receptor–positive," Dr. Galimberti said. In the involved sentinel nodes, 67% of the patients had micrometastasis less than 1.0 mm, 29% had micrometastasis from 1.1-2.0, 2% had metastasis greater than 2.0, and 2% were unknown, she said.

In all, 96% of the patients underwent lymphoscintigraphy and evidence of one or two sentinel nodes was found in 85% of them, Dr. Galimberti reported. Previous excision biopsy was performed in 16% of the patients, and conservative surgery was the definitive treatment in three-quarters of the patients while 25% received mastectomy. Similar rates of adjuvant radiotherapy, hormonal therapy, and chemotherapy were seen in both groups, she said.

Long-term adverse events were more prevalent in the dissection group, with 18% experiencing sensory neuropathy, compared with 12% of those not undergoing dissection. Similarly, the respective rates of lymphedema were 13% and 4% and the respective rates of motor neuropathy were 8% and 3%, Dr. Galimberti reported.

The 5-year disease-free survival rates in the dissection and no dissection groups were 87.3% and 88.4%, respectively, said Dr. Galimberti. The 5-year overall survival rates were similar between both groups as well, at 97.6% in the dissection group and 98% in the no-dissection group.

"In total, there were 17 [3.7%] deaths among the patients who underwent dissection and 12 [2.6%] among those who did not," she said.

The lack of a difference between the groups for the primary end point of disease-free survival fulfilled the protocol-specified criterion for noninferiority. Indeed, Dr. Galimberti noted, "The 5-year disease-free survival of 88% in the patients who did not undergo dissection was much better than the 70% that was anticipated in the original plan," she said. The rate of reappearance of tumor in the undissected axilla was also unexpectedly low, at about 1%, she added.

"It seems likely that the results of the IBCSG Trial 23-01 and Z0011 will change clinical practice, allowing no axillary dissection in early breast cancer, especially when the sentinel node is minimally involved, to reduce [associated] complications with no adverse effect on survival," Dr. Galimberti concluded.

Dr. Galimberti reported having no relevant financial conflicts to disclose.

SAN ANTONIO – Axillary lymph node dissection is not warranted in patients with clinically node-negative breast cancer and micrometastases in the sentinel node, another randomized phase III clinical trial has found.

New 57-month follow-up data from the International Breast Cancer Study Group (IBCSG) trial 23-01 in breast cancer patients with minimal sentinel node involvement show no disease-free or overall survival differences between patients who underwent axillary dissection and those who did not, Dr. Viviana Galimberti reported at the San Antonio Breast Cancer Symposium.

This is consistent with the results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, which reported in February that it found no survival difference between early-stage breast cancer patients who underwent axillary lymph node dissection and those who did not after being found sentinel node positive on biopsy (JAMA 2011;305:569-75).

The IBCSG trial 23-01 randomized 934 patients from 27 centers to axillary dissection or no further axillary surgery. All of the patients had tumors no larger than 5 cm and minimal sentinel node involvement, defined as one or more micrometastatic (less than 2 mm) sentinel node were included in the analysis, said Dr. Galimberti of the European Institute of Oncology in Milan. Disease-free survival was the study’s primary end point, while overall survival and systemic disease-free survival were secondary end points, she said.

Of the 934 patients, 3 were excluded, including 2 patients in whom no tumor was found in the sentinel node and 1 patient who withdrew consent, Dr. Galimberti said. Of the remaining 931 patients in the intent to treat population, 17 of the 464 assigned to axial dissection did not receive it and 14 of the 467 assigned to no dissection did receive it, she said.

At study entry, mean patient age was 54 years, and more than half (56%) of the patients were postmenopausal. Regarding disease characteristics, 67% of the patients had tumors less than 2 cm, 7% had tumors 3 cm or larger, and 26% had grade 3 disease "Most of the tumors [89%] were estrogen receptor–positive and 75% were progesterone receptor–positive," Dr. Galimberti said. In the involved sentinel nodes, 67% of the patients had micrometastasis less than 1.0 mm, 29% had micrometastasis from 1.1-2.0, 2% had metastasis greater than 2.0, and 2% were unknown, she said.

In all, 96% of the patients underwent lymphoscintigraphy and evidence of one or two sentinel nodes was found in 85% of them, Dr. Galimberti reported. Previous excision biopsy was performed in 16% of the patients, and conservative surgery was the definitive treatment in three-quarters of the patients while 25% received mastectomy. Similar rates of adjuvant radiotherapy, hormonal therapy, and chemotherapy were seen in both groups, she said.

Long-term adverse events were more prevalent in the dissection group, with 18% experiencing sensory neuropathy, compared with 12% of those not undergoing dissection. Similarly, the respective rates of lymphedema were 13% and 4% and the respective rates of motor neuropathy were 8% and 3%, Dr. Galimberti reported.

The 5-year disease-free survival rates in the dissection and no dissection groups were 87.3% and 88.4%, respectively, said Dr. Galimberti. The 5-year overall survival rates were similar between both groups as well, at 97.6% in the dissection group and 98% in the no-dissection group.

"In total, there were 17 [3.7%] deaths among the patients who underwent dissection and 12 [2.6%] among those who did not," she said.

The lack of a difference between the groups for the primary end point of disease-free survival fulfilled the protocol-specified criterion for noninferiority. Indeed, Dr. Galimberti noted, "The 5-year disease-free survival of 88% in the patients who did not undergo dissection was much better than the 70% that was anticipated in the original plan," she said. The rate of reappearance of tumor in the undissected axilla was also unexpectedly low, at about 1%, she added.

"It seems likely that the results of the IBCSG Trial 23-01 and Z0011 will change clinical practice, allowing no axillary dissection in early breast cancer, especially when the sentinel node is minimally involved, to reduce [associated] complications with no adverse effect on survival," Dr. Galimberti concluded.

Dr. Galimberti reported having no relevant financial conflicts to disclose.

SAN ANTONIO – Axillary lymph node dissection is not warranted in patients with clinically node-negative breast cancer and micrometastases in the sentinel node, another randomized phase III clinical trial has found.

New 57-month follow-up data from the International Breast Cancer Study Group (IBCSG) trial 23-01 in breast cancer patients with minimal sentinel node involvement show no disease-free or overall survival differences between patients who underwent axillary dissection and those who did not, Dr. Viviana Galimberti reported at the San Antonio Breast Cancer Symposium.

This is consistent with the results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, which reported in February that it found no survival difference between early-stage breast cancer patients who underwent axillary lymph node dissection and those who did not after being found sentinel node positive on biopsy (JAMA 2011;305:569-75).

The IBCSG trial 23-01 randomized 934 patients from 27 centers to axillary dissection or no further axillary surgery. All of the patients had tumors no larger than 5 cm and minimal sentinel node involvement, defined as one or more micrometastatic (less than 2 mm) sentinel node were included in the analysis, said Dr. Galimberti of the European Institute of Oncology in Milan. Disease-free survival was the study’s primary end point, while overall survival and systemic disease-free survival were secondary end points, she said.

Of the 934 patients, 3 were excluded, including 2 patients in whom no tumor was found in the sentinel node and 1 patient who withdrew consent, Dr. Galimberti said. Of the remaining 931 patients in the intent to treat population, 17 of the 464 assigned to axial dissection did not receive it and 14 of the 467 assigned to no dissection did receive it, she said.

At study entry, mean patient age was 54 years, and more than half (56%) of the patients were postmenopausal. Regarding disease characteristics, 67% of the patients had tumors less than 2 cm, 7% had tumors 3 cm or larger, and 26% had grade 3 disease "Most of the tumors [89%] were estrogen receptor–positive and 75% were progesterone receptor–positive," Dr. Galimberti said. In the involved sentinel nodes, 67% of the patients had micrometastasis less than 1.0 mm, 29% had micrometastasis from 1.1-2.0, 2% had metastasis greater than 2.0, and 2% were unknown, she said.

In all, 96% of the patients underwent lymphoscintigraphy and evidence of one or two sentinel nodes was found in 85% of them, Dr. Galimberti reported. Previous excision biopsy was performed in 16% of the patients, and conservative surgery was the definitive treatment in three-quarters of the patients while 25% received mastectomy. Similar rates of adjuvant radiotherapy, hormonal therapy, and chemotherapy were seen in both groups, she said.

Long-term adverse events were more prevalent in the dissection group, with 18% experiencing sensory neuropathy, compared with 12% of those not undergoing dissection. Similarly, the respective rates of lymphedema were 13% and 4% and the respective rates of motor neuropathy were 8% and 3%, Dr. Galimberti reported.

The 5-year disease-free survival rates in the dissection and no dissection groups were 87.3% and 88.4%, respectively, said Dr. Galimberti. The 5-year overall survival rates were similar between both groups as well, at 97.6% in the dissection group and 98% in the no-dissection group.

"In total, there were 17 [3.7%] deaths among the patients who underwent dissection and 12 [2.6%] among those who did not," she said.

The lack of a difference between the groups for the primary end point of disease-free survival fulfilled the protocol-specified criterion for noninferiority. Indeed, Dr. Galimberti noted, "The 5-year disease-free survival of 88% in the patients who did not undergo dissection was much better than the 70% that was anticipated in the original plan," she said. The rate of reappearance of tumor in the undissected axilla was also unexpectedly low, at about 1%, she added.

"It seems likely that the results of the IBCSG Trial 23-01 and Z0011 will change clinical practice, allowing no axillary dissection in early breast cancer, especially when the sentinel node is minimally involved, to reduce [associated] complications with no adverse effect on survival," Dr. Galimberti concluded.

Dr. Galimberti reported having no relevant financial conflicts to disclose.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Photo courtesy Rhoda Baer/National Cancer Institute

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Photo courtesy Rhoda Baer/National Cancer Institute

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Photo courtesy Rhoda Baer/National Cancer Institute

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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