Breast Cancer

Among postmenopausal women who have hormone receptor–positive breast cancer, increasing age correlates with a rise in disease-specific mortality, independently of tumor, treatment, and patient characteristics, according to a report in the Feb. 9 issue of JAMA.

This increased cancer-specific mortality is particularly noteworthy because it occurs against a background in which other, competing causes of mortality are also increasing as these women age, said Dr. Willemien van de Water of the departments of surgical oncology and gerontology, Leiden (the Netherlands) University Medical Center, and associates.

To assess the relationship between aging and breast-cancer-specific mortality, the investigators analyzed data from the TEAM (Tamoxifen Exemestane Adjuvant Multinational) study, a phase III, randomized, open-label trial that had no upper age limit and included subjects up to 96 years old. The TEAM study involved 9,766 women who had estrogen receptor–positive tumors, progesterone receptor–positive tumors, or both, and were treated in Belgium, the Netherlands, the United Kingdom, Ireland, the United States, Japan, Greece, Germany, and France.

Because the 5-year TEAM trial found no significant differences in outcomes between the study groups and comparable mortality from other causes, it proved ideal for this post hoc analysis of disease-specific mortality, Dr. van de Water and colleagues said.

They divided the study subjects into three age groups: younger than 65 years (5,349 women; 55% of the entire cohort), 65-74 years (3,060 women; 31% of the cohort), and 75 years and older (1,357 women; 14% of the cohort).

The cumulative incidence of death from breast cancer rose from 5.7% in the youngest group to 6.3% in the intermediate group and 8.3% in the oldest group, the investigators said (JAMA 2012;307:590-7).

"Since tumor and treatment characteristics may be associated with disease-specific mortality, multivariable analyses were performed in an attempt to adjust for unequal distributions among age categories. ... Again, disease-specific mortality increased with age," with hazard ratios of 1.25 for patients aged 65-74 years and 1.62 for those aged 75 and older, compared with women younger than 65.

"To test the robustness of the age cut points, additional analyses were performed with age as a continuous variable, which confirmed an increased risk of breast cancer death per 10-year increase in age," they said.

Because there was a tendency for older patients to have larger tumors at diagnosis than did younger patients, additional analyses were performed to adjust for any residual confounding that might be related to tumor size. The results were unchanged.

Finally, the data were adjusted to account for mortality from competing causes such as infection, trauma, dementia, and cardiovascular disease. Again, the results were not affected by study subjects’ comorbidities.

This study was not designed to assess the reasons why breast-cancer mortality rises with increasing patient age, but the researchers proposed four possible underlying mechanisms.

First, older patients may be undertreated. Several other studies have shown that older age at diagnosis correlates with greater deviation from treatment guidelines for surgery, radiotherapy, chemotherapy, and endocrine therapy, as well as with more frequent cessation of medication.

Next, older patients may be more vulnerable to treatment-related toxicities. Third, tumor biology might be more aggressive in older patients. And fourth, polypharmacy, which is more common in older patients, might cause adverse interactions with anticancer therapies, rendering them less effective, Dr. van de Water and associates said.

The study findings "underline the need for age-specific breast cancer studies in order to improve breast cancer outcome in patients of all ages," they said.

The TEAM trial was supported by Pfizer. Dr. van de Water's associates reported ties to numerous industry sources.

Among postmenopausal women who have hormone receptor–positive breast cancer, increasing age correlates with a rise in disease-specific mortality, independently of tumor, treatment, and patient characteristics, according to a report in the Feb. 9 issue of JAMA.

This increased cancer-specific mortality is particularly noteworthy because it occurs against a background in which other, competing causes of mortality are also increasing as these women age, said Dr. Willemien van de Water of the departments of surgical oncology and gerontology, Leiden (the Netherlands) University Medical Center, and associates.

To assess the relationship between aging and breast-cancer-specific mortality, the investigators analyzed data from the TEAM (Tamoxifen Exemestane Adjuvant Multinational) study, a phase III, randomized, open-label trial that had no upper age limit and included subjects up to 96 years old. The TEAM study involved 9,766 women who had estrogen receptor–positive tumors, progesterone receptor–positive tumors, or both, and were treated in Belgium, the Netherlands, the United Kingdom, Ireland, the United States, Japan, Greece, Germany, and France.

Because the 5-year TEAM trial found no significant differences in outcomes between the study groups and comparable mortality from other causes, it proved ideal for this post hoc analysis of disease-specific mortality, Dr. van de Water and colleagues said.

They divided the study subjects into three age groups: younger than 65 years (5,349 women; 55% of the entire cohort), 65-74 years (3,060 women; 31% of the cohort), and 75 years and older (1,357 women; 14% of the cohort).

The cumulative incidence of death from breast cancer rose from 5.7% in the youngest group to 6.3% in the intermediate group and 8.3% in the oldest group, the investigators said (JAMA 2012;307:590-7).

"Since tumor and treatment characteristics may be associated with disease-specific mortality, multivariable analyses were performed in an attempt to adjust for unequal distributions among age categories. ... Again, disease-specific mortality increased with age," with hazard ratios of 1.25 for patients aged 65-74 years and 1.62 for those aged 75 and older, compared with women younger than 65.

"To test the robustness of the age cut points, additional analyses were performed with age as a continuous variable, which confirmed an increased risk of breast cancer death per 10-year increase in age," they said.

Because there was a tendency for older patients to have larger tumors at diagnosis than did younger patients, additional analyses were performed to adjust for any residual confounding that might be related to tumor size. The results were unchanged.

Finally, the data were adjusted to account for mortality from competing causes such as infection, trauma, dementia, and cardiovascular disease. Again, the results were not affected by study subjects’ comorbidities.

This study was not designed to assess the reasons why breast-cancer mortality rises with increasing patient age, but the researchers proposed four possible underlying mechanisms.

First, older patients may be undertreated. Several other studies have shown that older age at diagnosis correlates with greater deviation from treatment guidelines for surgery, radiotherapy, chemotherapy, and endocrine therapy, as well as with more frequent cessation of medication.

Next, older patients may be more vulnerable to treatment-related toxicities. Third, tumor biology might be more aggressive in older patients. And fourth, polypharmacy, which is more common in older patients, might cause adverse interactions with anticancer therapies, rendering them less effective, Dr. van de Water and associates said.

The study findings "underline the need for age-specific breast cancer studies in order to improve breast cancer outcome in patients of all ages," they said.

The TEAM trial was supported by Pfizer. Dr. van de Water's associates reported ties to numerous industry sources.

Among postmenopausal women who have hormone receptor–positive breast cancer, increasing age correlates with a rise in disease-specific mortality, independently of tumor, treatment, and patient characteristics, according to a report in the Feb. 9 issue of JAMA.

This increased cancer-specific mortality is particularly noteworthy because it occurs against a background in which other, competing causes of mortality are also increasing as these women age, said Dr. Willemien van de Water of the departments of surgical oncology and gerontology, Leiden (the Netherlands) University Medical Center, and associates.

To assess the relationship between aging and breast-cancer-specific mortality, the investigators analyzed data from the TEAM (Tamoxifen Exemestane Adjuvant Multinational) study, a phase III, randomized, open-label trial that had no upper age limit and included subjects up to 96 years old. The TEAM study involved 9,766 women who had estrogen receptor–positive tumors, progesterone receptor–positive tumors, or both, and were treated in Belgium, the Netherlands, the United Kingdom, Ireland, the United States, Japan, Greece, Germany, and France.

Because the 5-year TEAM trial found no significant differences in outcomes between the study groups and comparable mortality from other causes, it proved ideal for this post hoc analysis of disease-specific mortality, Dr. van de Water and colleagues said.

They divided the study subjects into three age groups: younger than 65 years (5,349 women; 55% of the entire cohort), 65-74 years (3,060 women; 31% of the cohort), and 75 years and older (1,357 women; 14% of the cohort).

The cumulative incidence of death from breast cancer rose from 5.7% in the youngest group to 6.3% in the intermediate group and 8.3% in the oldest group, the investigators said (JAMA 2012;307:590-7).

"Since tumor and treatment characteristics may be associated with disease-specific mortality, multivariable analyses were performed in an attempt to adjust for unequal distributions among age categories. ... Again, disease-specific mortality increased with age," with hazard ratios of 1.25 for patients aged 65-74 years and 1.62 for those aged 75 and older, compared with women younger than 65.

"To test the robustness of the age cut points, additional analyses were performed with age as a continuous variable, which confirmed an increased risk of breast cancer death per 10-year increase in age," they said.

Because there was a tendency for older patients to have larger tumors at diagnosis than did younger patients, additional analyses were performed to adjust for any residual confounding that might be related to tumor size. The results were unchanged.

Finally, the data were adjusted to account for mortality from competing causes such as infection, trauma, dementia, and cardiovascular disease. Again, the results were not affected by study subjects’ comorbidities.

This study was not designed to assess the reasons why breast-cancer mortality rises with increasing patient age, but the researchers proposed four possible underlying mechanisms.

First, older patients may be undertreated. Several other studies have shown that older age at diagnosis correlates with greater deviation from treatment guidelines for surgery, radiotherapy, chemotherapy, and endocrine therapy, as well as with more frequent cessation of medication.

Next, older patients may be more vulnerable to treatment-related toxicities. Third, tumor biology might be more aggressive in older patients. And fourth, polypharmacy, which is more common in older patients, might cause adverse interactions with anticancer therapies, rendering them less effective, Dr. van de Water and associates said.

The study findings "underline the need for age-specific breast cancer studies in order to improve breast cancer outcome in patients of all ages," they said.

The TEAM trial was supported by Pfizer. Dr. van de Water's associates reported ties to numerous industry sources.

Exemestane significantly decreases bone mineral density in healthy postmenopausal women who take it to reduce their risk of breast cancer, according to a study published online Feb. 7 in The Lancet Oncology.

Two years of daily oral treatment with the steroidal aromatase inhibitor was found to worsen age-related decreases in BMD "by about three times, even in the setting of adequate calcium and vitamin D intake," said Dr. Angela M. Cheung of the University Health Network in Toronto and her associates.

Dr. Cheung and her colleagues performed a safety substudy as part of the National Cancer Institute of Canada’s Mammary Prevention Trial 3 (MAP.3), a double-blind randomized study showing that exemestane significantly reduced the development of breast cancer in high-risk women, compared with placebo. Previous studies had suggested that exemestane exerted a small protective effect and caused less bone loss than other, nonsteroidal aromatase inhibitors such as anastrozole and letrozole.

This substudy focused on the drug’s effect on bone health and involved 351 subjects with T-scores above 2.0 at the lumbar spine, total hip, and femoral neck at baseline. The women had adequate dietary intake of calcium and vitamin D but received supplements as well. This was not a large enough sample to assess fracture risk directly, so the researchers instead assessed the intermediate end points of bone density and structure.

Theirs is the first study to use high-resolution peripheral quantitative CT scanning as well as the usual dual-energy x-ray absorptiometry to examine bone. Unlike the latter method, high-resolution peripheral quantitative CT captures aspects of bone fragility, including microarchitectural, geometric, and material properties that heavily influence fracture risk, the investigators noted.

The study subjects were treated and followed at three medical centers in Canada and two in the United States; median age was 61 years. A total of 176 were randomly assigned to receive daily oral exemestane and 175 to receive placebo.

The primary end point, percent change in total volumetric BMD at the distal radius after 2 years, was significantly greater with exemestane (mean loss of 6.1%) than placebo (mean loss of 1.8%). Exemestane also decreased cortical volumetric BMD at the distal radius by 4.6%, compared with 1.9% for placebo.

The drug also decreased total volumetric BMD at the distal tibia (loss of 5.0%) and cortical volumetric BMD at the distal tibia (loss of 5.3%), compared with placebo (losses of 1.3% and 2.3%, respectively).

In addition, exemestane was associated with a loss of 7.9% in mean cortical thickness at the distal radius (compared with –1.1% with placebo) and a loss of 7.6% in cortical thickness at the distal tibia (compared with –0.7% with placebo). Exemestane also cut mean total area and mean cortical area at both sites, compared with placebo, Dr. Cheung and her associates said (Lancet Oncol. 2012 [doi:10.1016/S1470-2045(11)70389-8]).

With exemestane, more women had clinically significant areal BMD loss at the lumbar spine (45%), total hip (26%), and femoral neck (22%), compared with placebo (20%, 19%, and 6%, respectively). Moreover, 65% of women taking exemestane showed clinically significant areal BMD loss at one of these three sites, compared with only 35% of women taking placebo.

These changes in bone strength, however, were not reflected in fracture rates during this relatively short study. There were no significant differences between the two study groups in fractures deemed to be attributable to bone fragility (1 with exemestane and 3 with placebo) or in total fractures (6 with exemestane and 11 with placebo), and the difference in height reduction (2 mm for exemestane vs. 1 mm for placebo) also was not significant, the researchers noted.

More importantly, "the minor areal BMD changes detected by dual-energy x-ray absorptiometry did not reflect the underlying structural deterioration seen with high-resolution peripheral quantitative CT. Although dual x-ray absorptiometry is the current clinical gold standard for skeletal assessment of fracture risk, it does not capture bone geometry, microarchitecture, or biomechanical properties, which also contribute to fracture risk," Dr. Cheung and her colleagues noted.

Unfortunately, this CT technique is not yet available for routine clinical care, they added.

This study was limited in that it involved healthy, predominantly white women with normal BMD and adequate calcium and vitamin D intake, so the findings may not be generalizable to women with osteoporosis, women with breast cancer, or nonwhite women. Also, follow-up was only 2 years; longer follow-up (up to 5 years) is needed to assess exemestane’s long-term effects on bone, the researchers said.

Nonetheless, the findings do reinforce the importance of monitoring bone health in these patients, they said.

This substudy was supported by the Canadian Breast Cancer Research Alliance, a joint initiative between the Canadian Institutes of Health Research and the Canadian Cancer Society. The main MAP.3 study also was supported by Pfizer. Jamieson Laboratories provided calcium and vitamin D supplements and Pfizer Pharmaceuticals provided exemestane and placebo. Dr. Cheung is supported in part by a Canadian Institutes of Health Research/Institute of Gender and Health Senior Investigator Award, and the Lillian Love Chair in Women’s Health at the University of Toronto/University Health Network. One of Dr. Cheung’s associates reported ties to Pfizer and Avon Foundation. None of the other researchers reported conflicts of interest.

Exemestane significantly decreases bone mineral density in healthy postmenopausal women who take it to reduce their risk of breast cancer, according to a study published online Feb. 7 in The Lancet Oncology.

Two years of daily oral treatment with the steroidal aromatase inhibitor was found to worsen age-related decreases in BMD "by about three times, even in the setting of adequate calcium and vitamin D intake," said Dr. Angela M. Cheung of the University Health Network in Toronto and her associates.

Dr. Cheung and her colleagues performed a safety substudy as part of the National Cancer Institute of Canada’s Mammary Prevention Trial 3 (MAP.3), a double-blind randomized study showing that exemestane significantly reduced the development of breast cancer in high-risk women, compared with placebo. Previous studies had suggested that exemestane exerted a small protective effect and caused less bone loss than other, nonsteroidal aromatase inhibitors such as anastrozole and letrozole.

This substudy focused on the drug’s effect on bone health and involved 351 subjects with T-scores above 2.0 at the lumbar spine, total hip, and femoral neck at baseline. The women had adequate dietary intake of calcium and vitamin D but received supplements as well. This was not a large enough sample to assess fracture risk directly, so the researchers instead assessed the intermediate end points of bone density and structure.

Theirs is the first study to use high-resolution peripheral quantitative CT scanning as well as the usual dual-energy x-ray absorptiometry to examine bone. Unlike the latter method, high-resolution peripheral quantitative CT captures aspects of bone fragility, including microarchitectural, geometric, and material properties that heavily influence fracture risk, the investigators noted.

The study subjects were treated and followed at three medical centers in Canada and two in the United States; median age was 61 years. A total of 176 were randomly assigned to receive daily oral exemestane and 175 to receive placebo.

The primary end point, percent change in total volumetric BMD at the distal radius after 2 years, was significantly greater with exemestane (mean loss of 6.1%) than placebo (mean loss of 1.8%). Exemestane also decreased cortical volumetric BMD at the distal radius by 4.6%, compared with 1.9% for placebo.

The drug also decreased total volumetric BMD at the distal tibia (loss of 5.0%) and cortical volumetric BMD at the distal tibia (loss of 5.3%), compared with placebo (losses of 1.3% and 2.3%, respectively).

In addition, exemestane was associated with a loss of 7.9% in mean cortical thickness at the distal radius (compared with –1.1% with placebo) and a loss of 7.6% in cortical thickness at the distal tibia (compared with –0.7% with placebo). Exemestane also cut mean total area and mean cortical area at both sites, compared with placebo, Dr. Cheung and her associates said (Lancet Oncol. 2012 [doi:10.1016/S1470-2045(11)70389-8]).

With exemestane, more women had clinically significant areal BMD loss at the lumbar spine (45%), total hip (26%), and femoral neck (22%), compared with placebo (20%, 19%, and 6%, respectively). Moreover, 65% of women taking exemestane showed clinically significant areal BMD loss at one of these three sites, compared with only 35% of women taking placebo.

These changes in bone strength, however, were not reflected in fracture rates during this relatively short study. There were no significant differences between the two study groups in fractures deemed to be attributable to bone fragility (1 with exemestane and 3 with placebo) or in total fractures (6 with exemestane and 11 with placebo), and the difference in height reduction (2 mm for exemestane vs. 1 mm for placebo) also was not significant, the researchers noted.

More importantly, "the minor areal BMD changes detected by dual-energy x-ray absorptiometry did not reflect the underlying structural deterioration seen with high-resolution peripheral quantitative CT. Although dual x-ray absorptiometry is the current clinical gold standard for skeletal assessment of fracture risk, it does not capture bone geometry, microarchitecture, or biomechanical properties, which also contribute to fracture risk," Dr. Cheung and her colleagues noted.

Unfortunately, this CT technique is not yet available for routine clinical care, they added.

This study was limited in that it involved healthy, predominantly white women with normal BMD and adequate calcium and vitamin D intake, so the findings may not be generalizable to women with osteoporosis, women with breast cancer, or nonwhite women. Also, follow-up was only 2 years; longer follow-up (up to 5 years) is needed to assess exemestane’s long-term effects on bone, the researchers said.

Nonetheless, the findings do reinforce the importance of monitoring bone health in these patients, they said.

This substudy was supported by the Canadian Breast Cancer Research Alliance, a joint initiative between the Canadian Institutes of Health Research and the Canadian Cancer Society. The main MAP.3 study also was supported by Pfizer. Jamieson Laboratories provided calcium and vitamin D supplements and Pfizer Pharmaceuticals provided exemestane and placebo. Dr. Cheung is supported in part by a Canadian Institutes of Health Research/Institute of Gender and Health Senior Investigator Award, and the Lillian Love Chair in Women’s Health at the University of Toronto/University Health Network. One of Dr. Cheung’s associates reported ties to Pfizer and Avon Foundation. None of the other researchers reported conflicts of interest.

Exemestane significantly decreases bone mineral density in healthy postmenopausal women who take it to reduce their risk of breast cancer, according to a study published online Feb. 7 in The Lancet Oncology.

Two years of daily oral treatment with the steroidal aromatase inhibitor was found to worsen age-related decreases in BMD "by about three times, even in the setting of adequate calcium and vitamin D intake," said Dr. Angela M. Cheung of the University Health Network in Toronto and her associates.

Dr. Cheung and her colleagues performed a safety substudy as part of the National Cancer Institute of Canada’s Mammary Prevention Trial 3 (MAP.3), a double-blind randomized study showing that exemestane significantly reduced the development of breast cancer in high-risk women, compared with placebo. Previous studies had suggested that exemestane exerted a small protective effect and caused less bone loss than other, nonsteroidal aromatase inhibitors such as anastrozole and letrozole.

This substudy focused on the drug’s effect on bone health and involved 351 subjects with T-scores above 2.0 at the lumbar spine, total hip, and femoral neck at baseline. The women had adequate dietary intake of calcium and vitamin D but received supplements as well. This was not a large enough sample to assess fracture risk directly, so the researchers instead assessed the intermediate end points of bone density and structure.

Theirs is the first study to use high-resolution peripheral quantitative CT scanning as well as the usual dual-energy x-ray absorptiometry to examine bone. Unlike the latter method, high-resolution peripheral quantitative CT captures aspects of bone fragility, including microarchitectural, geometric, and material properties that heavily influence fracture risk, the investigators noted.

The study subjects were treated and followed at three medical centers in Canada and two in the United States; median age was 61 years. A total of 176 were randomly assigned to receive daily oral exemestane and 175 to receive placebo.

The primary end point, percent change in total volumetric BMD at the distal radius after 2 years, was significantly greater with exemestane (mean loss of 6.1%) than placebo (mean loss of 1.8%). Exemestane also decreased cortical volumetric BMD at the distal radius by 4.6%, compared with 1.9% for placebo.

The drug also decreased total volumetric BMD at the distal tibia (loss of 5.0%) and cortical volumetric BMD at the distal tibia (loss of 5.3%), compared with placebo (losses of 1.3% and 2.3%, respectively).

In addition, exemestane was associated with a loss of 7.9% in mean cortical thickness at the distal radius (compared with –1.1% with placebo) and a loss of 7.6% in cortical thickness at the distal tibia (compared with –0.7% with placebo). Exemestane also cut mean total area and mean cortical area at both sites, compared with placebo, Dr. Cheung and her associates said (Lancet Oncol. 2012 [doi:10.1016/S1470-2045(11)70389-8]).

With exemestane, more women had clinically significant areal BMD loss at the lumbar spine (45%), total hip (26%), and femoral neck (22%), compared with placebo (20%, 19%, and 6%, respectively). Moreover, 65% of women taking exemestane showed clinically significant areal BMD loss at one of these three sites, compared with only 35% of women taking placebo.

These changes in bone strength, however, were not reflected in fracture rates during this relatively short study. There were no significant differences between the two study groups in fractures deemed to be attributable to bone fragility (1 with exemestane and 3 with placebo) or in total fractures (6 with exemestane and 11 with placebo), and the difference in height reduction (2 mm for exemestane vs. 1 mm for placebo) also was not significant, the researchers noted.

More importantly, "the minor areal BMD changes detected by dual-energy x-ray absorptiometry did not reflect the underlying structural deterioration seen with high-resolution peripheral quantitative CT. Although dual x-ray absorptiometry is the current clinical gold standard for skeletal assessment of fracture risk, it does not capture bone geometry, microarchitecture, or biomechanical properties, which also contribute to fracture risk," Dr. Cheung and her colleagues noted.

Unfortunately, this CT technique is not yet available for routine clinical care, they added.

This study was limited in that it involved healthy, predominantly white women with normal BMD and adequate calcium and vitamin D intake, so the findings may not be generalizable to women with osteoporosis, women with breast cancer, or nonwhite women. Also, follow-up was only 2 years; longer follow-up (up to 5 years) is needed to assess exemestane’s long-term effects on bone, the researchers said.

Nonetheless, the findings do reinforce the importance of monitoring bone health in these patients, they said.

This substudy was supported by the Canadian Breast Cancer Research Alliance, a joint initiative between the Canadian Institutes of Health Research and the Canadian Cancer Society. The main MAP.3 study also was supported by Pfizer. Jamieson Laboratories provided calcium and vitamin D supplements and Pfizer Pharmaceuticals provided exemestane and placebo. Dr. Cheung is supported in part by a Canadian Institutes of Health Research/Institute of Gender and Health Senior Investigator Award, and the Lillian Love Chair in Women’s Health at the University of Toronto/University Health Network. One of Dr. Cheung’s associates reported ties to Pfizer and Avon Foundation. None of the other researchers reported conflicts of interest.

The anti-HER2 monoclonal antibody trastuzumab works by binding to subdomain IV of the HER2 extracellular domain, thereby blocking HER2 cleavage; stimulating antibody-dependent, cell-mediated cytotoxicity; and preventing ligand-independent, HER2- mediated mitogenic signaling. Pertuzumab is an anti- HER2 monoclonal antibody that binds to subdomain II of the HER2 extracellular domain, preventing HER2 from dimerizing with other ligand-activated HER receptors; like trastuzumab, pertuzumab also stimulates antibodydependent cell-mediated cytotoxicity. Pertuzumab’s binding at a different HER2 epitope than trastuzumab represents a complementary mechanism of action that provides more comprehensive inhibition of HER2 signaling when the two agents are used together; the combination has been shown to produce greater antitumor activity than either agent alone in HER2-positive tumor models...

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

The anti-HER2 monoclonal antibody trastuzumab works by binding to subdomain IV of the HER2 extracellular domain, thereby blocking HER2 cleavage; stimulating antibody-dependent, cell-mediated cytotoxicity; and preventing ligand-independent, HER2- mediated mitogenic signaling. Pertuzumab is an anti- HER2 monoclonal antibody that binds to subdomain II of the HER2 extracellular domain, preventing HER2 from dimerizing with other ligand-activated HER receptors; like trastuzumab, pertuzumab also stimulates antibodydependent cell-mediated cytotoxicity. Pertuzumab’s binding at a different HER2 epitope than trastuzumab represents a complementary mechanism of action that provides more comprehensive inhibition of HER2 signaling when the two agents are used together; the combination has been shown to produce greater antitumor activity than either agent alone in HER2-positive tumor models...

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

The anti-HER2 monoclonal antibody trastuzumab works by binding to subdomain IV of the HER2 extracellular domain, thereby blocking HER2 cleavage; stimulating antibody-dependent, cell-mediated cytotoxicity; and preventing ligand-independent, HER2- mediated mitogenic signaling. Pertuzumab is an anti- HER2 monoclonal antibody that binds to subdomain II of the HER2 extracellular domain, preventing HER2 from dimerizing with other ligand-activated HER receptors; like trastuzumab, pertuzumab also stimulates antibodydependent cell-mediated cytotoxicity. Pertuzumab’s binding at a different HER2 epitope than trastuzumab represents a complementary mechanism of action that provides more comprehensive inhibition of HER2 signaling when the two agents are used together; the combination has been shown to produce greater antitumor activity than either agent alone in HER2-positive tumor models...

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

Rates of re-excision after initial breast-conserving surgery for invasive breast cancer vary greatly across surgeons and across medical centers, according to a report in the Feb. 1 issue of JAMA.

These variations are only partly explained by the basic clinical and demographic factors that dictate treatment decisions, such as tumor size and patient age. The remaining reasons for the profound differences in re-excision rates remain unexplained.

Nevertheless, these variations certainly are a barrier to consistent, high-quality, cost-effective care for breast cancer. "Outcomes such as local recurrence and even overall survival could be affected by variability in initial surgical care," said Dr. Laurence E. McCahill of the Richard J. Lacks Cancer Center, Van Andel Research Institute, and department of surgery at Michigan State University, Grand Rapids, and his associates.

Noting that "currently, there are no readily identifiable quality measures that allow for meaningful comparisons of breast cancer surgical outcomes among treating surgeons and hospitals," the investigators examined re-excision rates across four geographically diverse health systems. Their chief goal was to determine whether significant variations existed, which would in turn determine whether the re-excision rate is a meaningful measure of surgical quality.

They assessed detailed data on initial and subsequent surgeries for invasive ductal carcinoma or invasive lobular carcinoma in 2,206 women who underwent an initial breast-conserving procedure for incident cancer.

Overall, 509 patients (23%) underwent re-excision of the affected breast during 5 years of follow-up. A total of 454 women had a single re-excision, 48 had two re-excisions, and 7 had three re-excisions. Approximately 9% of the study subjects (190 women) underwent total mastectomy after the initial breast-conserving surgery.

The rate of re-excision varied greatly from one surgeon to another, ranging from 0% to 70%. This implies that patients with the same clinical presentations are likely to undergo re-excision based on who is doing their procedure, not on their clinical traits, the investigators said (JAMA 2012;307:467-75).

This study was designed to determine whether such variations exist, not the reasons why they exist. But the researchers suggested that "differences in surgical training, surgeon confidence in their operative technique in localizing tumors, utilization of intraoperative assessment of margins, and surgeon’s and pathologist’s coordination of specimen orientation and margin interpretation" may all play a role.

Surprisingly, the volume of procedures a surgeon performs did not affect his or her re-excision rate in this study, so surgical experience may not play an important role in these variations, Dr. McCahill and his colleagues added.

The rate of re-excision also varied greatly from one medical center to another, ranging from 1.7% at the center with the lowest rate to 21% at the center with the highest rate. In particular, the rate of re-excision for cases with positive margins ranged from 74% to 94%. Any variation in this statistic is surprising because positive margins are known to correlate with local recurrence and are "almost always" re-excised, the researchers said.

Again, this study was not designed to determine why re-excision rates differ so greatly between medical centers, but the investigators suggested that "institutional variation in surgeon’s training, regional variation in interpretation of the required criteria for [re-excision], or both" may account, at least in part, for the variation.

The need for re-excision in patients who have negative (pathologically clear) margins at the initial surgery is controversial, because "there is no clear consensus on the appropriate distance required for a clear margin to be deemed adequate." So perhaps it should not be surprising that almost half of the re-excisions (242 of the 509) in this study were performed in patients who had negative margins, the researchers said.

One major limitation of this study was that some factors that greatly influence treatment decisions, including patient preferences, were not included in the data and so could not be factored into the analysis, they noted.

This study was funded by the National Institutes of Health under the American Recovery and Reinvestment Act. The authors reported no financial conflicts of interest.

Rates of re-excision after initial breast-conserving surgery for invasive breast cancer vary greatly across surgeons and across medical centers, according to a report in the Feb. 1 issue of JAMA.

These variations are only partly explained by the basic clinical and demographic factors that dictate treatment decisions, such as tumor size and patient age. The remaining reasons for the profound differences in re-excision rates remain unexplained.

Nevertheless, these variations certainly are a barrier to consistent, high-quality, cost-effective care for breast cancer. "Outcomes such as local recurrence and even overall survival could be affected by variability in initial surgical care," said Dr. Laurence E. McCahill of the Richard J. Lacks Cancer Center, Van Andel Research Institute, and department of surgery at Michigan State University, Grand Rapids, and his associates.

Noting that "currently, there are no readily identifiable quality measures that allow for meaningful comparisons of breast cancer surgical outcomes among treating surgeons and hospitals," the investigators examined re-excision rates across four geographically diverse health systems. Their chief goal was to determine whether significant variations existed, which would in turn determine whether the re-excision rate is a meaningful measure of surgical quality.

They assessed detailed data on initial and subsequent surgeries for invasive ductal carcinoma or invasive lobular carcinoma in 2,206 women who underwent an initial breast-conserving procedure for incident cancer.

Overall, 509 patients (23%) underwent re-excision of the affected breast during 5 years of follow-up. A total of 454 women had a single re-excision, 48 had two re-excisions, and 7 had three re-excisions. Approximately 9% of the study subjects (190 women) underwent total mastectomy after the initial breast-conserving surgery.

The rate of re-excision varied greatly from one surgeon to another, ranging from 0% to 70%. This implies that patients with the same clinical presentations are likely to undergo re-excision based on who is doing their procedure, not on their clinical traits, the investigators said (JAMA 2012;307:467-75).

This study was designed to determine whether such variations exist, not the reasons why they exist. But the researchers suggested that "differences in surgical training, surgeon confidence in their operative technique in localizing tumors, utilization of intraoperative assessment of margins, and surgeon’s and pathologist’s coordination of specimen orientation and margin interpretation" may all play a role.

Surprisingly, the volume of procedures a surgeon performs did not affect his or her re-excision rate in this study, so surgical experience may not play an important role in these variations, Dr. McCahill and his colleagues added.

The rate of re-excision also varied greatly from one medical center to another, ranging from 1.7% at the center with the lowest rate to 21% at the center with the highest rate. In particular, the rate of re-excision for cases with positive margins ranged from 74% to 94%. Any variation in this statistic is surprising because positive margins are known to correlate with local recurrence and are "almost always" re-excised, the researchers said.

Again, this study was not designed to determine why re-excision rates differ so greatly between medical centers, but the investigators suggested that "institutional variation in surgeon’s training, regional variation in interpretation of the required criteria for [re-excision], or both" may account, at least in part, for the variation.

The need for re-excision in patients who have negative (pathologically clear) margins at the initial surgery is controversial, because "there is no clear consensus on the appropriate distance required for a clear margin to be deemed adequate." So perhaps it should not be surprising that almost half of the re-excisions (242 of the 509) in this study were performed in patients who had negative margins, the researchers said.

One major limitation of this study was that some factors that greatly influence treatment decisions, including patient preferences, were not included in the data and so could not be factored into the analysis, they noted.

This study was funded by the National Institutes of Health under the American Recovery and Reinvestment Act. The authors reported no financial conflicts of interest.

Rates of re-excision after initial breast-conserving surgery for invasive breast cancer vary greatly across surgeons and across medical centers, according to a report in the Feb. 1 issue of JAMA.

These variations are only partly explained by the basic clinical and demographic factors that dictate treatment decisions, such as tumor size and patient age. The remaining reasons for the profound differences in re-excision rates remain unexplained.

Nevertheless, these variations certainly are a barrier to consistent, high-quality, cost-effective care for breast cancer. "Outcomes such as local recurrence and even overall survival could be affected by variability in initial surgical care," said Dr. Laurence E. McCahill of the Richard J. Lacks Cancer Center, Van Andel Research Institute, and department of surgery at Michigan State University, Grand Rapids, and his associates.

Noting that "currently, there are no readily identifiable quality measures that allow for meaningful comparisons of breast cancer surgical outcomes among treating surgeons and hospitals," the investigators examined re-excision rates across four geographically diverse health systems. Their chief goal was to determine whether significant variations existed, which would in turn determine whether the re-excision rate is a meaningful measure of surgical quality.

They assessed detailed data on initial and subsequent surgeries for invasive ductal carcinoma or invasive lobular carcinoma in 2,206 women who underwent an initial breast-conserving procedure for incident cancer.

Overall, 509 patients (23%) underwent re-excision of the affected breast during 5 years of follow-up. A total of 454 women had a single re-excision, 48 had two re-excisions, and 7 had three re-excisions. Approximately 9% of the study subjects (190 women) underwent total mastectomy after the initial breast-conserving surgery.

The rate of re-excision varied greatly from one surgeon to another, ranging from 0% to 70%. This implies that patients with the same clinical presentations are likely to undergo re-excision based on who is doing their procedure, not on their clinical traits, the investigators said (JAMA 2012;307:467-75).

This study was designed to determine whether such variations exist, not the reasons why they exist. But the researchers suggested that "differences in surgical training, surgeon confidence in their operative technique in localizing tumors, utilization of intraoperative assessment of margins, and surgeon’s and pathologist’s coordination of specimen orientation and margin interpretation" may all play a role.

Surprisingly, the volume of procedures a surgeon performs did not affect his or her re-excision rate in this study, so surgical experience may not play an important role in these variations, Dr. McCahill and his colleagues added.

The rate of re-excision also varied greatly from one medical center to another, ranging from 1.7% at the center with the lowest rate to 21% at the center with the highest rate. In particular, the rate of re-excision for cases with positive margins ranged from 74% to 94%. Any variation in this statistic is surprising because positive margins are known to correlate with local recurrence and are "almost always" re-excised, the researchers said.

Again, this study was not designed to determine why re-excision rates differ so greatly between medical centers, but the investigators suggested that "institutional variation in surgeon’s training, regional variation in interpretation of the required criteria for [re-excision], or both" may account, at least in part, for the variation.

The need for re-excision in patients who have negative (pathologically clear) margins at the initial surgery is controversial, because "there is no clear consensus on the appropriate distance required for a clear margin to be deemed adequate." So perhaps it should not be surprising that almost half of the re-excisions (242 of the 509) in this study were performed in patients who had negative margins, the researchers said.

One major limitation of this study was that some factors that greatly influence treatment decisions, including patient preferences, were not included in the data and so could not be factored into the analysis, they noted.

This study was funded by the National Institutes of Health under the American Recovery and Reinvestment Act. The authors reported no financial conflicts of interest.

Adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage HER2-negative breast cancer significantly improves pathological complete response, according to preliminary reports from two large randomized clinical trials.

The published results are likely to reopen debate over the recent U.S. Food and Drug Administration decision to revoke an indication for bevacizumab (Avastin) in metastatic breast cancer and the use of surrogate end points for survival in breast cancer trials.

Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial and the GeparQuinto (GBG44) trial appear in the Jan. 26 issue of The New England Journal of Medicine.

Docetaxel-Based Chemo in NSABP B-40

In NSABP B-40, 1,206 patients were enrolled between Jan. 5, 2007 and June 20, 2101 and randomly assigned to receive docetaxel (Taxotere), docetaxel plus capecitabine (Xeloda), or docetaxel plus gemcitabine (Gemzar) for four cycles. All groups received doxorubicin and cyclophosphamide for an additional four cycles, and the participants were additionally assigned to receive or not receive bevacizumab (Avastin) – an antiangiogenic monoclonal antibody against vascular endothelial growth factor (VEGF), for the first 6 of the 8 treatment cycles.

The addition of the antimetabolites capecitabine or gemcitabine had no significant effect on pathological complete response in the breast, with, respectively 29.7% and 31.8% of patients achieving that primary end point, compared with 32.7% of those receiving only docetaxel, Dr. Harry D. Bear of Virginia Commonwealth University, Richmond and his colleagues reported (N. Engl. J. Med. 2012;366:310-20).

Adding bevacizumab, however, increased the rate of pathological complete response in the breast significantly from 28.2% to 34.5%. Subgroup analysis indicated the effect was more pronounced in patients with hormone receptor–positive tumors (the rate increasing significantly from 15.1% without bevacizumab to 23.2% with bevacizumab) than in hormone receptor–negative tumors (47.1% and 51.5%, respectively), the investigators said. The benefit of bevacizumab tended to be seen more in patients with a high tumor grade.

Epirubicin-based Chemo in GeparQuinto

In the GeparQuinto trial, 1,948 patients were enrolled from November 2007 through June 2010 and randomized to receive neoadjuvant epirubicin (Ellence) and cyclophosphamide followed by docetaxel either with or without bevacizumab.

Pathological complete response occurred in 18.4% of those who received bevacizumab, compared with 14.9% of those who did not (odds ratio, 1.29), Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, Germany and his colleagues reported. (N. Engl. J. Med. 2012;366:299-309). After adjusting for age, clinical tumor and nodal stage, hormone-receptor status, tumor grade, and histologic type, the odds ratio was 1.36.

In contrast with the findings from NSABP B-40, the greatest effects of bevacizumab in GBG44 were seen in the 633 patients with triple-negative tumors (27.9% without vs. 39.3% with bevacizumab), compared with the 1,262 patients with hormone-receptor-positive tumors (7.8% and 7.7%, respectively). The test for interaction for this finding was not significant, but the study was not powered to show these differential effects, the investigators noted.

Investigators from both trials suggested that possible reasons for the divergent findings between the studies include differences in inclusion criteria and drug dosing and/or sequencing.

The NSABP B-40 investigators noted that "the increased rate of pathological complete response in patients with hormone receptor–positive tumors is encouraging, since this group tends to have low rates of pathological complete response with chemotherapy."

Bevacizumab was associated with toxic effects in both studies, including hand-foot syndrome, mucositis, hypertension, and left ventricular systolic dysfunction in NSABP B-40, and with bleeding, febrile neutropenia, mucositis, hand-foot syndrome, infection, and hypertension in GBG44.

Survival Results Pending

The NSABP B-40 investigators said that the potential for bevacizumab to improve patient outcomes should be clarified when disease-free and overall survival results become available for those who underwent surgery in this study, and for those in other ongoing studies.

They also noted that "the collection of tissue samples from all our patients before treatment, a major advantage of the neoadjuvant approach, offers an opportunity to discover molecular markers that might predict a benefit from bevacizumab."

The GBG44 investigators noted that because of the short follow-up in their study, it cannot be confirmed that the observed increases in the rate of pathological complete response will translate into a survival advantage.

"However, given that pathological complete response has been shown to be highly correlated with outcome, particularly in patients with triple-negative disease, we speculate that the beneficial effects will be sustained," they said, adding, "Long-term follow-up data are needed before this treatment option can be fully understood."

Dosing in the studies was as follows:

In NSABP B-40, docetaxel was administered intravenously at 100 mg/m² on day 1 of the cycle every 3 weeks in the docetaxel-only group, followed by four cycles of doxorubicin-cyclophosphamide at 60 mg/m² and 600 mg/m², respectively, administered intravenously every 3 weeks. Docetaxel was administered at a dose of 75 mg/m² on day 1 in the docetaxel plus capecitabine or gemcitabine groups followed by the doxorubicin-cyclophosphamide. The capecitabine dose was 825 mg/m² twice daily on days 1-14; the gemcitabine dose was 1,000 mg/m² on days 1 and 8. The bevacizumab dose was 15 mg/kg administered intravenously for the first six cycles.

In GBG44, epirubicin was administered at a dose of 90 mg/m²and cyclophosphamide was administered at a dose of 600 mg/m²– both on day 1, every 3 weeks for four cycles, followed by four cycles of docetaxel a dose of 100 mg/m² on day 1, every 3 weeks. As in NSABP B-40, bevacizumab was administered at a dose of 15 mg/kg intravenously. In this study, however, it was administered every 3 weeks starting on day 1 of the first epirubicin-cyclophosphamide cycle for 8 cycles.

NSABP B-40 was supported by grants from the National Cancer Institute, the Department of Health and Human Services, the Public Health Service, F. Hoffman-La Roche, Genentech USA, and Eli Lilly. GeparQuinto was supported by grants from Sanofi-Aventis and Roche, Germany. Detailed individual author disclosures are available with the full text of the articles at NEJM.org.

Adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage HER2-negative breast cancer significantly improves pathological complete response, according to preliminary reports from two large randomized clinical trials.

The published results are likely to reopen debate over the recent U.S. Food and Drug Administration decision to revoke an indication for bevacizumab (Avastin) in metastatic breast cancer and the use of surrogate end points for survival in breast cancer trials.

Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial and the GeparQuinto (GBG44) trial appear in the Jan. 26 issue of The New England Journal of Medicine.

Docetaxel-Based Chemo in NSABP B-40

In NSABP B-40, 1,206 patients were enrolled between Jan. 5, 2007 and June 20, 2101 and randomly assigned to receive docetaxel (Taxotere), docetaxel plus capecitabine (Xeloda), or docetaxel plus gemcitabine (Gemzar) for four cycles. All groups received doxorubicin and cyclophosphamide for an additional four cycles, and the participants were additionally assigned to receive or not receive bevacizumab (Avastin) – an antiangiogenic monoclonal antibody against vascular endothelial growth factor (VEGF), for the first 6 of the 8 treatment cycles.

The addition of the antimetabolites capecitabine or gemcitabine had no significant effect on pathological complete response in the breast, with, respectively 29.7% and 31.8% of patients achieving that primary end point, compared with 32.7% of those receiving only docetaxel, Dr. Harry D. Bear of Virginia Commonwealth University, Richmond and his colleagues reported (N. Engl. J. Med. 2012;366:310-20).

Adding bevacizumab, however, increased the rate of pathological complete response in the breast significantly from 28.2% to 34.5%. Subgroup analysis indicated the effect was more pronounced in patients with hormone receptor–positive tumors (the rate increasing significantly from 15.1% without bevacizumab to 23.2% with bevacizumab) than in hormone receptor–negative tumors (47.1% and 51.5%, respectively), the investigators said. The benefit of bevacizumab tended to be seen more in patients with a high tumor grade.

Epirubicin-based Chemo in GeparQuinto

In the GeparQuinto trial, 1,948 patients were enrolled from November 2007 through June 2010 and randomized to receive neoadjuvant epirubicin (Ellence) and cyclophosphamide followed by docetaxel either with or without bevacizumab.

Pathological complete response occurred in 18.4% of those who received bevacizumab, compared with 14.9% of those who did not (odds ratio, 1.29), Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, Germany and his colleagues reported. (N. Engl. J. Med. 2012;366:299-309). After adjusting for age, clinical tumor and nodal stage, hormone-receptor status, tumor grade, and histologic type, the odds ratio was 1.36.

In contrast with the findings from NSABP B-40, the greatest effects of bevacizumab in GBG44 were seen in the 633 patients with triple-negative tumors (27.9% without vs. 39.3% with bevacizumab), compared with the 1,262 patients with hormone-receptor-positive tumors (7.8% and 7.7%, respectively). The test for interaction for this finding was not significant, but the study was not powered to show these differential effects, the investigators noted.

Investigators from both trials suggested that possible reasons for the divergent findings between the studies include differences in inclusion criteria and drug dosing and/or sequencing.

The NSABP B-40 investigators noted that "the increased rate of pathological complete response in patients with hormone receptor–positive tumors is encouraging, since this group tends to have low rates of pathological complete response with chemotherapy."

Bevacizumab was associated with toxic effects in both studies, including hand-foot syndrome, mucositis, hypertension, and left ventricular systolic dysfunction in NSABP B-40, and with bleeding, febrile neutropenia, mucositis, hand-foot syndrome, infection, and hypertension in GBG44.

Survival Results Pending

The NSABP B-40 investigators said that the potential for bevacizumab to improve patient outcomes should be clarified when disease-free and overall survival results become available for those who underwent surgery in this study, and for those in other ongoing studies.

They also noted that "the collection of tissue samples from all our patients before treatment, a major advantage of the neoadjuvant approach, offers an opportunity to discover molecular markers that might predict a benefit from bevacizumab."

The GBG44 investigators noted that because of the short follow-up in their study, it cannot be confirmed that the observed increases in the rate of pathological complete response will translate into a survival advantage.

"However, given that pathological complete response has been shown to be highly correlated with outcome, particularly in patients with triple-negative disease, we speculate that the beneficial effects will be sustained," they said, adding, "Long-term follow-up data are needed before this treatment option can be fully understood."

Dosing in the studies was as follows:

In NSABP B-40, docetaxel was administered intravenously at 100 mg/m² on day 1 of the cycle every 3 weeks in the docetaxel-only group, followed by four cycles of doxorubicin-cyclophosphamide at 60 mg/m² and 600 mg/m², respectively, administered intravenously every 3 weeks. Docetaxel was administered at a dose of 75 mg/m² on day 1 in the docetaxel plus capecitabine or gemcitabine groups followed by the doxorubicin-cyclophosphamide. The capecitabine dose was 825 mg/m² twice daily on days 1-14; the gemcitabine dose was 1,000 mg/m² on days 1 and 8. The bevacizumab dose was 15 mg/kg administered intravenously for the first six cycles.

In GBG44, epirubicin was administered at a dose of 90 mg/m²and cyclophosphamide was administered at a dose of 600 mg/m²– both on day 1, every 3 weeks for four cycles, followed by four cycles of docetaxel a dose of 100 mg/m² on day 1, every 3 weeks. As in NSABP B-40, bevacizumab was administered at a dose of 15 mg/kg intravenously. In this study, however, it was administered every 3 weeks starting on day 1 of the first epirubicin-cyclophosphamide cycle for 8 cycles.

NSABP B-40 was supported by grants from the National Cancer Institute, the Department of Health and Human Services, the Public Health Service, F. Hoffman-La Roche, Genentech USA, and Eli Lilly. GeparQuinto was supported by grants from Sanofi-Aventis and Roche, Germany. Detailed individual author disclosures are available with the full text of the articles at NEJM.org.

Adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage HER2-negative breast cancer significantly improves pathological complete response, according to preliminary reports from two large randomized clinical trials.

The published results are likely to reopen debate over the recent U.S. Food and Drug Administration decision to revoke an indication for bevacizumab (Avastin) in metastatic breast cancer and the use of surrogate end points for survival in breast cancer trials.

Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial and the GeparQuinto (GBG44) trial appear in the Jan. 26 issue of The New England Journal of Medicine.

Docetaxel-Based Chemo in NSABP B-40

In NSABP B-40, 1,206 patients were enrolled between Jan. 5, 2007 and June 20, 2101 and randomly assigned to receive docetaxel (Taxotere), docetaxel plus capecitabine (Xeloda), or docetaxel plus gemcitabine (Gemzar) for four cycles. All groups received doxorubicin and cyclophosphamide for an additional four cycles, and the participants were additionally assigned to receive or not receive bevacizumab (Avastin) – an antiangiogenic monoclonal antibody against vascular endothelial growth factor (VEGF), for the first 6 of the 8 treatment cycles.

The addition of the antimetabolites capecitabine or gemcitabine had no significant effect on pathological complete response in the breast, with, respectively 29.7% and 31.8% of patients achieving that primary end point, compared with 32.7% of those receiving only docetaxel, Dr. Harry D. Bear of Virginia Commonwealth University, Richmond and his colleagues reported (N. Engl. J. Med. 2012;366:310-20).

Adding bevacizumab, however, increased the rate of pathological complete response in the breast significantly from 28.2% to 34.5%. Subgroup analysis indicated the effect was more pronounced in patients with hormone receptor–positive tumors (the rate increasing significantly from 15.1% without bevacizumab to 23.2% with bevacizumab) than in hormone receptor–negative tumors (47.1% and 51.5%, respectively), the investigators said. The benefit of bevacizumab tended to be seen more in patients with a high tumor grade.

Epirubicin-based Chemo in GeparQuinto

In the GeparQuinto trial, 1,948 patients were enrolled from November 2007 through June 2010 and randomized to receive neoadjuvant epirubicin (Ellence) and cyclophosphamide followed by docetaxel either with or without bevacizumab.

Pathological complete response occurred in 18.4% of those who received bevacizumab, compared with 14.9% of those who did not (odds ratio, 1.29), Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, Germany and his colleagues reported. (N. Engl. J. Med. 2012;366:299-309). After adjusting for age, clinical tumor and nodal stage, hormone-receptor status, tumor grade, and histologic type, the odds ratio was 1.36.

In contrast with the findings from NSABP B-40, the greatest effects of bevacizumab in GBG44 were seen in the 633 patients with triple-negative tumors (27.9% without vs. 39.3% with bevacizumab), compared with the 1,262 patients with hormone-receptor-positive tumors (7.8% and 7.7%, respectively). The test for interaction for this finding was not significant, but the study was not powered to show these differential effects, the investigators noted.

Investigators from both trials suggested that possible reasons for the divergent findings between the studies include differences in inclusion criteria and drug dosing and/or sequencing.

The NSABP B-40 investigators noted that "the increased rate of pathological complete response in patients with hormone receptor–positive tumors is encouraging, since this group tends to have low rates of pathological complete response with chemotherapy."

Bevacizumab was associated with toxic effects in both studies, including hand-foot syndrome, mucositis, hypertension, and left ventricular systolic dysfunction in NSABP B-40, and with bleeding, febrile neutropenia, mucositis, hand-foot syndrome, infection, and hypertension in GBG44.

Survival Results Pending

The NSABP B-40 investigators said that the potential for bevacizumab to improve patient outcomes should be clarified when disease-free and overall survival results become available for those who underwent surgery in this study, and for those in other ongoing studies.

They also noted that "the collection of tissue samples from all our patients before treatment, a major advantage of the neoadjuvant approach, offers an opportunity to discover molecular markers that might predict a benefit from bevacizumab."

The GBG44 investigators noted that because of the short follow-up in their study, it cannot be confirmed that the observed increases in the rate of pathological complete response will translate into a survival advantage.

"However, given that pathological complete response has been shown to be highly correlated with outcome, particularly in patients with triple-negative disease, we speculate that the beneficial effects will be sustained," they said, adding, "Long-term follow-up data are needed before this treatment option can be fully understood."

Dosing in the studies was as follows:

In NSABP B-40, docetaxel was administered intravenously at 100 mg/m² on day 1 of the cycle every 3 weeks in the docetaxel-only group, followed by four cycles of doxorubicin-cyclophosphamide at 60 mg/m² and 600 mg/m², respectively, administered intravenously every 3 weeks. Docetaxel was administered at a dose of 75 mg/m² on day 1 in the docetaxel plus capecitabine or gemcitabine groups followed by the doxorubicin-cyclophosphamide. The capecitabine dose was 825 mg/m² twice daily on days 1-14; the gemcitabine dose was 1,000 mg/m² on days 1 and 8. The bevacizumab dose was 15 mg/kg administered intravenously for the first six cycles.

In GBG44, epirubicin was administered at a dose of 90 mg/m²and cyclophosphamide was administered at a dose of 600 mg/m²– both on day 1, every 3 weeks for four cycles, followed by four cycles of docetaxel a dose of 100 mg/m² on day 1, every 3 weeks. As in NSABP B-40, bevacizumab was administered at a dose of 15 mg/kg intravenously. In this study, however, it was administered every 3 weeks starting on day 1 of the first epirubicin-cyclophosphamide cycle for 8 cycles.

NSABP B-40 was supported by grants from the National Cancer Institute, the Department of Health and Human Services, the Public Health Service, F. Hoffman-La Roche, Genentech USA, and Eli Lilly. GeparQuinto was supported by grants from Sanofi-Aventis and Roche, Germany. Detailed individual author disclosures are available with the full text of the articles at NEJM.org.

Trastuzumab is significantly more effective alone or in combination with lapatinib than is lapatinib alone for the treatment of human epidermal growth factor receptor 2–positive breast cancer in patients receiving neoadjuvant chemotherapy, according to findings from two randomized phase III trials.

The studies – GeparQuinto and the NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial – underscore the value of testing new therapies in the neoadjuvant setting.

In the GeparQuinto trial, 30% of 307 HER2-positive patients treated with the anti-HER2 humanized monoclonal antibody trastuzumab had a pathological complete response, compared with only 23% of 308 HER2-positive patients treated with the tyrosine kinase inhibitor lapatinib, which targets both HER1 and HER2 (odds ratio, 0.68).

Although the patients randomized to receive trastuzumab had significantly more edema (39% vs. 29%) and dyspnea (30% vs. 21%), those randomized to receive lapatinib experienced significantly more diarrhea (75% vs. 47%) and skin rash (55% vs. 32%), and significantly more patients in the lapatinib group discontinued treatment (33% vs. 14%), Dr. Michael Untch and his colleagues reported in the Jan. 17 issue of the Lancet Oncology.

Women with previously untreated unilateral or bilateral primary invasive breast carcinoma were enrolled in the study between Nov. 7, 2007, and July 9, 2010, at 126 centers in Germany and 1 center in Switzerland. Patients were eligible for inclusion if they had locally advanced tumor stages cT3 or cT4, hormone receptor (HR)-negative tumors, or HR-positive tumors with clinically positive axillary nodes (cN+ for cT2) or pNSLN+ for cT1 disease (Lancet Oncol. 2012 Jan. 17 [doi:10.1016/S1470-2045(11)70397-7]).

They received neoadjuvant treatment including four cycles of epirubicin given at 90 mg/m² intravenously along with cyclophosphamide at a dose of 600 mg/m² intravenously, every 3 weeks, and four cycles of docetaxel at 100 mg/m² intravenously every 3 weeks, plus either trastuzumab or lapatinib throughout all cycles prior to surgery. Trastuzumab was given at a starting loading dose of 8 mg/kg and then at 6 mg/kg intravenously every 3 weeks; the lapatinib dose was 1,000-1,250 mg/day orally.

"Pathological complete response rates were significantly lower with lapatinib treatment than with trastuzumab, irrespective of the definitions of pathological complete response that were used. These results confirm the efficacy of a neoadjuvant regimen containing trastuzumab," wrote Dr. Untch, of Helios-Klinikum, Berlin-Buch, Berlin, and his colleagues from the German Breast Group and the Arbeitsgemeinschaft Gynäkologische Onkologie-Breast (AGO-B) Study Group.

The investigators noted that lapatinib may provide a lower pathological complete response because of a reduced ability to block the HER2 pathway, compared with trastuzumab. Also, trastuzumab may have additional antitumor efficacy "by inducing an immune response via antibody-derived cellular cytotoxicity," they wrote.

In addition to providing additional evidence of the feasibility – and low cardiac toxicity – of "exposing the tumor for as long as possible to the synergistic effect of chemotherapy and trastuzumab before surgery," these findings suggest lapatinib should not be used outside of clinical trials as single anti-HER2 treatment in patients undergoing neoadjuvant chemotherapy, the investigators concluded.

Indeed, these findings "should lead to the conclusion that this regimen [the combination of lapatinib with standard chemotherapy] does not seem to have any advantages compared with a standard trastuzumab-based regimen for the adjuvant treatment of HER2-positive, early-stage breast cancer," Dr. Stephen K. Chia of the British Columbia Cancer Agency, Vancouver, B.C., wrote in an accompanying editorial (Lancet Oncol. 2012 Jan. 17 [doi:10.106/S1470-2045(12)70013-X]).

Another lesson learned from the GeparQuinto trial, according to Dr. Chia, is that the preoperative setting, which the research community and patients "seem to have embraced as both standard of care therapy and as an important strategy to test new therapeutic regimens," is ideally suited for this purpose.

"Moving forward into the future, no adjuvant trials should be done without an adequate signal from preoperative trials showing safety, efficacy, target modulation, and, ideally, the identification of predictive biomarkers such that we no longer pick a loser to study in larger and more resource-intensive adjuvant trials," he said. Dr. Chia noted that the second study demonstrating improved efficacy of trastuzumab – NeoALTTO – is a good example of such a preoperative study supporting the rationale for adjuvant trials with the combination of these agents, in this case the ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial, which is underway. The lapatinib group for ALTTO has been closed due to the demonstration of futility.

In NeoALTTO, which was published concomitantly with GeparQuinto in the Lancet, trastuzumab was more effective – although not significantly – than lapatinib alone for the treatment of HER2-positive breast cancer, but it was most effective in combination with lapatinib, Dr. José Baselga of Massachusetts General Hospital Cancer Center, Boston, and his colleagues from the NeoALTTO Study Team reported.

Pathological complete response in this parallel groups, open-label study, occurred in 51% of 152 patients in the combination treatment group, compared with 30% of the 149 patients in the trastuzumab group and 25% of the 154 patients in the lapatinib group, for an adjusted odds ratio of 2.6 for the combination vs. trastuzumab alone (Lancet 2012 Jan. 17 [doi:10.106/S0140-6736(11)61847-3]).

As in the GeparQuinto Trial, no major cardiac dysfunction occurred, and diarrhea was more frequent in the patients receiving lapatinib (23% and 21% of those in the lapatinib and combination groups, respectively, vs. 2% in the trastuzumab group who had grade 3 diarrhea).

NeoALTTO participants were enrolled between Jan. 5, 2008, and May 27, 2010, at 86 sites in 23 countries. Participants had histologically confirmed invasive HER2-positive breast cancer with tumors at least 2 cm in diameter. Lapatinib was given at 1,500 mg orally to those in the lapatinib-only group, and at 1,000 mg for those in the combination group; trastuzumab was given at a loading dose of 4 mg/m² followed by 2 mg/kg on subsequent doses for both groups.

The anti-HER2 treatments were given alone for 6 weeks, and paclitaxel at 80 mg/m² weekly was then added for an additional 12 weeks.

"Dual targeting of HER2-positive tumors with trastuzumab and lapatinib is undertaken because of primary and acquired resistance to both agents, their partly non-overlapping mechanisms of action, and the well characterized synergistic interaction between them in HER2 breast-cancer models," the investigators noted.

These findings provide proof of concept that dual inhibition of HER2 is better than a single-agent approach, Dr. Baselga and his colleagues said, noting that the higher pathological complete response rate for the combination was clear across all subgroups tested, which is consistent with the findings from other studies of anti-HER2 treatment in HER2-positive tumors.

"Our study also supports investigation of novel targeted agents for breast cancer in the neoadjuvant setting, when tumors have not yet acquired resistance to therapy and when chances of clinical benefit are highest," they said.

GeparQuinto was funded by GlaxoSmithKline, Roche, and Sanofi-Aventis; lapatinib was provided free of charge. Dr. Untch said he had no relevant financial disclosures, but several other GeparQuinto investigators made financial disclosures relating to these and other pharmaceutical companies. The NeoALTTO trial was funded by GlaxoSmithKline. Dr. Baselga said he has received honoraria from Roche, and his institution has received funding from GlaxoSmithKline and Roche. Several other NeoALTTO investigators made financial disclosures involving GlaxoSmithKline and/or other pharmaceutical companies. Dr. Chia, the author of the editorial that accompanied the article in the Lancet Oncology on the GeparQuinto trial, disclosed that he has received honoraria from GlaxoSmithKline, manufacturer of lapatinib, and F. Hoffmann-La Roche, manufacturer of trastuzumab, as well as an unrestricted research grant from Hoffmann-La Roche.

Trastuzumab is significantly more effective alone or in combination with lapatinib than is lapatinib alone for the treatment of human epidermal growth factor receptor 2–positive breast cancer in patients receiving neoadjuvant chemotherapy, according to findings from two randomized phase III trials.

The studies – GeparQuinto and the NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial – underscore the value of testing new therapies in the neoadjuvant setting.

In the GeparQuinto trial, 30% of 307 HER2-positive patients treated with the anti-HER2 humanized monoclonal antibody trastuzumab had a pathological complete response, compared with only 23% of 308 HER2-positive patients treated with the tyrosine kinase inhibitor lapatinib, which targets both HER1 and HER2 (odds ratio, 0.68).

Although the patients randomized to receive trastuzumab had significantly more edema (39% vs. 29%) and dyspnea (30% vs. 21%), those randomized to receive lapatinib experienced significantly more diarrhea (75% vs. 47%) and skin rash (55% vs. 32%), and significantly more patients in the lapatinib group discontinued treatment (33% vs. 14%), Dr. Michael Untch and his colleagues reported in the Jan. 17 issue of the Lancet Oncology.

Women with previously untreated unilateral or bilateral primary invasive breast carcinoma were enrolled in the study between Nov. 7, 2007, and July 9, 2010, at 126 centers in Germany and 1 center in Switzerland. Patients were eligible for inclusion if they had locally advanced tumor stages cT3 or cT4, hormone receptor (HR)-negative tumors, or HR-positive tumors with clinically positive axillary nodes (cN+ for cT2) or pNSLN+ for cT1 disease (Lancet Oncol. 2012 Jan. 17 [doi:10.1016/S1470-2045(11)70397-7]).

They received neoadjuvant treatment including four cycles of epirubicin given at 90 mg/m² intravenously along with cyclophosphamide at a dose of 600 mg/m² intravenously, every 3 weeks, and four cycles of docetaxel at 100 mg/m² intravenously every 3 weeks, plus either trastuzumab or lapatinib throughout all cycles prior to surgery. Trastuzumab was given at a starting loading dose of 8 mg/kg and then at 6 mg/kg intravenously every 3 weeks; the lapatinib dose was 1,000-1,250 mg/day orally.

"Pathological complete response rates were significantly lower with lapatinib treatment than with trastuzumab, irrespective of the definitions of pathological complete response that were used. These results confirm the efficacy of a neoadjuvant regimen containing trastuzumab," wrote Dr. Untch, of Helios-Klinikum, Berlin-Buch, Berlin, and his colleagues from the German Breast Group and the Arbeitsgemeinschaft Gynäkologische Onkologie-Breast (AGO-B) Study Group.

The investigators noted that lapatinib may provide a lower pathological complete response because of a reduced ability to block the HER2 pathway, compared with trastuzumab. Also, trastuzumab may have additional antitumor efficacy "by inducing an immune response via antibody-derived cellular cytotoxicity," they wrote.

In addition to providing additional evidence of the feasibility – and low cardiac toxicity – of "exposing the tumor for as long as possible to the synergistic effect of chemotherapy and trastuzumab before surgery," these findings suggest lapatinib should not be used outside of clinical trials as single anti-HER2 treatment in patients undergoing neoadjuvant chemotherapy, the investigators concluded.

Indeed, these findings "should lead to the conclusion that this regimen [the combination of lapatinib with standard chemotherapy] does not seem to have any advantages compared with a standard trastuzumab-based regimen for the adjuvant treatment of HER2-positive, early-stage breast cancer," Dr. Stephen K. Chia of the British Columbia Cancer Agency, Vancouver, B.C., wrote in an accompanying editorial (Lancet Oncol. 2012 Jan. 17 [doi:10.106/S1470-2045(12)70013-X]).

Another lesson learned from the GeparQuinto trial, according to Dr. Chia, is that the preoperative setting, which the research community and patients "seem to have embraced as both standard of care therapy and as an important strategy to test new therapeutic regimens," is ideally suited for this purpose.

"Moving forward into the future, no adjuvant trials should be done without an adequate signal from preoperative trials showing safety, efficacy, target modulation, and, ideally, the identification of predictive biomarkers such that we no longer pick a loser to study in larger and more resource-intensive adjuvant trials," he said. Dr. Chia noted that the second study demonstrating improved efficacy of trastuzumab – NeoALTTO – is a good example of such a preoperative study supporting the rationale for adjuvant trials with the combination of these agents, in this case the ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial, which is underway. The lapatinib group for ALTTO has been closed due to the demonstration of futility.

In NeoALTTO, which was published concomitantly with GeparQuinto in the Lancet, trastuzumab was more effective – although not significantly – than lapatinib alone for the treatment of HER2-positive breast cancer, but it was most effective in combination with lapatinib, Dr. José Baselga of Massachusetts General Hospital Cancer Center, Boston, and his colleagues from the NeoALTTO Study Team reported.

Pathological complete response in this parallel groups, open-label study, occurred in 51% of 152 patients in the combination treatment group, compared with 30% of the 149 patients in the trastuzumab group and 25% of the 154 patients in the lapatinib group, for an adjusted odds ratio of 2.6 for the combination vs. trastuzumab alone (Lancet 2012 Jan. 17 [doi:10.106/S0140-6736(11)61847-3]).

As in the GeparQuinto Trial, no major cardiac dysfunction occurred, and diarrhea was more frequent in the patients receiving lapatinib (23% and 21% of those in the lapatinib and combination groups, respectively, vs. 2% in the trastuzumab group who had grade 3 diarrhea).

NeoALTTO participants were enrolled between Jan. 5, 2008, and May 27, 2010, at 86 sites in 23 countries. Participants had histologically confirmed invasive HER2-positive breast cancer with tumors at least 2 cm in diameter. Lapatinib was given at 1,500 mg orally to those in the lapatinib-only group, and at 1,000 mg for those in the combination group; trastuzumab was given at a loading dose of 4 mg/m² followed by 2 mg/kg on subsequent doses for both groups.

The anti-HER2 treatments were given alone for 6 weeks, and paclitaxel at 80 mg/m² weekly was then added for an additional 12 weeks.

"Dual targeting of HER2-positive tumors with trastuzumab and lapatinib is undertaken because of primary and acquired resistance to both agents, their partly non-overlapping mechanisms of action, and the well characterized synergistic interaction between them in HER2 breast-cancer models," the investigators noted.

These findings provide proof of concept that dual inhibition of HER2 is better than a single-agent approach, Dr. Baselga and his colleagues said, noting that the higher pathological complete response rate for the combination was clear across all subgroups tested, which is consistent with the findings from other studies of anti-HER2 treatment in HER2-positive tumors.

"Our study also supports investigation of novel targeted agents for breast cancer in the neoadjuvant setting, when tumors have not yet acquired resistance to therapy and when chances of clinical benefit are highest," they said.

GeparQuinto was funded by GlaxoSmithKline, Roche, and Sanofi-Aventis; lapatinib was provided free of charge. Dr. Untch said he had no relevant financial disclosures, but several other GeparQuinto investigators made financial disclosures relating to these and other pharmaceutical companies. The NeoALTTO trial was funded by GlaxoSmithKline. Dr. Baselga said he has received honoraria from Roche, and his institution has received funding from GlaxoSmithKline and Roche. Several other NeoALTTO investigators made financial disclosures involving GlaxoSmithKline and/or other pharmaceutical companies. Dr. Chia, the author of the editorial that accompanied the article in the Lancet Oncology on the GeparQuinto trial, disclosed that he has received honoraria from GlaxoSmithKline, manufacturer of lapatinib, and F. Hoffmann-La Roche, manufacturer of trastuzumab, as well as an unrestricted research grant from Hoffmann-La Roche.

Trastuzumab is significantly more effective alone or in combination with lapatinib than is lapatinib alone for the treatment of human epidermal growth factor receptor 2–positive breast cancer in patients receiving neoadjuvant chemotherapy, according to findings from two randomized phase III trials.

The studies – GeparQuinto and the NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial – underscore the value of testing new therapies in the neoadjuvant setting.

In the GeparQuinto trial, 30% of 307 HER2-positive patients treated with the anti-HER2 humanized monoclonal antibody trastuzumab had a pathological complete response, compared with only 23% of 308 HER2-positive patients treated with the tyrosine kinase inhibitor lapatinib, which targets both HER1 and HER2 (odds ratio, 0.68).

Although the patients randomized to receive trastuzumab had significantly more edema (39% vs. 29%) and dyspnea (30% vs. 21%), those randomized to receive lapatinib experienced significantly more diarrhea (75% vs. 47%) and skin rash (55% vs. 32%), and significantly more patients in the lapatinib group discontinued treatment (33% vs. 14%), Dr. Michael Untch and his colleagues reported in the Jan. 17 issue of the Lancet Oncology.

Women with previously untreated unilateral or bilateral primary invasive breast carcinoma were enrolled in the study between Nov. 7, 2007, and July 9, 2010, at 126 centers in Germany and 1 center in Switzerland. Patients were eligible for inclusion if they had locally advanced tumor stages cT3 or cT4, hormone receptor (HR)-negative tumors, or HR-positive tumors with clinically positive axillary nodes (cN+ for cT2) or pNSLN+ for cT1 disease (Lancet Oncol. 2012 Jan. 17 [doi:10.1016/S1470-2045(11)70397-7]).

They received neoadjuvant treatment including four cycles of epirubicin given at 90 mg/m² intravenously along with cyclophosphamide at a dose of 600 mg/m² intravenously, every 3 weeks, and four cycles of docetaxel at 100 mg/m² intravenously every 3 weeks, plus either trastuzumab or lapatinib throughout all cycles prior to surgery. Trastuzumab was given at a starting loading dose of 8 mg/kg and then at 6 mg/kg intravenously every 3 weeks; the lapatinib dose was 1,000-1,250 mg/day orally.

"Pathological complete response rates were significantly lower with lapatinib treatment than with trastuzumab, irrespective of the definitions of pathological complete response that were used. These results confirm the efficacy of a neoadjuvant regimen containing trastuzumab," wrote Dr. Untch, of Helios-Klinikum, Berlin-Buch, Berlin, and his colleagues from the German Breast Group and the Arbeitsgemeinschaft Gynäkologische Onkologie-Breast (AGO-B) Study Group.

The investigators noted that lapatinib may provide a lower pathological complete response because of a reduced ability to block the HER2 pathway, compared with trastuzumab. Also, trastuzumab may have additional antitumor efficacy "by inducing an immune response via antibody-derived cellular cytotoxicity," they wrote.

In addition to providing additional evidence of the feasibility – and low cardiac toxicity – of "exposing the tumor for as long as possible to the synergistic effect of chemotherapy and trastuzumab before surgery," these findings suggest lapatinib should not be used outside of clinical trials as single anti-HER2 treatment in patients undergoing neoadjuvant chemotherapy, the investigators concluded.

Indeed, these findings "should lead to the conclusion that this regimen [the combination of lapatinib with standard chemotherapy] does not seem to have any advantages compared with a standard trastuzumab-based regimen for the adjuvant treatment of HER2-positive, early-stage breast cancer," Dr. Stephen K. Chia of the British Columbia Cancer Agency, Vancouver, B.C., wrote in an accompanying editorial (Lancet Oncol. 2012 Jan. 17 [doi:10.106/S1470-2045(12)70013-X]).

Another lesson learned from the GeparQuinto trial, according to Dr. Chia, is that the preoperative setting, which the research community and patients "seem to have embraced as both standard of care therapy and as an important strategy to test new therapeutic regimens," is ideally suited for this purpose.

"Moving forward into the future, no adjuvant trials should be done without an adequate signal from preoperative trials showing safety, efficacy, target modulation, and, ideally, the identification of predictive biomarkers such that we no longer pick a loser to study in larger and more resource-intensive adjuvant trials," he said. Dr. Chia noted that the second study demonstrating improved efficacy of trastuzumab – NeoALTTO – is a good example of such a preoperative study supporting the rationale for adjuvant trials with the combination of these agents, in this case the ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial, which is underway. The lapatinib group for ALTTO has been closed due to the demonstration of futility.

In NeoALTTO, which was published concomitantly with GeparQuinto in the Lancet, trastuzumab was more effective – although not significantly – than lapatinib alone for the treatment of HER2-positive breast cancer, but it was most effective in combination with lapatinib, Dr. José Baselga of Massachusetts General Hospital Cancer Center, Boston, and his colleagues from the NeoALTTO Study Team reported.

Pathological complete response in this parallel groups, open-label study, occurred in 51% of 152 patients in the combination treatment group, compared with 30% of the 149 patients in the trastuzumab group and 25% of the 154 patients in the lapatinib group, for an adjusted odds ratio of 2.6 for the combination vs. trastuzumab alone (Lancet 2012 Jan. 17 [doi:10.106/S0140-6736(11)61847-3]).

As in the GeparQuinto Trial, no major cardiac dysfunction occurred, and diarrhea was more frequent in the patients receiving lapatinib (23% and 21% of those in the lapatinib and combination groups, respectively, vs. 2% in the trastuzumab group who had grade 3 diarrhea).

NeoALTTO participants were enrolled between Jan. 5, 2008, and May 27, 2010, at 86 sites in 23 countries. Participants had histologically confirmed invasive HER2-positive breast cancer with tumors at least 2 cm in diameter. Lapatinib was given at 1,500 mg orally to those in the lapatinib-only group, and at 1,000 mg for those in the combination group; trastuzumab was given at a loading dose of 4 mg/m² followed by 2 mg/kg on subsequent doses for both groups.

The anti-HER2 treatments were given alone for 6 weeks, and paclitaxel at 80 mg/m² weekly was then added for an additional 12 weeks.

"Dual targeting of HER2-positive tumors with trastuzumab and lapatinib is undertaken because of primary and acquired resistance to both agents, their partly non-overlapping mechanisms of action, and the well characterized synergistic interaction between them in HER2 breast-cancer models," the investigators noted.

These findings provide proof of concept that dual inhibition of HER2 is better than a single-agent approach, Dr. Baselga and his colleagues said, noting that the higher pathological complete response rate for the combination was clear across all subgroups tested, which is consistent with the findings from other studies of anti-HER2 treatment in HER2-positive tumors.

"Our study also supports investigation of novel targeted agents for breast cancer in the neoadjuvant setting, when tumors have not yet acquired resistance to therapy and when chances of clinical benefit are highest," they said.

GeparQuinto was funded by GlaxoSmithKline, Roche, and Sanofi-Aventis; lapatinib was provided free of charge. Dr. Untch said he had no relevant financial disclosures, but several other GeparQuinto investigators made financial disclosures relating to these and other pharmaceutical companies. The NeoALTTO trial was funded by GlaxoSmithKline. Dr. Baselga said he has received honoraria from Roche, and his institution has received funding from GlaxoSmithKline and Roche. Several other NeoALTTO investigators made financial disclosures involving GlaxoSmithKline and/or other pharmaceutical companies. Dr. Chia, the author of the editorial that accompanied the article in the Lancet Oncology on the GeparQuinto trial, disclosed that he has received honoraria from GlaxoSmithKline, manufacturer of lapatinib, and F. Hoffmann-La Roche, manufacturer of trastuzumab, as well as an unrestricted research grant from Hoffmann-La Roche.

Catch up with what you missed as we count down the 10 most-read stories on OncologyReport.com last year.

10. Everolimus Posts Big Win in ER-Positive Breast Cancer By Patrice Wendling
This first report of the BOLERO-2 trial -- a potential practice changer -- came out of the European Multidisciplinary Cancer Congress in Stockholm.

Courtesy flickr user woodleywonderworks (Creative Commons)

9. Multimodal DCIS Therapy, Tamoxifen Cuts Breast Cancer Deaths By Neil Osterweil
A meta-analysis from Australia found that adding radiotherapy and tamoxifen to breast-conserving surgery significantly reduces the local recurrence rate and the breast cancer–specific death rate in women with ductal carcinoma in situ. It was presented at the American Society of Radiation Oncology (ASTRO) meeitng in Miami Beach.

8. Crizotinib Approval Personalizes Lung Cancer Therapy By Miriam E. Tucker
The swift approval of crizotinib capsules by the Food and Drug Administration as the first and only targeted therapy for locally advanced or metastatic ALK-positive non–small cell lung cancer represented another milestone in biomarker-driven, personalized medicine. Crizotinib was approved, along with a companion diagnostic test, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit, which identifies the anaplastic lymphoma kinase (ALK) fusion gene that the drug targets.

7. Clinicians Slow to Embrace Sipuleucel-T for Prostate Cancer By Diana Mahoney
Most physicians have strong opinions on sipuleucel-T, including dubbing its approval "a milestone in the history of oncology," but many of them refused to speak about it on the record. Our persistent reporter found the reasons for their reluctance to use the first cancer vaccine went beyond reimbursement issues belabored in the financial press.

6. Drug Shortages Increasingly Take Toll on Care By Elizabeth Mechcatie
With their increasing prevalence, drug shortages in the United States have led to delays in treatment, forced the use of less effective alternatives, and encouraged a burgeoning gray market that sells tough-to-obtain medications at highly inflated prices, according to stakeholders gathered at a recent Food and Drug Administration meeting.

5. Practice Changers Expected at San Antonio Breast Cancer Symposium By Jane Salodof MacNeil
The 2011 San Antonio Breast Cancer Symposium featured a hefty number of studies that could change clinical practice. One of the most exciting SABCS meetings in recent years, it featured the phase III BOLERO-2 and CLEOPATRA trials, a new Oncotype DX assay for ductal carcinoma in situ, reports from four bisphosphonate trials, and a controversial brachytherapy study.

4. FDA Approves Brentuximab for Two Lymphomas By Elizabeth Mechcatie
The Food and Drug Administration on Aug. 19 gave an accelerated approval to brentuximab, a CD30-directed antibody drug-conjugate, for the treatment of Hodgkin’s lymphoma and systemic anaplastic large-cell lymphoma, after other treatments have failed.

3. FDA Approves Vemurafenib for Advanced Melanoma By Jane Salodof MacNeil
The Food and Drug Administration announced on August 17 the approval of vemurafenib, a highly anticipated metastatic melanoma therapy that targets the BRAF V600E mutation found in 40%-60% of patients. It also approved the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test designed to help determine whether a patient’s melanoma cells carry the BRAF V600E mutation.

2. Novel Therapies Put Multiple Myeloma 'On the Ropes' By Susan London
A sweep of new agents are poised to deliver what could be a knock-out blow to multiple myeloma, according to the director of the myeloma program at the University of California, San Francisco. Some are second- or third-generation agents in a mainstay class that appear to have less toxicity than and/or overcome resistance to their predecessors, Dr. Jeffrey L. Wolf said at the annual Oncology Congress in San Francisco. Others come from classes not previously used in this disease.

1. NICE Rejects Ipilimumab by Jennie Smith
A drug considered a breakthrough treatment for advanced melanoma was turned down by England’s clinical and cost-effectiveness agency. The National Institute for Health and Clinical Excellence, which makes recommendations to the National Health Service in England and Wales, said that it was not likely to recommend ipilimumab (Bristol-Myers Squibb’s Yervoy). The agency cited cost concerns and what it called insufficient follow-up results from a manufacturer-sponsored, phase III, randomized, placebo-controlled trial of ipilimumab.

Did you miss any of last year's top reads in oncology? Click here to receive our weekly e-newsletter.

Catch up with what you missed as we count down the 10 most-read stories on OncologyReport.com last year.

10. Everolimus Posts Big Win in ER-Positive Breast Cancer By Patrice Wendling
This first report of the BOLERO-2 trial -- a potential practice changer -- came out of the European Multidisciplinary Cancer Congress in Stockholm.

Courtesy flickr user woodleywonderworks (Creative Commons)

9. Multimodal DCIS Therapy, Tamoxifen Cuts Breast Cancer Deaths By Neil Osterweil
A meta-analysis from Australia found that adding radiotherapy and tamoxifen to breast-conserving surgery significantly reduces the local recurrence rate and the breast cancer–specific death rate in women with ductal carcinoma in situ. It was presented at the American Society of Radiation Oncology (ASTRO) meeitng in Miami Beach.

8. Crizotinib Approval Personalizes Lung Cancer Therapy By Miriam E. Tucker
The swift approval of crizotinib capsules by the Food and Drug Administration as the first and only targeted therapy for locally advanced or metastatic ALK-positive non–small cell lung cancer represented another milestone in biomarker-driven, personalized medicine. Crizotinib was approved, along with a companion diagnostic test, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit, which identifies the anaplastic lymphoma kinase (ALK) fusion gene that the drug targets.

7. Clinicians Slow to Embrace Sipuleucel-T for Prostate Cancer By Diana Mahoney
Most physicians have strong opinions on sipuleucel-T, including dubbing its approval "a milestone in the history of oncology," but many of them refused to speak about it on the record. Our persistent reporter found the reasons for their reluctance to use the first cancer vaccine went beyond reimbursement issues belabored in the financial press.

6. Drug Shortages Increasingly Take Toll on Care By Elizabeth Mechcatie
With their increasing prevalence, drug shortages in the United States have led to delays in treatment, forced the use of less effective alternatives, and encouraged a burgeoning gray market that sells tough-to-obtain medications at highly inflated prices, according to stakeholders gathered at a recent Food and Drug Administration meeting.

5. Practice Changers Expected at San Antonio Breast Cancer Symposium By Jane Salodof MacNeil
The 2011 San Antonio Breast Cancer Symposium featured a hefty number of studies that could change clinical practice. One of the most exciting SABCS meetings in recent years, it featured the phase III BOLERO-2 and CLEOPATRA trials, a new Oncotype DX assay for ductal carcinoma in situ, reports from four bisphosphonate trials, and a controversial brachytherapy study.

4. FDA Approves Brentuximab for Two Lymphomas By Elizabeth Mechcatie
The Food and Drug Administration on Aug. 19 gave an accelerated approval to brentuximab, a CD30-directed antibody drug-conjugate, for the treatment of Hodgkin’s lymphoma and systemic anaplastic large-cell lymphoma, after other treatments have failed.

3. FDA Approves Vemurafenib for Advanced Melanoma By Jane Salodof MacNeil
The Food and Drug Administration announced on August 17 the approval of vemurafenib, a highly anticipated metastatic melanoma therapy that targets the BRAF V600E mutation found in 40%-60% of patients. It also approved the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test designed to help determine whether a patient’s melanoma cells carry the BRAF V600E mutation.

2. Novel Therapies Put Multiple Myeloma 'On the Ropes' By Susan London
A sweep of new agents are poised to deliver what could be a knock-out blow to multiple myeloma, according to the director of the myeloma program at the University of California, San Francisco. Some are second- or third-generation agents in a mainstay class that appear to have less toxicity than and/or overcome resistance to their predecessors, Dr. Jeffrey L. Wolf said at the annual Oncology Congress in San Francisco. Others come from classes not previously used in this disease.

1. NICE Rejects Ipilimumab by Jennie Smith
A drug considered a breakthrough treatment for advanced melanoma was turned down by England’s clinical and cost-effectiveness agency. The National Institute for Health and Clinical Excellence, which makes recommendations to the National Health Service in England and Wales, said that it was not likely to recommend ipilimumab (Bristol-Myers Squibb’s Yervoy). The agency cited cost concerns and what it called insufficient follow-up results from a manufacturer-sponsored, phase III, randomized, placebo-controlled trial of ipilimumab.

Did you miss any of last year's top reads in oncology? Click here to receive our weekly e-newsletter.

Catch up with what you missed as we count down the 10 most-read stories on OncologyReport.com last year.

10. Everolimus Posts Big Win in ER-Positive Breast Cancer By Patrice Wendling
This first report of the BOLERO-2 trial -- a potential practice changer -- came out of the European Multidisciplinary Cancer Congress in Stockholm.

Courtesy flickr user woodleywonderworks (Creative Commons)

9. Multimodal DCIS Therapy, Tamoxifen Cuts Breast Cancer Deaths By Neil Osterweil
A meta-analysis from Australia found that adding radiotherapy and tamoxifen to breast-conserving surgery significantly reduces the local recurrence rate and the breast cancer–specific death rate in women with ductal carcinoma in situ. It was presented at the American Society of Radiation Oncology (ASTRO) meeitng in Miami Beach.

8. Crizotinib Approval Personalizes Lung Cancer Therapy By Miriam E. Tucker
The swift approval of crizotinib capsules by the Food and Drug Administration as the first and only targeted therapy for locally advanced or metastatic ALK-positive non–small cell lung cancer represented another milestone in biomarker-driven, personalized medicine. Crizotinib was approved, along with a companion diagnostic test, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit, which identifies the anaplastic lymphoma kinase (ALK) fusion gene that the drug targets.

7. Clinicians Slow to Embrace Sipuleucel-T for Prostate Cancer By Diana Mahoney
Most physicians have strong opinions on sipuleucel-T, including dubbing its approval "a milestone in the history of oncology," but many of them refused to speak about it on the record. Our persistent reporter found the reasons for their reluctance to use the first cancer vaccine went beyond reimbursement issues belabored in the financial press.

6. Drug Shortages Increasingly Take Toll on Care By Elizabeth Mechcatie
With their increasing prevalence, drug shortages in the United States have led to delays in treatment, forced the use of less effective alternatives, and encouraged a burgeoning gray market that sells tough-to-obtain medications at highly inflated prices, according to stakeholders gathered at a recent Food and Drug Administration meeting.

5. Practice Changers Expected at San Antonio Breast Cancer Symposium By Jane Salodof MacNeil
The 2011 San Antonio Breast Cancer Symposium featured a hefty number of studies that could change clinical practice. One of the most exciting SABCS meetings in recent years, it featured the phase III BOLERO-2 and CLEOPATRA trials, a new Oncotype DX assay for ductal carcinoma in situ, reports from four bisphosphonate trials, and a controversial brachytherapy study.

4. FDA Approves Brentuximab for Two Lymphomas By Elizabeth Mechcatie
The Food and Drug Administration on Aug. 19 gave an accelerated approval to brentuximab, a CD30-directed antibody drug-conjugate, for the treatment of Hodgkin’s lymphoma and systemic anaplastic large-cell lymphoma, after other treatments have failed.

3. FDA Approves Vemurafenib for Advanced Melanoma By Jane Salodof MacNeil
The Food and Drug Administration announced on August 17 the approval of vemurafenib, a highly anticipated metastatic melanoma therapy that targets the BRAF V600E mutation found in 40%-60% of patients. It also approved the cobas 4800 BRAF V600 Mutation Test, a companion diagnostic test designed to help determine whether a patient’s melanoma cells carry the BRAF V600E mutation.

2. Novel Therapies Put Multiple Myeloma 'On the Ropes' By Susan London
A sweep of new agents are poised to deliver what could be a knock-out blow to multiple myeloma, according to the director of the myeloma program at the University of California, San Francisco. Some are second- or third-generation agents in a mainstay class that appear to have less toxicity than and/or overcome resistance to their predecessors, Dr. Jeffrey L. Wolf said at the annual Oncology Congress in San Francisco. Others come from classes not previously used in this disease.

1. NICE Rejects Ipilimumab by Jennie Smith
A drug considered a breakthrough treatment for advanced melanoma was turned down by England’s clinical and cost-effectiveness agency. The National Institute for Health and Clinical Excellence, which makes recommendations to the National Health Service in England and Wales, said that it was not likely to recommend ipilimumab (Bristol-Myers Squibb’s Yervoy). The agency cited cost concerns and what it called insufficient follow-up results from a manufacturer-sponsored, phase III, randomized, placebo-controlled trial of ipilimumab.

Did you miss any of last year's top reads in oncology? Click here to receive our weekly e-newsletter.

SAN ANTONIO – Total skin-sparing mastectomy with complete preservation of the breast skin envelope was associated with favorable oncologic and ischemic outcomes in a large, high-risk cohort of women who underwent the procedure over a 10-year period in San Francisco, a study has shown.

The findings suggest that the surgery, which produces superior cosmesis and is associated with a high rate of patient satisfaction, is a reasonable option for many women facing therapeutic or prophylactic mastectomy, Dr. Anne G. Warren Peled said at the San Antonio Breast Cancer Symposium.

The total skin-sparing mastectomy (TSSM) allows preservation of the nipple-areola dermal layer when ductal tissue is removed during mastectomy. "The procedure is increasingly offered to women for both therapeutic and prophylactic indications, and when combined with immediate breast reconstruction, can produce excellent aesthetic results," explained Dr. Warren Peled, a surgical resident at the University of California, San Francisco.

Because the oncologic safety of the procedure and the potential for higher rates of postoperative complications continue to be debated, Dr. Warren Peled and her colleagues sought to evaluate both outcomes using data collected in a prospectively maintained database. The investigators analyzed patient and tumor characteristics, treatment details, and the development of any postoperative complications, as well as local or distant recurrences, for 428 patients (mean age, 46.9 years) who underwent 657 TSSMs and immediate breast reconstruction at the UCSF Medical Center in 2001-2010.

"The mastectomy incisions included radial, lateral, periareolar, and inframammary incisions, and the areolar and nipple complex tissue was separated from the dermal layer of skin by sharp dissection with inversion of the nipple skin to ensure the removal of all of the nipple duct tissue," Dr. Warren Peled said during a poster discussion. Of the 657 mastectomies, 412 were therapeutic procedures, and 245 (58 bilateral and 187 contralateral) were prophylactic, she said.

Most of the tumors were stage 0 (111) or stage I (135), although stage II (95), III (48), and IV (7) tumors were also observed, Dr. Warren Peled reported. Some 14 mastectomies were for recurrent cancer, she noted. In addition, 210 patients underwent neoadjuvant chemotherapy, 144 had postmastectomy radiation therapy, and 78 had adjuvant chemotherapy, she said.

With respect to nipple involvement on pathological analysis, 11 specimens had evidence of in situ cancer and 9 had evidence of invasive cancer, leading to re-excision in 7 cases, removal of the nipple-areolar complex (NAC) in 9 cases, and NAC radiation in 4 cases, said Dr. Warren Peled.

The conventional, two-stage, expander-implant method – in which a tissue expander placed under the chest muscle is implanted and gradually inflated to expand the tissue in preparation for the synthetic implant 3-6 months later – was used in 80% of the postmastectomy reconstructions, Dr. Warren Peled said. The remaining 20% of the reconstructions included either the placement of a permanent silicon implant at the time of mastectomy (4.7%) or autologous reconstruction (15.3%), she said.

A review of the oncologic outcomes in the 412 patients who underwent therapeutic mastectomies showed that, at a median follow-up of 28 months, four patients (1%) experienced local recurrence only, eight (1.9%) experienced distant recurrence only, and four experienced both local and distant recurrence (1%), Dr. Warren Peled reported. Among the local recurrences, two each were invasive (0.7%) and in situ cancer (1.8%), and among the distant recurrences, all eight (2.7) were invasive cancers. Among those with both local and distant recurrences, three (1%) and one (0.9%) were invasive and in situ, respectively, she said,

Of the 126 patients who had a minimum 36 months’ follow-up (median, 45 months), 2 patients (1.6%) had local recurrence only, one of which was invasive; 1 patient (0.8%) had distant recurrence only; and 1 (0.8%) had both, Dr. Peled said, noting that the recurrences in the latter two patients were invasive.

An assessment of ischemic complications showed 13 cases (1.9%) of partial nipple loss; 10 cases (1.5%) of complete nipple loss, and 78 cases (11.8%) of skin flap necrosis, Dr. Peled said, noting that the group’s current nipple loss rate is lower than 1%, thanks to serial improvements in surgical technique.

The findings indicate that TSSM "can be performed with low rates of nipple involvement and locoregional recurrence," Dr. Warren Peled stated. Although the short-term findings are encouraging, the study cannot speak to the long-term oncologic safety of the procedure. "Longer term follow-up is needed to confirm the oncologic safety over time," she said.

Dr. Warren Peled had no relevant financial conflicts to disclose.

SAN ANTONIO – Total skin-sparing mastectomy with complete preservation of the breast skin envelope was associated with favorable oncologic and ischemic outcomes in a large, high-risk cohort of women who underwent the procedure over a 10-year period in San Francisco, a study has shown.

The findings suggest that the surgery, which produces superior cosmesis and is associated with a high rate of patient satisfaction, is a reasonable option for many women facing therapeutic or prophylactic mastectomy, Dr. Anne G. Warren Peled said at the San Antonio Breast Cancer Symposium.

The total skin-sparing mastectomy (TSSM) allows preservation of the nipple-areola dermal layer when ductal tissue is removed during mastectomy. "The procedure is increasingly offered to women for both therapeutic and prophylactic indications, and when combined with immediate breast reconstruction, can produce excellent aesthetic results," explained Dr. Warren Peled, a surgical resident at the University of California, San Francisco.

Because the oncologic safety of the procedure and the potential for higher rates of postoperative complications continue to be debated, Dr. Warren Peled and her colleagues sought to evaluate both outcomes using data collected in a prospectively maintained database. The investigators analyzed patient and tumor characteristics, treatment details, and the development of any postoperative complications, as well as local or distant recurrences, for 428 patients (mean age, 46.9 years) who underwent 657 TSSMs and immediate breast reconstruction at the UCSF Medical Center in 2001-2010.

"The mastectomy incisions included radial, lateral, periareolar, and inframammary incisions, and the areolar and nipple complex tissue was separated from the dermal layer of skin by sharp dissection with inversion of the nipple skin to ensure the removal of all of the nipple duct tissue," Dr. Warren Peled said during a poster discussion. Of the 657 mastectomies, 412 were therapeutic procedures, and 245 (58 bilateral and 187 contralateral) were prophylactic, she said.

Most of the tumors were stage 0 (111) or stage I (135), although stage II (95), III (48), and IV (7) tumors were also observed, Dr. Warren Peled reported. Some 14 mastectomies were for recurrent cancer, she noted. In addition, 210 patients underwent neoadjuvant chemotherapy, 144 had postmastectomy radiation therapy, and 78 had adjuvant chemotherapy, she said.

With respect to nipple involvement on pathological analysis, 11 specimens had evidence of in situ cancer and 9 had evidence of invasive cancer, leading to re-excision in 7 cases, removal of the nipple-areolar complex (NAC) in 9 cases, and NAC radiation in 4 cases, said Dr. Warren Peled.

The conventional, two-stage, expander-implant method – in which a tissue expander placed under the chest muscle is implanted and gradually inflated to expand the tissue in preparation for the synthetic implant 3-6 months later – was used in 80% of the postmastectomy reconstructions, Dr. Warren Peled said. The remaining 20% of the reconstructions included either the placement of a permanent silicon implant at the time of mastectomy (4.7%) or autologous reconstruction (15.3%), she said.

A review of the oncologic outcomes in the 412 patients who underwent therapeutic mastectomies showed that, at a median follow-up of 28 months, four patients (1%) experienced local recurrence only, eight (1.9%) experienced distant recurrence only, and four experienced both local and distant recurrence (1%), Dr. Warren Peled reported. Among the local recurrences, two each were invasive (0.7%) and in situ cancer (1.8%), and among the distant recurrences, all eight (2.7) were invasive cancers. Among those with both local and distant recurrences, three (1%) and one (0.9%) were invasive and in situ, respectively, she said,

Of the 126 patients who had a minimum 36 months’ follow-up (median, 45 months), 2 patients (1.6%) had local recurrence only, one of which was invasive; 1 patient (0.8%) had distant recurrence only; and 1 (0.8%) had both, Dr. Peled said, noting that the recurrences in the latter two patients were invasive.

An assessment of ischemic complications showed 13 cases (1.9%) of partial nipple loss; 10 cases (1.5%) of complete nipple loss, and 78 cases (11.8%) of skin flap necrosis, Dr. Peled said, noting that the group’s current nipple loss rate is lower than 1%, thanks to serial improvements in surgical technique.

The findings indicate that TSSM "can be performed with low rates of nipple involvement and locoregional recurrence," Dr. Warren Peled stated. Although the short-term findings are encouraging, the study cannot speak to the long-term oncologic safety of the procedure. "Longer term follow-up is needed to confirm the oncologic safety over time," she said.

Dr. Warren Peled had no relevant financial conflicts to disclose.

SAN ANTONIO – Total skin-sparing mastectomy with complete preservation of the breast skin envelope was associated with favorable oncologic and ischemic outcomes in a large, high-risk cohort of women who underwent the procedure over a 10-year period in San Francisco, a study has shown.

The findings suggest that the surgery, which produces superior cosmesis and is associated with a high rate of patient satisfaction, is a reasonable option for many women facing therapeutic or prophylactic mastectomy, Dr. Anne G. Warren Peled said at the San Antonio Breast Cancer Symposium.

The total skin-sparing mastectomy (TSSM) allows preservation of the nipple-areola dermal layer when ductal tissue is removed during mastectomy. "The procedure is increasingly offered to women for both therapeutic and prophylactic indications, and when combined with immediate breast reconstruction, can produce excellent aesthetic results," explained Dr. Warren Peled, a surgical resident at the University of California, San Francisco.

Because the oncologic safety of the procedure and the potential for higher rates of postoperative complications continue to be debated, Dr. Warren Peled and her colleagues sought to evaluate both outcomes using data collected in a prospectively maintained database. The investigators analyzed patient and tumor characteristics, treatment details, and the development of any postoperative complications, as well as local or distant recurrences, for 428 patients (mean age, 46.9 years) who underwent 657 TSSMs and immediate breast reconstruction at the UCSF Medical Center in 2001-2010.

"The mastectomy incisions included radial, lateral, periareolar, and inframammary incisions, and the areolar and nipple complex tissue was separated from the dermal layer of skin by sharp dissection with inversion of the nipple skin to ensure the removal of all of the nipple duct tissue," Dr. Warren Peled said during a poster discussion. Of the 657 mastectomies, 412 were therapeutic procedures, and 245 (58 bilateral and 187 contralateral) were prophylactic, she said.

Most of the tumors were stage 0 (111) or stage I (135), although stage II (95), III (48), and IV (7) tumors were also observed, Dr. Warren Peled reported. Some 14 mastectomies were for recurrent cancer, she noted. In addition, 210 patients underwent neoadjuvant chemotherapy, 144 had postmastectomy radiation therapy, and 78 had adjuvant chemotherapy, she said.

With respect to nipple involvement on pathological analysis, 11 specimens had evidence of in situ cancer and 9 had evidence of invasive cancer, leading to re-excision in 7 cases, removal of the nipple-areolar complex (NAC) in 9 cases, and NAC radiation in 4 cases, said Dr. Warren Peled.

The conventional, two-stage, expander-implant method – in which a tissue expander placed under the chest muscle is implanted and gradually inflated to expand the tissue in preparation for the synthetic implant 3-6 months later – was used in 80% of the postmastectomy reconstructions, Dr. Warren Peled said. The remaining 20% of the reconstructions included either the placement of a permanent silicon implant at the time of mastectomy (4.7%) or autologous reconstruction (15.3%), she said.

A review of the oncologic outcomes in the 412 patients who underwent therapeutic mastectomies showed that, at a median follow-up of 28 months, four patients (1%) experienced local recurrence only, eight (1.9%) experienced distant recurrence only, and four experienced both local and distant recurrence (1%), Dr. Warren Peled reported. Among the local recurrences, two each were invasive (0.7%) and in situ cancer (1.8%), and among the distant recurrences, all eight (2.7) were invasive cancers. Among those with both local and distant recurrences, three (1%) and one (0.9%) were invasive and in situ, respectively, she said,

Of the 126 patients who had a minimum 36 months’ follow-up (median, 45 months), 2 patients (1.6%) had local recurrence only, one of which was invasive; 1 patient (0.8%) had distant recurrence only; and 1 (0.8%) had both, Dr. Peled said, noting that the recurrences in the latter two patients were invasive.

An assessment of ischemic complications showed 13 cases (1.9%) of partial nipple loss; 10 cases (1.5%) of complete nipple loss, and 78 cases (11.8%) of skin flap necrosis, Dr. Peled said, noting that the group’s current nipple loss rate is lower than 1%, thanks to serial improvements in surgical technique.

The findings indicate that TSSM "can be performed with low rates of nipple involvement and locoregional recurrence," Dr. Warren Peled stated. Although the short-term findings are encouraging, the study cannot speak to the long-term oncologic safety of the procedure. "Longer term follow-up is needed to confirm the oncologic safety over time," she said.

Dr. Warren Peled had no relevant financial conflicts to disclose.

SAN ANTONIO – Dr. Howard A. Burris III, Dr. William J. Gradishar, and Dr. Hope S. Rugo remark on the implications of the CLEOPATRA trial, in which 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, at the 2011 San Antonio Breast Cancer Symposium.

SAN ANTONIO – Dr. Howard A. Burris III, Dr. William J. Gradishar, and Dr. Hope S. Rugo remark on the implications of the CLEOPATRA trial, in which 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, at the 2011 San Antonio Breast Cancer Symposium.

SAN ANTONIO – Dr. Howard A. Burris III, Dr. William J. Gradishar, and Dr. Hope S. Rugo remark on the implications of the CLEOPATRA trial, in which 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, at the 2011 San Antonio Breast Cancer Symposium.