Breast Cancer

Women with HER2-positive metastatic breast cancer have been given a double-edged sword, with the Food and Drug Administration granting approval to pertuzumab on Friday, June 8, as a first-line therapy.*

The addition of pertuzumab (Perjeta), a new HER2 blocker, to a standard chemotherapy combination of trastuzumab (Herceptin) and docetaxel (Taxotere) has been shown to extend progression-free survival in these patients. Overall survival data are not yet available.

Pertuzumab is a humanized monoclonal antibody, manufactured through biotechnology methods by Genentech, a subsidiary of Roche. It also blocks other HER family members, including EGFR, HER3, and HER4, and is believed to complement HER2 inhibition by trastuzumab, also made by Genentech and Roche.

The approval rides largely on the results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial. Dual HER2 blockade boosted median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in a group treated with standard therapy plus-pertuzumab. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival. These results were published in the New England Journal of Medicine (2012;366:109-19).

For the double-blind phase III trial, 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized either to a control group that received placebo plus trastuzumab and docetaxel or to the pertuzumab group, which received pertuzumab plus trastuzumab and docetaxel.

Preliminary data from the CLEOPATRA trial were presented at the annual San Antonio Breast Cancer Symposium in early December 2011. For expert commentary on the trial, see our video report.

Supply, Cost Could Be Concerns

In their announcements of pertuzumab approval, Genentech, maker of the drug, and the FDA disclosed that production issues could affect the long-term supply of the drug.

"We expect to meet demand for Perjeta following today\'s FDA approval. We recently identified a cell growth issue that might affect our future supply of the medicine," said Patrick Y. Yang, Ph.D., head, Pharma Global Technical Operations. "We take this very seriously and are working with the FDA to ensure a consistent manufacturing process that maintains drug supply for the people who need it."

With the approval, Genentech has agreed to postmarketing commitments related to the manufacturing process for Perjeta. These include FDA review of data from the next several productions of the medicine.

The FDA limited its approval to drug product that has not been affected by production issues, according to Dr. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research.

"Given the need for additional treatments for metastatic breast cancer, we made the decision to approve this drug today and not to delay its availability to patients pending resolution of the production issues relating to future supply," she said in the FDA announcement.

"Genentech is currently developing a plan to mitigate the effect on patients of any potential shortage of Perjeta."

An added concern is the high cost of dual HER2 inhibition at a time when oncologists are under pressure to contain costs. According to the New York Times, Genentech is putting the wholesale cost of pertuzumab at $5,900/month, which added to the typical $4,500/month costs of trastuzumab, would drive the cost of 18 months of treatment to $187,000.

Boxed Warning Put on Label

Pertuzumab is indicated in combination with trastuzumab and docetaxel for "patients with HER2-positive metastatic breast cancer who have not received prior anti–HER2 therapy or chemotherapy for metastatic disease."

The FDA announced that pertuzumab would have a boxed warning on its label. This is to alert clinicians and patients to the potential risk of death or severe effects to a fetus. "Pregnancy status must be verified prior to the start of Perjeta treatment," it said; patients should be advised "of these risks and need for effective contraception prior to starting pertuzumab."

According to the agency, the most common side effects observed with use of pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral sensory neuropathy.

Although left ventricular dysfunction was observed, the FDA said the combination of pertuzumab with standard therapy "was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction or decreases in left ventricular ejection fraction, compared with placebo in combination with trastuzumab and docetaxel.

The FDA recommended that pertuzumab be started at an initial dose of 840 mg administered as a 60-minute IV infusion, followed every 3 weeks, thereafter, by 420 mg administered as a 30- to 60-minute IV infusion. It also recommended that when trastuzumab is used with pertuzumab, trastuzumab should be started at 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks by a dose of 6 mg/kg administered IV over 30 to 90 minutes. When docetaxel is given with pertuzumab, the recommended starting docetaxel dose is 75 mg/m² administered as an IV infusion. If well tolerated, docetaxel may be escalated to 100 mg/m² every 3 weeks.

* This story was updated on 11/30/2012.

Women with HER2-positive metastatic breast cancer have been given a double-edged sword, with the Food and Drug Administration granting approval to pertuzumab on Friday, June 8, as a first-line therapy.*

The addition of pertuzumab (Perjeta), a new HER2 blocker, to a standard chemotherapy combination of trastuzumab (Herceptin) and docetaxel (Taxotere) has been shown to extend progression-free survival in these patients. Overall survival data are not yet available.

Pertuzumab is a humanized monoclonal antibody, manufactured through biotechnology methods by Genentech, a subsidiary of Roche. It also blocks other HER family members, including EGFR, HER3, and HER4, and is believed to complement HER2 inhibition by trastuzumab, also made by Genentech and Roche.

The approval rides largely on the results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial. Dual HER2 blockade boosted median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in a group treated with standard therapy plus-pertuzumab. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival. These results were published in the New England Journal of Medicine (2012;366:109-19).

For the double-blind phase III trial, 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized either to a control group that received placebo plus trastuzumab and docetaxel or to the pertuzumab group, which received pertuzumab plus trastuzumab and docetaxel.

Preliminary data from the CLEOPATRA trial were presented at the annual San Antonio Breast Cancer Symposium in early December 2011. For expert commentary on the trial, see our video report.

Supply, Cost Could Be Concerns

In their announcements of pertuzumab approval, Genentech, maker of the drug, and the FDA disclosed that production issues could affect the long-term supply of the drug.

"We expect to meet demand for Perjeta following today\'s FDA approval. We recently identified a cell growth issue that might affect our future supply of the medicine," said Patrick Y. Yang, Ph.D., head, Pharma Global Technical Operations. "We take this very seriously and are working with the FDA to ensure a consistent manufacturing process that maintains drug supply for the people who need it."

With the approval, Genentech has agreed to postmarketing commitments related to the manufacturing process for Perjeta. These include FDA review of data from the next several productions of the medicine.

The FDA limited its approval to drug product that has not been affected by production issues, according to Dr. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research.

"Given the need for additional treatments for metastatic breast cancer, we made the decision to approve this drug today and not to delay its availability to patients pending resolution of the production issues relating to future supply," she said in the FDA announcement.

"Genentech is currently developing a plan to mitigate the effect on patients of any potential shortage of Perjeta."

An added concern is the high cost of dual HER2 inhibition at a time when oncologists are under pressure to contain costs. According to the New York Times, Genentech is putting the wholesale cost of pertuzumab at $5,900/month, which added to the typical $4,500/month costs of trastuzumab, would drive the cost of 18 months of treatment to $187,000.

Boxed Warning Put on Label

Pertuzumab is indicated in combination with trastuzumab and docetaxel for "patients with HER2-positive metastatic breast cancer who have not received prior anti–HER2 therapy or chemotherapy for metastatic disease."

The FDA announced that pertuzumab would have a boxed warning on its label. This is to alert clinicians and patients to the potential risk of death or severe effects to a fetus. "Pregnancy status must be verified prior to the start of Perjeta treatment," it said; patients should be advised "of these risks and need for effective contraception prior to starting pertuzumab."

According to the agency, the most common side effects observed with use of pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral sensory neuropathy.

Although left ventricular dysfunction was observed, the FDA said the combination of pertuzumab with standard therapy "was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction or decreases in left ventricular ejection fraction, compared with placebo in combination with trastuzumab and docetaxel.

The FDA recommended that pertuzumab be started at an initial dose of 840 mg administered as a 60-minute IV infusion, followed every 3 weeks, thereafter, by 420 mg administered as a 30- to 60-minute IV infusion. It also recommended that when trastuzumab is used with pertuzumab, trastuzumab should be started at 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks by a dose of 6 mg/kg administered IV over 30 to 90 minutes. When docetaxel is given with pertuzumab, the recommended starting docetaxel dose is 75 mg/m² administered as an IV infusion. If well tolerated, docetaxel may be escalated to 100 mg/m² every 3 weeks.

* This story was updated on 11/30/2012.

Women with HER2-positive metastatic breast cancer have been given a double-edged sword, with the Food and Drug Administration granting approval to pertuzumab on Friday, June 8, as a first-line therapy.*

The addition of pertuzumab (Perjeta), a new HER2 blocker, to a standard chemotherapy combination of trastuzumab (Herceptin) and docetaxel (Taxotere) has been shown to extend progression-free survival in these patients. Overall survival data are not yet available.

Pertuzumab is a humanized monoclonal antibody, manufactured through biotechnology methods by Genentech, a subsidiary of Roche. It also blocks other HER family members, including EGFR, HER3, and HER4, and is believed to complement HER2 inhibition by trastuzumab, also made by Genentech and Roche.

The approval rides largely on the results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial. Dual HER2 blockade boosted median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in a group treated with standard therapy plus-pertuzumab. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival. These results were published in the New England Journal of Medicine (2012;366:109-19).

For the double-blind phase III trial, 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized either to a control group that received placebo plus trastuzumab and docetaxel or to the pertuzumab group, which received pertuzumab plus trastuzumab and docetaxel.

Preliminary data from the CLEOPATRA trial were presented at the annual San Antonio Breast Cancer Symposium in early December 2011. For expert commentary on the trial, see our video report.

Supply, Cost Could Be Concerns

In their announcements of pertuzumab approval, Genentech, maker of the drug, and the FDA disclosed that production issues could affect the long-term supply of the drug.

"We expect to meet demand for Perjeta following today\'s FDA approval. We recently identified a cell growth issue that might affect our future supply of the medicine," said Patrick Y. Yang, Ph.D., head, Pharma Global Technical Operations. "We take this very seriously and are working with the FDA to ensure a consistent manufacturing process that maintains drug supply for the people who need it."

With the approval, Genentech has agreed to postmarketing commitments related to the manufacturing process for Perjeta. These include FDA review of data from the next several productions of the medicine.

The FDA limited its approval to drug product that has not been affected by production issues, according to Dr. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research.

"Given the need for additional treatments for metastatic breast cancer, we made the decision to approve this drug today and not to delay its availability to patients pending resolution of the production issues relating to future supply," she said in the FDA announcement.

"Genentech is currently developing a plan to mitigate the effect on patients of any potential shortage of Perjeta."

An added concern is the high cost of dual HER2 inhibition at a time when oncologists are under pressure to contain costs. According to the New York Times, Genentech is putting the wholesale cost of pertuzumab at $5,900/month, which added to the typical $4,500/month costs of trastuzumab, would drive the cost of 18 months of treatment to $187,000.

Boxed Warning Put on Label

Pertuzumab is indicated in combination with trastuzumab and docetaxel for "patients with HER2-positive metastatic breast cancer who have not received prior anti–HER2 therapy or chemotherapy for metastatic disease."

The FDA announced that pertuzumab would have a boxed warning on its label. This is to alert clinicians and patients to the potential risk of death or severe effects to a fetus. "Pregnancy status must be verified prior to the start of Perjeta treatment," it said; patients should be advised "of these risks and need for effective contraception prior to starting pertuzumab."

According to the agency, the most common side effects observed with use of pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral sensory neuropathy.

Although left ventricular dysfunction was observed, the FDA said the combination of pertuzumab with standard therapy "was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction or decreases in left ventricular ejection fraction, compared with placebo in combination with trastuzumab and docetaxel.

The FDA recommended that pertuzumab be started at an initial dose of 840 mg administered as a 60-minute IV infusion, followed every 3 weeks, thereafter, by 420 mg administered as a 30- to 60-minute IV infusion. It also recommended that when trastuzumab is used with pertuzumab, trastuzumab should be started at 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks by a dose of 6 mg/kg administered IV over 30 to 90 minutes. When docetaxel is given with pertuzumab, the recommended starting docetaxel dose is 75 mg/m² administered as an IV infusion. If well tolerated, docetaxel may be escalated to 100 mg/m² every 3 weeks.

* This story was updated on 11/30/2012.

SAN FRANCISCO – Regional recurrence is rare in breast cancer patients with a negative sentinel lymph node biopsy and does not appear to be associated with reduced overall survival, based on the latest results of a clinical trial including more than 5,500 patients.

"Regional recurrences were very low and remained so over the follow-up period," Dr. Kelly K. Hunt said at the annual meeting of the American Surgical Association. The 3-year cumulative incidence rate for regional recurrence was 0.003, and the rate at 5 years was 0.005. In comparison, the 3-year and 5-year rates for local recurrence were 0.013 and 0.024, respectively; the 3-year and 5-year rates for distant recurrence were 0.017 and 0.028, respectively.

Sentinel lymph node (SLN) dissection has been shown to improve staging, compared with axillary lymph node dissection (ALND) alone, and reduced morbidity and improved quality of life have been associated with SLN dissection. Thus, SLN dissection has replaced ALND in clinical practice for staging of regional lymph nodes in women with clinically node-negative, early-stage breast cancer. However, studies have shown false-negative rates ranging from 5% to 17%, noted Dr. Hunt of the department of surgical oncology at the MD Anderson Cancer Center in Houston.

She and her fellow researchers analyzed data from the American College of Surgeons Oncology Group (ACOSOG) Z0010 trial, a prospective multicenter trial designed to evaluate the prognostic implications of SLN and bone marrow micrometastases in women with early-stage breast cancer.

Eligible patients had biopsy-proven T1 or T2 breast cancer with clinically negative lymph nodes and were candidates for lumpectomy and whole breast irradiation. A total of 5,539 patients were enrolled from 126 participating sites. A total of 5,200 patients were fully evaluable, and a sentinel node was identified in 5,119.

Of those, 3,904 patients had negative lymph nodes based on standard H&E staining. Of the patients with negative SLNs on H&E staining, there were 3,326 who had sufficient samples for immunohistochemical staining for cytokeratin. Ten percent of these patients had positive nodes on immunohistochemistry (IHC).

In outcomes published last year, women with H&E positive sentinel nodes had decreased survival compared with those with H&E negative sentinel nodes (JAMA 2011;306:385-93 [doi:10.1001/jama.2011.1034]).

Patients were largely postmenopausal women with ductal breast cancers. They had mostly T1 tumors, many of which were hormone receptor–positive, low to intermediate grade. The majority of patients (98%) had breast-conserving surgery, and 68% patients received hormonal therapy as part of adjuvant treatment. Most patients (92%) finished adjuvant radiation, and almost half (44%) also received systemic chemotherapy. The median follow-up was 8.4 years. There were 127 local failures, 20 regional recurrences, and 134 distant recurrences. There were 317 deaths.

"Within this small group of locoregional recurrences, we did look at the differences in the patients who had IHC-positive vs. IHC-negative sentinel nodes and we did not see any difference between those two groups," Dr. Hunt said. As a result, they combined the two groups for subsequent analyses. "We did not see a difference in recurrence rates based on IHC status, despite the fact that we would suspect that some of these patients have residual disease in the axilla based on published false-negative rates from multicenter trials."

They also examined clinical factors, pathologic factors, and treatment factors that may have affected local and regional recurrences on univariable and multivariable analyses. In both models, younger age and negative hormone receptor status predicted both a greater rate of local failures and locoregional recurrences. With respect to distant recurrence, the important factors were increasing tumor size, the presence of lymphovascular invasion, and higher tumor grade.

Older age, larger tumor size, higher tumor grade, and the presence of a local recurrence predicted reduced overall survival. The hazard rate for local recurrence alone on multivariable analysis was 6.73 (P less than .0001).

"This study reassures anyone practicing in this field ... that those early clinical judgments we all made that drove early adoption of sentinel lymph node axillary staging and early, occasionally angst-ridden decisions to forgo axillary dissection in patients with early-stage breast cancer and minimal axillary nodal disease ... that those choices were correct," said invited discussant Dr. Barbara L. Bass, the John F. and Carolyn Bookout Distinguished Endowed Chair in the department of surgery at the Methodist Hospital in Houston and a professor of surgery at Cornell University in New York.

The regional recurrence rates are particularly interesting, she noted. "It practically makes you think that the axilla – our current bedrock for decision making and staging – is in fact a hostile soil for tumor cells, compared to the breast and distant sites." She asked why the axilla was practically immune from recurrence. "Clearly, those lymph nodes in that space were still there, but tumor does not go or grow there."

Dr. Hunt said earlier studies have suggested that some nodal disease is not clinically relevant and requires no treatment. However, with SLN surgery, "the more that we look, the more we find these micrometastases, and the bias is to treat them."

With improved adjuvant therapy, "we are eradicating disease with those treatments. We know that from neoadjuvant trials as well," Dr. Hunt added. In trials at MD Anderson, after chemotherapy 25% of patients who had fine-needle biopsy at initial diagnosis have complete eradication of disease in the nodes, she said.

"Now that we understand more about the subtypes, we see that in HER-2 positive disease, we’re eradicating about 75% of the disease in regional nodes with targeted therapies." Systemic therapy has gotten better, but it also appears that there are metastases that are not clinically or biologically relevant.

Because the first site of failure is generally the only site recorded, the researchers also performed a competing risk regression model to account for patients with local, regional, and distant recurrences. Evaluating competing risks demonstrated that hormone receptor–negative disease and lack of systemic chemotherapy are associated with increased risk of local recurrence. Older age, higher tumor size, greater tumor grade, and local recurrence predicted decreased survival.

Dr. Bass observed that currently, staging is based largely on the features of the primary tumor – gene assessments, tumor markers, and so on. In light of this, she wondered how long will it will be necessary to surgically stage the clinically negative axilla in patients with early-stage disease who are treated with breast-conserving therapy.

"Do the results of this trial mean that it might be possible to forgo sentinel lymph node staging of the axilla in some patients?" she asked.

That question remains to be answered, according to Dr. Hunt. Planning is underway for a trial in early-stage breast cancer to compare SLN surgery with no treatment of the axilla. "This is based on the fact that we know that different biologic subtypes have very different local and regional recurrence patterns." So, for example, in women with HER-2 positive or triple-negative disease, the systemic treatment regimen is clear with or without nodal involvement.

The researchers reported that they have no relevant conflicts of interest.

The complete manuscript of this presentation is anticipated to be published in the Annals of Surgery pending editorial review.

SAN FRANCISCO – Regional recurrence is rare in breast cancer patients with a negative sentinel lymph node biopsy and does not appear to be associated with reduced overall survival, based on the latest results of a clinical trial including more than 5,500 patients.

"Regional recurrences were very low and remained so over the follow-up period," Dr. Kelly K. Hunt said at the annual meeting of the American Surgical Association. The 3-year cumulative incidence rate for regional recurrence was 0.003, and the rate at 5 years was 0.005. In comparison, the 3-year and 5-year rates for local recurrence were 0.013 and 0.024, respectively; the 3-year and 5-year rates for distant recurrence were 0.017 and 0.028, respectively.

Sentinel lymph node (SLN) dissection has been shown to improve staging, compared with axillary lymph node dissection (ALND) alone, and reduced morbidity and improved quality of life have been associated with SLN dissection. Thus, SLN dissection has replaced ALND in clinical practice for staging of regional lymph nodes in women with clinically node-negative, early-stage breast cancer. However, studies have shown false-negative rates ranging from 5% to 17%, noted Dr. Hunt of the department of surgical oncology at the MD Anderson Cancer Center in Houston.

She and her fellow researchers analyzed data from the American College of Surgeons Oncology Group (ACOSOG) Z0010 trial, a prospective multicenter trial designed to evaluate the prognostic implications of SLN and bone marrow micrometastases in women with early-stage breast cancer.

Eligible patients had biopsy-proven T1 or T2 breast cancer with clinically negative lymph nodes and were candidates for lumpectomy and whole breast irradiation. A total of 5,539 patients were enrolled from 126 participating sites. A total of 5,200 patients were fully evaluable, and a sentinel node was identified in 5,119.

Of those, 3,904 patients had negative lymph nodes based on standard H&E staining. Of the patients with negative SLNs on H&E staining, there were 3,326 who had sufficient samples for immunohistochemical staining for cytokeratin. Ten percent of these patients had positive nodes on immunohistochemistry (IHC).

In outcomes published last year, women with H&E positive sentinel nodes had decreased survival compared with those with H&E negative sentinel nodes (JAMA 2011;306:385-93 [doi:10.1001/jama.2011.1034]).

Patients were largely postmenopausal women with ductal breast cancers. They had mostly T1 tumors, many of which were hormone receptor–positive, low to intermediate grade. The majority of patients (98%) had breast-conserving surgery, and 68% patients received hormonal therapy as part of adjuvant treatment. Most patients (92%) finished adjuvant radiation, and almost half (44%) also received systemic chemotherapy. The median follow-up was 8.4 years. There were 127 local failures, 20 regional recurrences, and 134 distant recurrences. There were 317 deaths.

"Within this small group of locoregional recurrences, we did look at the differences in the patients who had IHC-positive vs. IHC-negative sentinel nodes and we did not see any difference between those two groups," Dr. Hunt said. As a result, they combined the two groups for subsequent analyses. "We did not see a difference in recurrence rates based on IHC status, despite the fact that we would suspect that some of these patients have residual disease in the axilla based on published false-negative rates from multicenter trials."

They also examined clinical factors, pathologic factors, and treatment factors that may have affected local and regional recurrences on univariable and multivariable analyses. In both models, younger age and negative hormone receptor status predicted both a greater rate of local failures and locoregional recurrences. With respect to distant recurrence, the important factors were increasing tumor size, the presence of lymphovascular invasion, and higher tumor grade.

Older age, larger tumor size, higher tumor grade, and the presence of a local recurrence predicted reduced overall survival. The hazard rate for local recurrence alone on multivariable analysis was 6.73 (P less than .0001).

"This study reassures anyone practicing in this field ... that those early clinical judgments we all made that drove early adoption of sentinel lymph node axillary staging and early, occasionally angst-ridden decisions to forgo axillary dissection in patients with early-stage breast cancer and minimal axillary nodal disease ... that those choices were correct," said invited discussant Dr. Barbara L. Bass, the John F. and Carolyn Bookout Distinguished Endowed Chair in the department of surgery at the Methodist Hospital in Houston and a professor of surgery at Cornell University in New York.

The regional recurrence rates are particularly interesting, she noted. "It practically makes you think that the axilla – our current bedrock for decision making and staging – is in fact a hostile soil for tumor cells, compared to the breast and distant sites." She asked why the axilla was practically immune from recurrence. "Clearly, those lymph nodes in that space were still there, but tumor does not go or grow there."

Dr. Hunt said earlier studies have suggested that some nodal disease is not clinically relevant and requires no treatment. However, with SLN surgery, "the more that we look, the more we find these micrometastases, and the bias is to treat them."

With improved adjuvant therapy, "we are eradicating disease with those treatments. We know that from neoadjuvant trials as well," Dr. Hunt added. In trials at MD Anderson, after chemotherapy 25% of patients who had fine-needle biopsy at initial diagnosis have complete eradication of disease in the nodes, she said.

"Now that we understand more about the subtypes, we see that in HER-2 positive disease, we’re eradicating about 75% of the disease in regional nodes with targeted therapies." Systemic therapy has gotten better, but it also appears that there are metastases that are not clinically or biologically relevant.

Because the first site of failure is generally the only site recorded, the researchers also performed a competing risk regression model to account for patients with local, regional, and distant recurrences. Evaluating competing risks demonstrated that hormone receptor–negative disease and lack of systemic chemotherapy are associated with increased risk of local recurrence. Older age, higher tumor size, greater tumor grade, and local recurrence predicted decreased survival.

Dr. Bass observed that currently, staging is based largely on the features of the primary tumor – gene assessments, tumor markers, and so on. In light of this, she wondered how long will it will be necessary to surgically stage the clinically negative axilla in patients with early-stage disease who are treated with breast-conserving therapy.

"Do the results of this trial mean that it might be possible to forgo sentinel lymph node staging of the axilla in some patients?" she asked.

That question remains to be answered, according to Dr. Hunt. Planning is underway for a trial in early-stage breast cancer to compare SLN surgery with no treatment of the axilla. "This is based on the fact that we know that different biologic subtypes have very different local and regional recurrence patterns." So, for example, in women with HER-2 positive or triple-negative disease, the systemic treatment regimen is clear with or without nodal involvement.

The researchers reported that they have no relevant conflicts of interest.

The complete manuscript of this presentation is anticipated to be published in the Annals of Surgery pending editorial review.

SAN FRANCISCO – Regional recurrence is rare in breast cancer patients with a negative sentinel lymph node biopsy and does not appear to be associated with reduced overall survival, based on the latest results of a clinical trial including more than 5,500 patients.

"Regional recurrences were very low and remained so over the follow-up period," Dr. Kelly K. Hunt said at the annual meeting of the American Surgical Association. The 3-year cumulative incidence rate for regional recurrence was 0.003, and the rate at 5 years was 0.005. In comparison, the 3-year and 5-year rates for local recurrence were 0.013 and 0.024, respectively; the 3-year and 5-year rates for distant recurrence were 0.017 and 0.028, respectively.

Sentinel lymph node (SLN) dissection has been shown to improve staging, compared with axillary lymph node dissection (ALND) alone, and reduced morbidity and improved quality of life have been associated with SLN dissection. Thus, SLN dissection has replaced ALND in clinical practice for staging of regional lymph nodes in women with clinically node-negative, early-stage breast cancer. However, studies have shown false-negative rates ranging from 5% to 17%, noted Dr. Hunt of the department of surgical oncology at the MD Anderson Cancer Center in Houston.

She and her fellow researchers analyzed data from the American College of Surgeons Oncology Group (ACOSOG) Z0010 trial, a prospective multicenter trial designed to evaluate the prognostic implications of SLN and bone marrow micrometastases in women with early-stage breast cancer.

Eligible patients had biopsy-proven T1 or T2 breast cancer with clinically negative lymph nodes and were candidates for lumpectomy and whole breast irradiation. A total of 5,539 patients were enrolled from 126 participating sites. A total of 5,200 patients were fully evaluable, and a sentinel node was identified in 5,119.

Of those, 3,904 patients had negative lymph nodes based on standard H&E staining. Of the patients with negative SLNs on H&E staining, there were 3,326 who had sufficient samples for immunohistochemical staining for cytokeratin. Ten percent of these patients had positive nodes on immunohistochemistry (IHC).

In outcomes published last year, women with H&E positive sentinel nodes had decreased survival compared with those with H&E negative sentinel nodes (JAMA 2011;306:385-93 [doi:10.1001/jama.2011.1034]).

Patients were largely postmenopausal women with ductal breast cancers. They had mostly T1 tumors, many of which were hormone receptor–positive, low to intermediate grade. The majority of patients (98%) had breast-conserving surgery, and 68% patients received hormonal therapy as part of adjuvant treatment. Most patients (92%) finished adjuvant radiation, and almost half (44%) also received systemic chemotherapy. The median follow-up was 8.4 years. There were 127 local failures, 20 regional recurrences, and 134 distant recurrences. There were 317 deaths.

"Within this small group of locoregional recurrences, we did look at the differences in the patients who had IHC-positive vs. IHC-negative sentinel nodes and we did not see any difference between those two groups," Dr. Hunt said. As a result, they combined the two groups for subsequent analyses. "We did not see a difference in recurrence rates based on IHC status, despite the fact that we would suspect that some of these patients have residual disease in the axilla based on published false-negative rates from multicenter trials."

They also examined clinical factors, pathologic factors, and treatment factors that may have affected local and regional recurrences on univariable and multivariable analyses. In both models, younger age and negative hormone receptor status predicted both a greater rate of local failures and locoregional recurrences. With respect to distant recurrence, the important factors were increasing tumor size, the presence of lymphovascular invasion, and higher tumor grade.

Older age, larger tumor size, higher tumor grade, and the presence of a local recurrence predicted reduced overall survival. The hazard rate for local recurrence alone on multivariable analysis was 6.73 (P less than .0001).

"This study reassures anyone practicing in this field ... that those early clinical judgments we all made that drove early adoption of sentinel lymph node axillary staging and early, occasionally angst-ridden decisions to forgo axillary dissection in patients with early-stage breast cancer and minimal axillary nodal disease ... that those choices were correct," said invited discussant Dr. Barbara L. Bass, the John F. and Carolyn Bookout Distinguished Endowed Chair in the department of surgery at the Methodist Hospital in Houston and a professor of surgery at Cornell University in New York.

The regional recurrence rates are particularly interesting, she noted. "It practically makes you think that the axilla – our current bedrock for decision making and staging – is in fact a hostile soil for tumor cells, compared to the breast and distant sites." She asked why the axilla was practically immune from recurrence. "Clearly, those lymph nodes in that space were still there, but tumor does not go or grow there."

Dr. Hunt said earlier studies have suggested that some nodal disease is not clinically relevant and requires no treatment. However, with SLN surgery, "the more that we look, the more we find these micrometastases, and the bias is to treat them."

With improved adjuvant therapy, "we are eradicating disease with those treatments. We know that from neoadjuvant trials as well," Dr. Hunt added. In trials at MD Anderson, after chemotherapy 25% of patients who had fine-needle biopsy at initial diagnosis have complete eradication of disease in the nodes, she said.

"Now that we understand more about the subtypes, we see that in HER-2 positive disease, we’re eradicating about 75% of the disease in regional nodes with targeted therapies." Systemic therapy has gotten better, but it also appears that there are metastases that are not clinically or biologically relevant.

Because the first site of failure is generally the only site recorded, the researchers also performed a competing risk regression model to account for patients with local, regional, and distant recurrences. Evaluating competing risks demonstrated that hormone receptor–negative disease and lack of systemic chemotherapy are associated with increased risk of local recurrence. Older age, higher tumor size, greater tumor grade, and local recurrence predicted decreased survival.

Dr. Bass observed that currently, staging is based largely on the features of the primary tumor – gene assessments, tumor markers, and so on. In light of this, she wondered how long will it will be necessary to surgically stage the clinically negative axilla in patients with early-stage disease who are treated with breast-conserving therapy.

"Do the results of this trial mean that it might be possible to forgo sentinel lymph node staging of the axilla in some patients?" she asked.

That question remains to be answered, according to Dr. Hunt. Planning is underway for a trial in early-stage breast cancer to compare SLN surgery with no treatment of the axilla. "This is based on the fact that we know that different biologic subtypes have very different local and regional recurrence patterns." So, for example, in women with HER-2 positive or triple-negative disease, the systemic treatment regimen is clear with or without nodal involvement.

The researchers reported that they have no relevant conflicts of interest.

The complete manuscript of this presentation is anticipated to be published in the Annals of Surgery pending editorial review.

CHICAGO – Women taking zoledronic acid monthly for metastatic breast cancer that has spread to the bone may be able to get by with quarterly injections after a year of standard treatment.

The first phase III trial to compare the two dosing schedules for the bisphosphonate found that less frequent therapy produced "noninferior" outcomes compared with the current standard of care, Dr. Carla Ripamonti reported at the annual meeting of the American Society of Clinical Oncology.

Zoledronic acid (Zometa) has been shown to reduce skeletal-related events for up to 2 years in such patients, and international guidelines recommend its use until they experience a substantial decrease in performance status, said Dr. Ripamonti of the National Cancer Institute in Milan, Italy. The thinking behind the current trial was that after a year of treatment, a more convenient regimen "might contribute to improved patient compliance and safety, and help reduce cost while maintaining the efficacy of the drug."

Underscoring the universality of the issue, the invited discussant, Dr. Thomas J. Smith, director of palliative medicine at Johns Hopkins University’s Sidney Kimmel Cancer Center in Baltimore, introduced his comments with the observation, "I’m a breast cancer doctor, and so I see so many people who ask, ‘Do I have to come in every month for my zoledronic acid?’ And the answer is, ‘I don’t know.’ "

Dr. Ripamonti and her coinvestigators randomized 209 women to 4 mg of zoledronic acid every 12 weeks and 216 women to 4 mg every 4 weeks in the 12-month, open-label, multicenter ZOOM trial. All participants had received 9-12 infusions prior to entering the prospective study.

At the trial’s end, 149 and 142 women, respectively, had completed treatment with no difference in the skeletal morbidity rate, the primary end point, in an intent-to-treat analysis. The mean of the ratio of skeletal events per year to time on trial was 0.26 with quarterly treatment and 0.22 with monthly dosing, she reported.

The proportion of patients with skeletal-related events, a secondary end point, also was similar at 14.8% in the quarterly group and 15.3% in the monthly group.

Both schedules were well tolerated, with little difference in adverse events, she reported. The rate of renal side effects was 4% in each arm; osteonecrosis of the jaw occurred in 4 patients on the quarterly schedule and 3 treated monthly.

An assessment of median NTx (N-telopeptides of type I collagen) levels at baseline and every 3 months on study raised some concern, in that the bone resorption marker was increased at 6 months and stayed elevated in the quarterly group, but it did not rise with standard care. This suggests that "caution is needed and longer follow-up is needed to assess whether zoledronic acid every 3 months can maintain adequate efficacy in skeletal-related events over time," said Dr. Ripamonti.

Despite the generally positive results, she noted that the trial was conducted in just one country as an open-label study, it did not have a prespecified imaging frequency, and patients were followed for only 1 year. She urged clinicians to wait for data from the double-blind, phase III Optimize-2 trial, which compared the same dose schedules. Results will be available in the next year, and then oncologists "can decide how to change our clinical practice," she said.

Dr. Smith agreed. It’s "too early" to use NTx levels, he said, recommending that clinicians wait for new data and guidelines. If quarterly dosing becomes possible, he predicted the "cost will be one-third of what it was before."

"So don’t change your current approach, but stay tuned," he told attendees.

Dr. Ripamonti said she had no relevant disclosures. Dr. Smith said he received research funds from the American Cancer Society.

CHICAGO – Women taking zoledronic acid monthly for metastatic breast cancer that has spread to the bone may be able to get by with quarterly injections after a year of standard treatment.

The first phase III trial to compare the two dosing schedules for the bisphosphonate found that less frequent therapy produced "noninferior" outcomes compared with the current standard of care, Dr. Carla Ripamonti reported at the annual meeting of the American Society of Clinical Oncology.

Zoledronic acid (Zometa) has been shown to reduce skeletal-related events for up to 2 years in such patients, and international guidelines recommend its use until they experience a substantial decrease in performance status, said Dr. Ripamonti of the National Cancer Institute in Milan, Italy. The thinking behind the current trial was that after a year of treatment, a more convenient regimen "might contribute to improved patient compliance and safety, and help reduce cost while maintaining the efficacy of the drug."

Underscoring the universality of the issue, the invited discussant, Dr. Thomas J. Smith, director of palliative medicine at Johns Hopkins University’s Sidney Kimmel Cancer Center in Baltimore, introduced his comments with the observation, "I’m a breast cancer doctor, and so I see so many people who ask, ‘Do I have to come in every month for my zoledronic acid?’ And the answer is, ‘I don’t know.’ "

Dr. Ripamonti and her coinvestigators randomized 209 women to 4 mg of zoledronic acid every 12 weeks and 216 women to 4 mg every 4 weeks in the 12-month, open-label, multicenter ZOOM trial. All participants had received 9-12 infusions prior to entering the prospective study.

At the trial’s end, 149 and 142 women, respectively, had completed treatment with no difference in the skeletal morbidity rate, the primary end point, in an intent-to-treat analysis. The mean of the ratio of skeletal events per year to time on trial was 0.26 with quarterly treatment and 0.22 with monthly dosing, she reported.

The proportion of patients with skeletal-related events, a secondary end point, also was similar at 14.8% in the quarterly group and 15.3% in the monthly group.

Both schedules were well tolerated, with little difference in adverse events, she reported. The rate of renal side effects was 4% in each arm; osteonecrosis of the jaw occurred in 4 patients on the quarterly schedule and 3 treated monthly.

An assessment of median NTx (N-telopeptides of type I collagen) levels at baseline and every 3 months on study raised some concern, in that the bone resorption marker was increased at 6 months and stayed elevated in the quarterly group, but it did not rise with standard care. This suggests that "caution is needed and longer follow-up is needed to assess whether zoledronic acid every 3 months can maintain adequate efficacy in skeletal-related events over time," said Dr. Ripamonti.

Despite the generally positive results, she noted that the trial was conducted in just one country as an open-label study, it did not have a prespecified imaging frequency, and patients were followed for only 1 year. She urged clinicians to wait for data from the double-blind, phase III Optimize-2 trial, which compared the same dose schedules. Results will be available in the next year, and then oncologists "can decide how to change our clinical practice," she said.

Dr. Smith agreed. It’s "too early" to use NTx levels, he said, recommending that clinicians wait for new data and guidelines. If quarterly dosing becomes possible, he predicted the "cost will be one-third of what it was before."

"So don’t change your current approach, but stay tuned," he told attendees.

Dr. Ripamonti said she had no relevant disclosures. Dr. Smith said he received research funds from the American Cancer Society.

CHICAGO – Women taking zoledronic acid monthly for metastatic breast cancer that has spread to the bone may be able to get by with quarterly injections after a year of standard treatment.

The first phase III trial to compare the two dosing schedules for the bisphosphonate found that less frequent therapy produced "noninferior" outcomes compared with the current standard of care, Dr. Carla Ripamonti reported at the annual meeting of the American Society of Clinical Oncology.

Zoledronic acid (Zometa) has been shown to reduce skeletal-related events for up to 2 years in such patients, and international guidelines recommend its use until they experience a substantial decrease in performance status, said Dr. Ripamonti of the National Cancer Institute in Milan, Italy. The thinking behind the current trial was that after a year of treatment, a more convenient regimen "might contribute to improved patient compliance and safety, and help reduce cost while maintaining the efficacy of the drug."

Underscoring the universality of the issue, the invited discussant, Dr. Thomas J. Smith, director of palliative medicine at Johns Hopkins University’s Sidney Kimmel Cancer Center in Baltimore, introduced his comments with the observation, "I’m a breast cancer doctor, and so I see so many people who ask, ‘Do I have to come in every month for my zoledronic acid?’ And the answer is, ‘I don’t know.’ "

Dr. Ripamonti and her coinvestigators randomized 209 women to 4 mg of zoledronic acid every 12 weeks and 216 women to 4 mg every 4 weeks in the 12-month, open-label, multicenter ZOOM trial. All participants had received 9-12 infusions prior to entering the prospective study.

At the trial’s end, 149 and 142 women, respectively, had completed treatment with no difference in the skeletal morbidity rate, the primary end point, in an intent-to-treat analysis. The mean of the ratio of skeletal events per year to time on trial was 0.26 with quarterly treatment and 0.22 with monthly dosing, she reported.

The proportion of patients with skeletal-related events, a secondary end point, also was similar at 14.8% in the quarterly group and 15.3% in the monthly group.

Both schedules were well tolerated, with little difference in adverse events, she reported. The rate of renal side effects was 4% in each arm; osteonecrosis of the jaw occurred in 4 patients on the quarterly schedule and 3 treated monthly.

An assessment of median NTx (N-telopeptides of type I collagen) levels at baseline and every 3 months on study raised some concern, in that the bone resorption marker was increased at 6 months and stayed elevated in the quarterly group, but it did not rise with standard care. This suggests that "caution is needed and longer follow-up is needed to assess whether zoledronic acid every 3 months can maintain adequate efficacy in skeletal-related events over time," said Dr. Ripamonti.

Despite the generally positive results, she noted that the trial was conducted in just one country as an open-label study, it did not have a prespecified imaging frequency, and patients were followed for only 1 year. She urged clinicians to wait for data from the double-blind, phase III Optimize-2 trial, which compared the same dose schedules. Results will be available in the next year, and then oncologists "can decide how to change our clinical practice," she said.

Dr. Smith agreed. It’s "too early" to use NTx levels, he said, recommending that clinicians wait for new data and guidelines. If quarterly dosing becomes possible, he predicted the "cost will be one-third of what it was before."

"So don’t change your current approach, but stay tuned," he told attendees.

Dr. Ripamonti said she had no relevant disclosures. Dr. Smith said he received research funds from the American Cancer Society.

Reflecting a psychological paradigm shift, a number of studies at the American Society of Clinical Oncology 2012 annual meeting focus on individuals’ inherent coping skills, sources of strength, and resilience.

One such study, from Australia, takes the important step of studying resiliency prospectively, drawing important conclusions about which cancer patients are most likely to negotiate the journey just fine, without professional psychological intervention.

Dr. Barbara Kaye Bennett of Prince of Wales Hospital in Sydney led the study of 218 women enrolled just following surgery for early-stage breast cancer. At baseline, she and her associates administered validated measures of mood, somatic symptoms, temperament, illness attitudes, and social support, following up at 1, 3, 6, 9, and 12 months with scales tracking mood and somatic changes.

More than a third of women (34%) never registered clinically relevant signs of psychological or somatic distress during a year of adjuvant treatment and adjustment. Another 15% were temporarily traumatized by the experience, but "recovered promptly and remained well," she reported in a poster displayed at ASCO June 2.

Importantly, the 49% of resilient women did not differ from those with higher psychosocial need in terms of age, marital status, tumor size, treatment modality, or treatment toxicity (nadir hemoglobin and neutrophil count). Mortality was identical, with eight patients in each group dying within 5 years post treatment.

Several factors did distinguish the two groups, including measures of neuroticism, primarily assessed in the study by the Eysenck Personality Questionnaire. Higher scores on the neuroticism scale of the EPQ were strongly, and negatively, correlated with resilience (with a correlation of –.351, P less than.001).

One of the so-called "Big Five" personality traits (openness, conscientiousness, extroversion, agreeableness, and neuroticism), neuroticism basically describes an emotionally reactive, anxious, sensitive, easily rattled temperament, widely believed to be genetic and essentially fixed throughout life.

People who score high on this measure are worriers, somatically focused and more prone than others are to pessimism, anxiety, and depressive symptoms. Resilient patients in the study, then, would be the opposite ... generally calm, optimistic, and not overly sensitive to somatic symptoms.

Other significant findings in the study lent support to the characterization of resilient patients as easy-going, unflappable people. Think of them as "Teflon" rather than "Velcro" responders to major life crises such a diagnosis of cancer and its day-to-day challenges of treatment pain, life disruption, and existential uncertainty.

In the study, they registered lower scores than nonresilient patients on the Illness Behavior Questionnaire scales of anxious concern, disease conviction (hypochondriasis, pain intensity and interference, psychological distress), psychological vs. somatic perception, affective inhibition, and mood disturbance.

Resilient patients perceived higher levels of social support than did their less-resilient peers, but social support was not actually predictive of a resilient psychological outcome. They were also more likely to have received more than 12 years of education and to work more than 20 hours a week – signs, perhaps, of an outward-focused outlook on life.

"Identifying low risk [of psychological distress] may have some important implications," said Dr. Bennett, a postdoctoral fellow in psychology, in an interview from ASCO’s meeting in Chicago. An overabundance of psychological resources for those who do not need them might "undermine [an] individual’s own resources," she noted.

Secondly, it wouldn’t make sense to "squander scarce health resources on those who may not be in need of them and who would not benefit further," if they received counseling or other forms of professional psychosocial care.

If half of patients are so resilient that they tend to do just fine on their own, it’s certainly an observation that deserves more study.

Betsy Bates Freed is a clinical psychologist in Santa Barbara, Calif., and a medical journalist.

Note: Dr. Bennett and her coauthors had no relevant disclosures.

Reflecting a psychological paradigm shift, a number of studies at the American Society of Clinical Oncology 2012 annual meeting focus on individuals’ inherent coping skills, sources of strength, and resilience.

One such study, from Australia, takes the important step of studying resiliency prospectively, drawing important conclusions about which cancer patients are most likely to negotiate the journey just fine, without professional psychological intervention.

Dr. Barbara Kaye Bennett of Prince of Wales Hospital in Sydney led the study of 218 women enrolled just following surgery for early-stage breast cancer. At baseline, she and her associates administered validated measures of mood, somatic symptoms, temperament, illness attitudes, and social support, following up at 1, 3, 6, 9, and 12 months with scales tracking mood and somatic changes.

More than a third of women (34%) never registered clinically relevant signs of psychological or somatic distress during a year of adjuvant treatment and adjustment. Another 15% were temporarily traumatized by the experience, but "recovered promptly and remained well," she reported in a poster displayed at ASCO June 2.

Importantly, the 49% of resilient women did not differ from those with higher psychosocial need in terms of age, marital status, tumor size, treatment modality, or treatment toxicity (nadir hemoglobin and neutrophil count). Mortality was identical, with eight patients in each group dying within 5 years post treatment.

Several factors did distinguish the two groups, including measures of neuroticism, primarily assessed in the study by the Eysenck Personality Questionnaire. Higher scores on the neuroticism scale of the EPQ were strongly, and negatively, correlated with resilience (with a correlation of –.351, P less than.001).

One of the so-called "Big Five" personality traits (openness, conscientiousness, extroversion, agreeableness, and neuroticism), neuroticism basically describes an emotionally reactive, anxious, sensitive, easily rattled temperament, widely believed to be genetic and essentially fixed throughout life.

People who score high on this measure are worriers, somatically focused and more prone than others are to pessimism, anxiety, and depressive symptoms. Resilient patients in the study, then, would be the opposite ... generally calm, optimistic, and not overly sensitive to somatic symptoms.

Other significant findings in the study lent support to the characterization of resilient patients as easy-going, unflappable people. Think of them as "Teflon" rather than "Velcro" responders to major life crises such a diagnosis of cancer and its day-to-day challenges of treatment pain, life disruption, and existential uncertainty.

In the study, they registered lower scores than nonresilient patients on the Illness Behavior Questionnaire scales of anxious concern, disease conviction (hypochondriasis, pain intensity and interference, psychological distress), psychological vs. somatic perception, affective inhibition, and mood disturbance.

Resilient patients perceived higher levels of social support than did their less-resilient peers, but social support was not actually predictive of a resilient psychological outcome. They were also more likely to have received more than 12 years of education and to work more than 20 hours a week – signs, perhaps, of an outward-focused outlook on life.

"Identifying low risk [of psychological distress] may have some important implications," said Dr. Bennett, a postdoctoral fellow in psychology, in an interview from ASCO’s meeting in Chicago. An overabundance of psychological resources for those who do not need them might "undermine [an] individual’s own resources," she noted.

Secondly, it wouldn’t make sense to "squander scarce health resources on those who may not be in need of them and who would not benefit further," if they received counseling or other forms of professional psychosocial care.

If half of patients are so resilient that they tend to do just fine on their own, it’s certainly an observation that deserves more study.

Betsy Bates Freed is a clinical psychologist in Santa Barbara, Calif., and a medical journalist.

Note: Dr. Bennett and her coauthors had no relevant disclosures.

Reflecting a psychological paradigm shift, a number of studies at the American Society of Clinical Oncology 2012 annual meeting focus on individuals’ inherent coping skills, sources of strength, and resilience.

One such study, from Australia, takes the important step of studying resiliency prospectively, drawing important conclusions about which cancer patients are most likely to negotiate the journey just fine, without professional psychological intervention.

Dr. Barbara Kaye Bennett of Prince of Wales Hospital in Sydney led the study of 218 women enrolled just following surgery for early-stage breast cancer. At baseline, she and her associates administered validated measures of mood, somatic symptoms, temperament, illness attitudes, and social support, following up at 1, 3, 6, 9, and 12 months with scales tracking mood and somatic changes.

More than a third of women (34%) never registered clinically relevant signs of psychological or somatic distress during a year of adjuvant treatment and adjustment. Another 15% were temporarily traumatized by the experience, but "recovered promptly and remained well," she reported in a poster displayed at ASCO June 2.

Importantly, the 49% of resilient women did not differ from those with higher psychosocial need in terms of age, marital status, tumor size, treatment modality, or treatment toxicity (nadir hemoglobin and neutrophil count). Mortality was identical, with eight patients in each group dying within 5 years post treatment.

Several factors did distinguish the two groups, including measures of neuroticism, primarily assessed in the study by the Eysenck Personality Questionnaire. Higher scores on the neuroticism scale of the EPQ were strongly, and negatively, correlated with resilience (with a correlation of –.351, P less than.001).

One of the so-called "Big Five" personality traits (openness, conscientiousness, extroversion, agreeableness, and neuroticism), neuroticism basically describes an emotionally reactive, anxious, sensitive, easily rattled temperament, widely believed to be genetic and essentially fixed throughout life.

People who score high on this measure are worriers, somatically focused and more prone than others are to pessimism, anxiety, and depressive symptoms. Resilient patients in the study, then, would be the opposite ... generally calm, optimistic, and not overly sensitive to somatic symptoms.

Other significant findings in the study lent support to the characterization of resilient patients as easy-going, unflappable people. Think of them as "Teflon" rather than "Velcro" responders to major life crises such a diagnosis of cancer and its day-to-day challenges of treatment pain, life disruption, and existential uncertainty.

In the study, they registered lower scores than nonresilient patients on the Illness Behavior Questionnaire scales of anxious concern, disease conviction (hypochondriasis, pain intensity and interference, psychological distress), psychological vs. somatic perception, affective inhibition, and mood disturbance.

Resilient patients perceived higher levels of social support than did their less-resilient peers, but social support was not actually predictive of a resilient psychological outcome. They were also more likely to have received more than 12 years of education and to work more than 20 hours a week – signs, perhaps, of an outward-focused outlook on life.

"Identifying low risk [of psychological distress] may have some important implications," said Dr. Bennett, a postdoctoral fellow in psychology, in an interview from ASCO’s meeting in Chicago. An overabundance of psychological resources for those who do not need them might "undermine [an] individual’s own resources," she noted.

Secondly, it wouldn’t make sense to "squander scarce health resources on those who may not be in need of them and who would not benefit further," if they received counseling or other forms of professional psychosocial care.

If half of patients are so resilient that they tend to do just fine on their own, it’s certainly an observation that deserves more study.

Betsy Bates Freed is a clinical psychologist in Santa Barbara, Calif., and a medical journalist.

Note: Dr. Bennett and her coauthors had no relevant disclosures.

CHICAGO – The antidepressant duloxetine reduces chronic pain from chemotherapy-induced peripheral neuropathy with fewer side effects than with current therapies, according to results of a phase III, double-blind trial.

Among evaluable patients, 59% reported less pain with duloxetine (Cymbalta), compared with 38% with placebo. A pain reduction of 30% or more – a measure considered clinically significant – was reported by 33% and 17%, respectively.

"Duloxetine 60 mg a day is the first drug to be shown to be effective in painful chemotherapy-induced peripheral neuropathy based on the results of a randomized trial," Ellen Lavoie Smith, Ph.D., said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A variety of other agents – including gabapentin and tricyclic antidepressants – have been shown to be effective in treating neuropathic pain and are routinely pressed into service in oncology practice, but have failed to demonstrate efficacy in randomized trials of peripheral neuropathy caused by chemotherapy, she noted.

"Some patients endure this painful neuropathy for months and possibly for as long as years following completion of chemotherapy," she said. "It’s chronic, it’s very distressing and it’s disabling. And there is nothing to date effective in treating this problem."

Duloxetine is approved to treat major depressive disorder, with an additional indication for chronic musculoskeletal pain added in 2010. The safety label was revised in September 2011 to include warnings for severe skin reactions including Stevens-Johnson Syndrome and erythema multiforme.

The Cancer and Leukemia Group B (CALGB) 170601 trial randomized 231 patients with painful neuropathy after receiving single-agent paclitaxel (Taxol) or oxaliplatin (Eloxatin) chemotherapy to duloxetine 30 mg for 1 week and 60 mg for 4 weeks, followed by crossover to placebo after a 1-week washout period or the same regimen in the opposite order. Pain levels were assessed weekly using the Brief Pain Inventory-Short Form (BPI-SF) in 220 patients.

The average change in BPI-SF score, the study’s primary outcome, was -1.09 in patients given duloxetine, compared with –0.33 given placebo (P = .003), reported Dr. Smith, with the University of Michigan, Ann Arbor.

During duloxetine treatment, patients also experienced a significant reduction in the BPI-SF pain interference score, a sum of seven items including interference with general activity, mood, walking, normal work, relations with people, sleep and enjoyment of life. There was no difference in duloxetine efficacy based on the specific neurotoxic chemotherapeutic agent received.

In all, 21% of patients said their pain was cut by at least one-half with duloxetine, while only 9% taking placebo did.

Interestingly, 11% of patients saw their pain increase with the serotonin-norepinephrine reuptake inhibitor, compared with 28% with placebo. The reason for the finding is unclear, Dr. Smith said in an interview.

"Pain is a very complicated thing to study," she said. "There are many things that go into it – psychosocial issues, environmental issues, cultural issues, but again, there may be patients who are more likely to respond to these drugs because their central nervous system isn’t really working normally."

Overall, duloxetine was well tolerated, but was associated with significantly more grade 2 or greater fatigue than placebo (11% vs. 3%; P = .029). Dr. Smith pointed out that the overall incidence of side effects was lower than observed in two studies of diabetes-related peripheral neuropathy, likely because they used the 60 mg dose without the lower 30 mg starting dose.

Dr. Hope Rugo, an oncologist at the University of California, San Francisco, who was not involved in the study, said one of the advantages of duloxetine is the lack of somnolence observed in the study – a side effect that is bothersome to many of her breast cancer patients taking gabapentin for chronic neuropathic pain induced by taxanes or platinum-based therapy.

Press briefing moderator Dr. Nicholas Vogelzang, head of genitourinary cancer at the Nevada Cancer Institute in Las Vegas, echoed those remarks and said that neuropathy is fairly common among his patients treated with platinum-based chemotherapy. Duloxetine is an addition to the oncologist’s armamentarium, he said, adding "I’m certainly going to use this when I get back to the office."

Dr. Smith acknowledged that not everyone responded to duloxetine, but said that the dual serotonin norepinephrine reuptake inhibitor improves compliance with chemotherapy treatment and that most patients saw improved function and quality of life.

Patients with depression were excluded from the trial, so the effect of duloxetine was not simply because of improved mood, she said. Instead, it is thought that the drug eases pain by increasing serotonin and norepinephrine, and that responders may have an abnormality in the way their brain processes pain because of lower levels of these two pain-inhibiting neurotransmitters. Future work will try to determine which patients are most likely to respond to the antidepressant.

CALBG 170601 was supported by the National Cancer Institute division of cancer prevention and Lilly Pharmaceuticals. Dr. Smith reported no conflicts of interest. A coauthor reported research funding from Merck. Dr. Rugo has received research funding from Genentech/Roche, Abraxis BioScience, and Bristol-Myers Squibb.

CHICAGO – The antidepressant duloxetine reduces chronic pain from chemotherapy-induced peripheral neuropathy with fewer side effects than with current therapies, according to results of a phase III, double-blind trial.

Among evaluable patients, 59% reported less pain with duloxetine (Cymbalta), compared with 38% with placebo. A pain reduction of 30% or more – a measure considered clinically significant – was reported by 33% and 17%, respectively.

"Duloxetine 60 mg a day is the first drug to be shown to be effective in painful chemotherapy-induced peripheral neuropathy based on the results of a randomized trial," Ellen Lavoie Smith, Ph.D., said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A variety of other agents – including gabapentin and tricyclic antidepressants – have been shown to be effective in treating neuropathic pain and are routinely pressed into service in oncology practice, but have failed to demonstrate efficacy in randomized trials of peripheral neuropathy caused by chemotherapy, she noted.

"Some patients endure this painful neuropathy for months and possibly for as long as years following completion of chemotherapy," she said. "It’s chronic, it’s very distressing and it’s disabling. And there is nothing to date effective in treating this problem."

Duloxetine is approved to treat major depressive disorder, with an additional indication for chronic musculoskeletal pain added in 2010. The safety label was revised in September 2011 to include warnings for severe skin reactions including Stevens-Johnson Syndrome and erythema multiforme.

The Cancer and Leukemia Group B (CALGB) 170601 trial randomized 231 patients with painful neuropathy after receiving single-agent paclitaxel (Taxol) or oxaliplatin (Eloxatin) chemotherapy to duloxetine 30 mg for 1 week and 60 mg for 4 weeks, followed by crossover to placebo after a 1-week washout period or the same regimen in the opposite order. Pain levels were assessed weekly using the Brief Pain Inventory-Short Form (BPI-SF) in 220 patients.

The average change in BPI-SF score, the study’s primary outcome, was -1.09 in patients given duloxetine, compared with –0.33 given placebo (P = .003), reported Dr. Smith, with the University of Michigan, Ann Arbor.

During duloxetine treatment, patients also experienced a significant reduction in the BPI-SF pain interference score, a sum of seven items including interference with general activity, mood, walking, normal work, relations with people, sleep and enjoyment of life. There was no difference in duloxetine efficacy based on the specific neurotoxic chemotherapeutic agent received.

In all, 21% of patients said their pain was cut by at least one-half with duloxetine, while only 9% taking placebo did.

Interestingly, 11% of patients saw their pain increase with the serotonin-norepinephrine reuptake inhibitor, compared with 28% with placebo. The reason for the finding is unclear, Dr. Smith said in an interview.

"Pain is a very complicated thing to study," she said. "There are many things that go into it – psychosocial issues, environmental issues, cultural issues, but again, there may be patients who are more likely to respond to these drugs because their central nervous system isn’t really working normally."

Overall, duloxetine was well tolerated, but was associated with significantly more grade 2 or greater fatigue than placebo (11% vs. 3%; P = .029). Dr. Smith pointed out that the overall incidence of side effects was lower than observed in two studies of diabetes-related peripheral neuropathy, likely because they used the 60 mg dose without the lower 30 mg starting dose.

Dr. Hope Rugo, an oncologist at the University of California, San Francisco, who was not involved in the study, said one of the advantages of duloxetine is the lack of somnolence observed in the study – a side effect that is bothersome to many of her breast cancer patients taking gabapentin for chronic neuropathic pain induced by taxanes or platinum-based therapy.

Press briefing moderator Dr. Nicholas Vogelzang, head of genitourinary cancer at the Nevada Cancer Institute in Las Vegas, echoed those remarks and said that neuropathy is fairly common among his patients treated with platinum-based chemotherapy. Duloxetine is an addition to the oncologist’s armamentarium, he said, adding "I’m certainly going to use this when I get back to the office."

Dr. Smith acknowledged that not everyone responded to duloxetine, but said that the dual serotonin norepinephrine reuptake inhibitor improves compliance with chemotherapy treatment and that most patients saw improved function and quality of life.

Patients with depression were excluded from the trial, so the effect of duloxetine was not simply because of improved mood, she said. Instead, it is thought that the drug eases pain by increasing serotonin and norepinephrine, and that responders may have an abnormality in the way their brain processes pain because of lower levels of these two pain-inhibiting neurotransmitters. Future work will try to determine which patients are most likely to respond to the antidepressant.

CALBG 170601 was supported by the National Cancer Institute division of cancer prevention and Lilly Pharmaceuticals. Dr. Smith reported no conflicts of interest. A coauthor reported research funding from Merck. Dr. Rugo has received research funding from Genentech/Roche, Abraxis BioScience, and Bristol-Myers Squibb.

CHICAGO – The antidepressant duloxetine reduces chronic pain from chemotherapy-induced peripheral neuropathy with fewer side effects than with current therapies, according to results of a phase III, double-blind trial.

Among evaluable patients, 59% reported less pain with duloxetine (Cymbalta), compared with 38% with placebo. A pain reduction of 30% or more – a measure considered clinically significant – was reported by 33% and 17%, respectively.

"Duloxetine 60 mg a day is the first drug to be shown to be effective in painful chemotherapy-induced peripheral neuropathy based on the results of a randomized trial," Ellen Lavoie Smith, Ph.D., said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A variety of other agents – including gabapentin and tricyclic antidepressants – have been shown to be effective in treating neuropathic pain and are routinely pressed into service in oncology practice, but have failed to demonstrate efficacy in randomized trials of peripheral neuropathy caused by chemotherapy, she noted.

"Some patients endure this painful neuropathy for months and possibly for as long as years following completion of chemotherapy," she said. "It’s chronic, it’s very distressing and it’s disabling. And there is nothing to date effective in treating this problem."

Duloxetine is approved to treat major depressive disorder, with an additional indication for chronic musculoskeletal pain added in 2010. The safety label was revised in September 2011 to include warnings for severe skin reactions including Stevens-Johnson Syndrome and erythema multiforme.

The Cancer and Leukemia Group B (CALGB) 170601 trial randomized 231 patients with painful neuropathy after receiving single-agent paclitaxel (Taxol) or oxaliplatin (Eloxatin) chemotherapy to duloxetine 30 mg for 1 week and 60 mg for 4 weeks, followed by crossover to placebo after a 1-week washout period or the same regimen in the opposite order. Pain levels were assessed weekly using the Brief Pain Inventory-Short Form (BPI-SF) in 220 patients.

The average change in BPI-SF score, the study’s primary outcome, was -1.09 in patients given duloxetine, compared with –0.33 given placebo (P = .003), reported Dr. Smith, with the University of Michigan, Ann Arbor.

During duloxetine treatment, patients also experienced a significant reduction in the BPI-SF pain interference score, a sum of seven items including interference with general activity, mood, walking, normal work, relations with people, sleep and enjoyment of life. There was no difference in duloxetine efficacy based on the specific neurotoxic chemotherapeutic agent received.

In all, 21% of patients said their pain was cut by at least one-half with duloxetine, while only 9% taking placebo did.

Interestingly, 11% of patients saw their pain increase with the serotonin-norepinephrine reuptake inhibitor, compared with 28% with placebo. The reason for the finding is unclear, Dr. Smith said in an interview.

"Pain is a very complicated thing to study," she said. "There are many things that go into it – psychosocial issues, environmental issues, cultural issues, but again, there may be patients who are more likely to respond to these drugs because their central nervous system isn’t really working normally."

Overall, duloxetine was well tolerated, but was associated with significantly more grade 2 or greater fatigue than placebo (11% vs. 3%; P = .029). Dr. Smith pointed out that the overall incidence of side effects was lower than observed in two studies of diabetes-related peripheral neuropathy, likely because they used the 60 mg dose without the lower 30 mg starting dose.

Dr. Hope Rugo, an oncologist at the University of California, San Francisco, who was not involved in the study, said one of the advantages of duloxetine is the lack of somnolence observed in the study – a side effect that is bothersome to many of her breast cancer patients taking gabapentin for chronic neuropathic pain induced by taxanes or platinum-based therapy.

Press briefing moderator Dr. Nicholas Vogelzang, head of genitourinary cancer at the Nevada Cancer Institute in Las Vegas, echoed those remarks and said that neuropathy is fairly common among his patients treated with platinum-based chemotherapy. Duloxetine is an addition to the oncologist’s armamentarium, he said, adding "I’m certainly going to use this when I get back to the office."

Dr. Smith acknowledged that not everyone responded to duloxetine, but said that the dual serotonin norepinephrine reuptake inhibitor improves compliance with chemotherapy treatment and that most patients saw improved function and quality of life.

Patients with depression were excluded from the trial, so the effect of duloxetine was not simply because of improved mood, she said. Instead, it is thought that the drug eases pain by increasing serotonin and norepinephrine, and that responders may have an abnormality in the way their brain processes pain because of lower levels of these two pain-inhibiting neurotransmitters. Future work will try to determine which patients are most likely to respond to the antidepressant.

CALBG 170601 was supported by the National Cancer Institute division of cancer prevention and Lilly Pharmaceuticals. Dr. Smith reported no conflicts of interest. A coauthor reported research funding from Merck. Dr. Rugo has received research funding from Genentech/Roche, Abraxis BioScience, and Bristol-Myers Squibb.

CHICAGO – Two fairly new and expensive drugs for breast cancer were no more effective or safer than a drug that has been used for this disease for over a decade, finds a phase III cooperative group trial among nearly 800 women with chemotherapy-naive locally recurrent or metastatic disease.

The trial pitted the newer nab-paclitaxel (Abraxane) and ixabepilone (Ixempra) against the older paclitaxel (Taxol) as a control, each given weekly, along with bevacizumab (Avastin) given every 2 weeks, as first-line therapy.

Trial results reported at the annual meeting of the American Society of Clinical Oncology showed that progression-free survival was not superior with nab-paclitaxel and was in fact inferior with ixabepilone, translating to a 53% higher risk of progression or death relative to paclitaxel, first author Dr. Hope S. Rugo reported in a press briefing.

Moreover, rates of grade 3 or worse adverse events were higher with both of the newer agents than with the old stand-by.

"These data suggest that similar patients could be appropriately treated with weekly paclitaxel," said Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.

"Interestingly, ixabepilone is an epothilone where preclinical and some clinical data suggest an ability to reverse resistance to the microtubule inhibitors like paclitaxel, and nab-paclitaxel has similar data," she added. "However, in this chemotherapy-naive population, these results showed equivalency or inferiority."

Susan London/IMNG Medical Media

"These are all good drugs, these are all major-league baseball players. I want them all on my team," asserted press briefing moderator Dr. Nicholas Vogelzang, chair and medical director, Developmental Therapeutics Committee, US Oncology, Comprehensive Cancer Centers of Nevada. "And when they are used to treat breast cancer, a patient should be considered for all of them, perhaps in different sequences for different patients."

The trial’s findings do not preclude use of at least nab-paclitaxel in selected patients similar to those studied or in other treatment settings, according to Dr. Rugo.

"Based on our data, it’s very unlikely that [nab-paclitaxel] is superior to paclitaxel, but it could be used as an alternative in patients who had a reason not to receive paclitaxel," such as an allergy to cremophor (paclitaxel’s solvent), or diabetes making it hard to tolerate the steroids needed as premedication, she said. Also, the drug is effective in patients with later-stage metastatic breast cancer or with cancers that have progressed on other taxanes.

Finally, nab-paclitaxel is a useful alternative in the context of drug shortages. "In the setting where paclitaxel is not readily available, nab-paclitaxel could clearly be used in its place," she said.

Of note, however, data have shown that nab-paclitaxel given at a lower dose of 100 mg/m² – one-third lower than the dose used in the trial – is less toxic. Therefore, "in patients in whom nab-paclitaxel is chosen ... we should be using the 100 mg/m² dose," Dr. Rugo recommended.

The trial, formally known as CALGB 40502/NCCTG N063H and sponsored by the National Cancer Institute, randomized 799 patients to open-label treatment with one of the three chemotherapies – paclitaxel (90 mg/m² weekly, the most commonly used dosage schedule), nab-paclitaxel (150 mg/m² weekly), or ixabepilone (16 mg/m² weekly) – plus bevacizumab every 2 weeks.

All chemotherapy was given on a 3-weeks-on, 1-week-off schedule. Patients who had a response or stable disease after six cycles could stop chemotherapy and continue with the bevacizumab alone.

With a median follow-up of 12 months, analyses showed that progression-free survival was no better with nab-paclitaxel (9.2 months; hazard ratio, 1.19; P = .12) and was actually worse with ixabepilone (7.6 months; hazard ratio, 1.53; P less than .0001) than with paclitaxel (10.6 months), Dr. Rugo reported.

The overall rate of grade 3 or worse adverse events was 55% with paclitaxel, compared with 79% with nab-paclitaxel and 59% with ixabepilone.

The rate of grade 3 or worse nonhematologic adverse events was significantly higher with the newer agents than with the older one. "We saw increased peripheral neuropathy in the experimental arms as compared with the control arms as well," Dr. Rugo noted. The rate of grade 3 or worse hematologic events was significantly higher with nab-paclitaxel and significantly lower with ixabepilone.

The findings are likely to remain relevant despite the Food and Drug Administration’s withdrawal of approval for bevacizumab, according to Dr. Rugo. "Interestingly, in our study, we obviously don’t have a control arm without bevacizumab, but the progression-free survival in the control arm was almost identical to ECOG 2100," which compared paclitaxel with and without bevacizumab. "And I think for that reason, it’s unlikely that there would be a big difference if you redid the whole study without bevacizumab," she said.

Dr. Rugo said she receives research funding from Abraxis BioScience, Bristol-Myers Squibb, and Roche/Genentech. Dr. Vogelzang said he is a consultant to Amgen, AVEO, Bayer, Celgene(U), Dendreon, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, Johnson & Johnson, Keryx, Medscape, Novartis, Oncogenex, Pfizer, and Wilex; he receives honoraria from Amgen, Bayer, Clinical Care Options, Genentech, Imedex, Lilly, Lippincott, Williams, and Wilkins, Medscape, Novartis, Onyx, Pfizer, and Veridex; and he receives research funding from Algeta, Pfizer, Progenics, and Tokai Pharmaceuticals.

CHICAGO – Two fairly new and expensive drugs for breast cancer were no more effective or safer than a drug that has been used for this disease for over a decade, finds a phase III cooperative group trial among nearly 800 women with chemotherapy-naive locally recurrent or metastatic disease.

The trial pitted the newer nab-paclitaxel (Abraxane) and ixabepilone (Ixempra) against the older paclitaxel (Taxol) as a control, each given weekly, along with bevacizumab (Avastin) given every 2 weeks, as first-line therapy.

Trial results reported at the annual meeting of the American Society of Clinical Oncology showed that progression-free survival was not superior with nab-paclitaxel and was in fact inferior with ixabepilone, translating to a 53% higher risk of progression or death relative to paclitaxel, first author Dr. Hope S. Rugo reported in a press briefing.

Moreover, rates of grade 3 or worse adverse events were higher with both of the newer agents than with the old stand-by.

"These data suggest that similar patients could be appropriately treated with weekly paclitaxel," said Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.

"Interestingly, ixabepilone is an epothilone where preclinical and some clinical data suggest an ability to reverse resistance to the microtubule inhibitors like paclitaxel, and nab-paclitaxel has similar data," she added. "However, in this chemotherapy-naive population, these results showed equivalency or inferiority."

Susan London/IMNG Medical Media

"These are all good drugs, these are all major-league baseball players. I want them all on my team," asserted press briefing moderator Dr. Nicholas Vogelzang, chair and medical director, Developmental Therapeutics Committee, US Oncology, Comprehensive Cancer Centers of Nevada. "And when they are used to treat breast cancer, a patient should be considered for all of them, perhaps in different sequences for different patients."

The trial’s findings do not preclude use of at least nab-paclitaxel in selected patients similar to those studied or in other treatment settings, according to Dr. Rugo.

"Based on our data, it’s very unlikely that [nab-paclitaxel] is superior to paclitaxel, but it could be used as an alternative in patients who had a reason not to receive paclitaxel," such as an allergy to cremophor (paclitaxel’s solvent), or diabetes making it hard to tolerate the steroids needed as premedication, she said. Also, the drug is effective in patients with later-stage metastatic breast cancer or with cancers that have progressed on other taxanes.

Finally, nab-paclitaxel is a useful alternative in the context of drug shortages. "In the setting where paclitaxel is not readily available, nab-paclitaxel could clearly be used in its place," she said.

Of note, however, data have shown that nab-paclitaxel given at a lower dose of 100 mg/m² – one-third lower than the dose used in the trial – is less toxic. Therefore, "in patients in whom nab-paclitaxel is chosen ... we should be using the 100 mg/m² dose," Dr. Rugo recommended.

The trial, formally known as CALGB 40502/NCCTG N063H and sponsored by the National Cancer Institute, randomized 799 patients to open-label treatment with one of the three chemotherapies – paclitaxel (90 mg/m² weekly, the most commonly used dosage schedule), nab-paclitaxel (150 mg/m² weekly), or ixabepilone (16 mg/m² weekly) – plus bevacizumab every 2 weeks.

All chemotherapy was given on a 3-weeks-on, 1-week-off schedule. Patients who had a response or stable disease after six cycles could stop chemotherapy and continue with the bevacizumab alone.

With a median follow-up of 12 months, analyses showed that progression-free survival was no better with nab-paclitaxel (9.2 months; hazard ratio, 1.19; P = .12) and was actually worse with ixabepilone (7.6 months; hazard ratio, 1.53; P less than .0001) than with paclitaxel (10.6 months), Dr. Rugo reported.

The overall rate of grade 3 or worse adverse events was 55% with paclitaxel, compared with 79% with nab-paclitaxel and 59% with ixabepilone.

The rate of grade 3 or worse nonhematologic adverse events was significantly higher with the newer agents than with the older one. "We saw increased peripheral neuropathy in the experimental arms as compared with the control arms as well," Dr. Rugo noted. The rate of grade 3 or worse hematologic events was significantly higher with nab-paclitaxel and significantly lower with ixabepilone.

The findings are likely to remain relevant despite the Food and Drug Administration’s withdrawal of approval for bevacizumab, according to Dr. Rugo. "Interestingly, in our study, we obviously don’t have a control arm without bevacizumab, but the progression-free survival in the control arm was almost identical to ECOG 2100," which compared paclitaxel with and without bevacizumab. "And I think for that reason, it’s unlikely that there would be a big difference if you redid the whole study without bevacizumab," she said.

Dr. Rugo said she receives research funding from Abraxis BioScience, Bristol-Myers Squibb, and Roche/Genentech. Dr. Vogelzang said he is a consultant to Amgen, AVEO, Bayer, Celgene(U), Dendreon, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, Johnson & Johnson, Keryx, Medscape, Novartis, Oncogenex, Pfizer, and Wilex; he receives honoraria from Amgen, Bayer, Clinical Care Options, Genentech, Imedex, Lilly, Lippincott, Williams, and Wilkins, Medscape, Novartis, Onyx, Pfizer, and Veridex; and he receives research funding from Algeta, Pfizer, Progenics, and Tokai Pharmaceuticals.

CHICAGO – Two fairly new and expensive drugs for breast cancer were no more effective or safer than a drug that has been used for this disease for over a decade, finds a phase III cooperative group trial among nearly 800 women with chemotherapy-naive locally recurrent or metastatic disease.

The trial pitted the newer nab-paclitaxel (Abraxane) and ixabepilone (Ixempra) against the older paclitaxel (Taxol) as a control, each given weekly, along with bevacizumab (Avastin) given every 2 weeks, as first-line therapy.

Trial results reported at the annual meeting of the American Society of Clinical Oncology showed that progression-free survival was not superior with nab-paclitaxel and was in fact inferior with ixabepilone, translating to a 53% higher risk of progression or death relative to paclitaxel, first author Dr. Hope S. Rugo reported in a press briefing.

Moreover, rates of grade 3 or worse adverse events were higher with both of the newer agents than with the old stand-by.

"These data suggest that similar patients could be appropriately treated with weekly paclitaxel," said Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.

"Interestingly, ixabepilone is an epothilone where preclinical and some clinical data suggest an ability to reverse resistance to the microtubule inhibitors like paclitaxel, and nab-paclitaxel has similar data," she added. "However, in this chemotherapy-naive population, these results showed equivalency or inferiority."

Susan London/IMNG Medical Media

"These are all good drugs, these are all major-league baseball players. I want them all on my team," asserted press briefing moderator Dr. Nicholas Vogelzang, chair and medical director, Developmental Therapeutics Committee, US Oncology, Comprehensive Cancer Centers of Nevada. "And when they are used to treat breast cancer, a patient should be considered for all of them, perhaps in different sequences for different patients."

The trial’s findings do not preclude use of at least nab-paclitaxel in selected patients similar to those studied or in other treatment settings, according to Dr. Rugo.

"Based on our data, it’s very unlikely that [nab-paclitaxel] is superior to paclitaxel, but it could be used as an alternative in patients who had a reason not to receive paclitaxel," such as an allergy to cremophor (paclitaxel’s solvent), or diabetes making it hard to tolerate the steroids needed as premedication, she said. Also, the drug is effective in patients with later-stage metastatic breast cancer or with cancers that have progressed on other taxanes.

Finally, nab-paclitaxel is a useful alternative in the context of drug shortages. "In the setting where paclitaxel is not readily available, nab-paclitaxel could clearly be used in its place," she said.

Of note, however, data have shown that nab-paclitaxel given at a lower dose of 100 mg/m² – one-third lower than the dose used in the trial – is less toxic. Therefore, "in patients in whom nab-paclitaxel is chosen ... we should be using the 100 mg/m² dose," Dr. Rugo recommended.

The trial, formally known as CALGB 40502/NCCTG N063H and sponsored by the National Cancer Institute, randomized 799 patients to open-label treatment with one of the three chemotherapies – paclitaxel (90 mg/m² weekly, the most commonly used dosage schedule), nab-paclitaxel (150 mg/m² weekly), or ixabepilone (16 mg/m² weekly) – plus bevacizumab every 2 weeks.

All chemotherapy was given on a 3-weeks-on, 1-week-off schedule. Patients who had a response or stable disease after six cycles could stop chemotherapy and continue with the bevacizumab alone.

With a median follow-up of 12 months, analyses showed that progression-free survival was no better with nab-paclitaxel (9.2 months; hazard ratio, 1.19; P = .12) and was actually worse with ixabepilone (7.6 months; hazard ratio, 1.53; P less than .0001) than with paclitaxel (10.6 months), Dr. Rugo reported.

The overall rate of grade 3 or worse adverse events was 55% with paclitaxel, compared with 79% with nab-paclitaxel and 59% with ixabepilone.

The rate of grade 3 or worse nonhematologic adverse events was significantly higher with the newer agents than with the older one. "We saw increased peripheral neuropathy in the experimental arms as compared with the control arms as well," Dr. Rugo noted. The rate of grade 3 or worse hematologic events was significantly higher with nab-paclitaxel and significantly lower with ixabepilone.

The findings are likely to remain relevant despite the Food and Drug Administration’s withdrawal of approval for bevacizumab, according to Dr. Rugo. "Interestingly, in our study, we obviously don’t have a control arm without bevacizumab, but the progression-free survival in the control arm was almost identical to ECOG 2100," which compared paclitaxel with and without bevacizumab. "And I think for that reason, it’s unlikely that there would be a big difference if you redid the whole study without bevacizumab," she said.

Dr. Rugo said she receives research funding from Abraxis BioScience, Bristol-Myers Squibb, and Roche/Genentech. Dr. Vogelzang said he is a consultant to Amgen, AVEO, Bayer, Celgene(U), Dendreon, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, Johnson & Johnson, Keryx, Medscape, Novartis, Oncogenex, Pfizer, and Wilex; he receives honoraria from Amgen, Bayer, Clinical Care Options, Genentech, Imedex, Lilly, Lippincott, Williams, and Wilkins, Medscape, Novartis, Onyx, Pfizer, and Veridex; and he receives research funding from Algeta, Pfizer, Progenics, and Tokai Pharmaceuticals.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – T-DM1, an investigational antibody-drug conjugate, is more efficacious and less toxic than standard treatment for advanced HER2-positive breast cancer, finds the randomized phase III EMILIA trial.

In the nearly 1,000 women studied, all of whom had previously received a taxane and trastuzumab, T-DM1 reduced the risk of progression-free survival events by 35% and the risk of death by 38% when compared with capecitabine plus lapatinib, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In addition, the rate of grade 3 or higher adverse events was about one-third lower with T-DM1 than with the combination therapy (41% vs. 57%).

"T-DM1 is a brand new way of treating HER2-positive breast cancer. I think it’s the first of many antibody-drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody," lead investigator Dr. Kimberly L. Blackwell predicted in a press briefing. "I think this will offer a very important therapeutic option for patients with HER2-positive metastatic breast cancer."

The manufacturer is preparing a filing with the Food and Drug Administration for approval of T-DM1 that will likely cover use in the same population eligible for the trial, namely, women in the first, second, and third lines of treatment, she added.

“I congratulate Dr. Blackwell and her colleagues for designing, implementing, and analyzing a phase III clinical trial that convincingly demonstrates the superiority of T-DM1 therapy compared to a standard reference regimen of capecitabine plus lapatinib in women with HER2-positive metastatic breast cancer that is refractory to trastuzumab,” said discussant Dr. Louis M. Weiner, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington. “Stated simply, T-DM1 really works in this patient population. The improved survival is particularly notable since effective palliative treatment of metastatic breast cancer has rarely been associated with substantially improved survival in the refractory setting.”

“Like any significant new finding, the success of the EMILIA trial raises many new avenues for further exploration,” Dr. Weiner added. “It will be important to define new clinical niches for T-DM1 therapy in metastatic HER2-positive breast cancer with an additional emphasis on defining effective T-DM1–based drug combinations; such combinations might include chemotherapy agents, other antibodies, targeted agents against the epidermal growth factor receptor network components or other targets, or even immune therapies that liberate nascent antitumor immune responses. While it is perhaps still early, future studies to determine the value of T-DM1 use in the adjuvant setting will be warranted.”

In an interview Dr. Andrew D. Seidman of the Memorial Sloan-Kettering Cancer Center in New York praised the drug’s mechanism of action, saying, “this is a way to teach an old dog new tricks, so to speak. We have a smart bomb: We have trained trastuzumab to deliver a toxic moiety to cancer cells. It’s precision medicine, and it’s superior to the combination of two oral medications that are the current standard of treatment.”

T-DM1 "keeps breast cancer from progressing and, at least in an early analysis, appears likely to prolong survival in HER2-positive metastatic breast cancer," Dr. Seidman added. "So this is, for me, good news. I’ve had hands-on experience with the drug in our own clinical trials at Memorial Sloan-Kettering. It’s kind and gentle. So it’s very welcome."

The investigators enrolled in EMILIA 991 women with locally advanced or metastatic HER2-positive breast cancer that had been previously treated with a taxane and trastuzumab (Herceptin).

They were assigned evenly to intravenous T-DM1 (also known as trastuzumab emtansine) once every 3 weeks, or to oral, standard-dose capecitabine (Xeloda) and lapatinib (Tykerb), currently the only approved combination for trastuzumab-refractory HER2-positive metastatic breast cancer. There was no planned cross-over at progression.

Median progression-free survival, one of the trial’s primary efficacy end points, was 9.6 months with T-DM1, compared with 6.4 months with capecitabine-lapatinib (hazard ratio, 0.65; P less than .0001). Results were largely the same across patient subgroups, except for an apparent lack of benefit among women aged 65 years or older.

The progression-free survival findings triggered an interim analysis of overall survival, the trial’s other primary efficacy end point, according to Dr. Blackwell, who is a professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University, Durham, N.C.

Although T-DM1 also improved median overall survival (not reached vs. 23.3 months; hazard ratio, 0.62; P less than .0005), the difference fell just short of the predefined statistical threshold for stopping the trial.

In addition, T-DM1 was superior to capecitabine-lapatinib in terms of the overall response rate and the duration of response.

T-DM1 was associated with higher rates of grade 3 or worse thrombocytopenia (12.9% vs. 0.2%) and elevations of aspartate aminotransferase (4.3% vs. 0.8%) and alanine aminotransferase (2.9% vs. 1.4%); notably, however, cardiac toxicity (an adverse effect seen with trastuzumab) was not elevated with T-DM1. On the other hand, capecitabine-lapatinib was associated with higher rates of diarrhea (20.7% vs. 1.6%), hand-foot syndrome (16.4% vs. 0%), and vomiting (4.5% vs. 0.8%).

Patients given capecitabine-lapatinib were significantly more likely to discontinue treatment because of toxicity, according to Dr. Blackwell.

"We would hope that these data would support the availability of the drug for patients faced with HER2-positive breast cancer," she concluded.

Dr. Blackwell disclosed no relevant conflicts of interest. The trial was sponsored by Genentech, manufacturer of T-DM1. Dr. Seidman disclosed that he is a consultant to Enzon and Wyeth, and receives honoraria from Celgene, Genentech, and Genomic Health. Dr. Weiner disclosed that he is a consultant to Abbott Laboratories, Celldex, Johnson and Johnson, Merrimack, Samsung Advanced Institute of Technology, and Symphogen; owns stock in Celldex and Merrimack; receives honoraria from Bristol-Myers Squibb; and receives research funding from Samsung Advanced Institute of Technology.

*This article was updated June 4, 2012.

CHICAGO – T-DM1, an investigational antibody-drug conjugate, is more efficacious and less toxic than standard treatment for advanced HER2-positive breast cancer, finds the randomized phase III EMILIA trial.

In the nearly 1,000 women studied, all of whom had previously received a taxane and trastuzumab, T-DM1 reduced the risk of progression-free survival events by 35% and the risk of death by 38% when compared with capecitabine plus lapatinib, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In addition, the rate of grade 3 or higher adverse events was about one-third lower with T-DM1 than with the combination therapy (41% vs. 57%).

"T-DM1 is a brand new way of treating HER2-positive breast cancer. I think it’s the first of many antibody-drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody," lead investigator Dr. Kimberly L. Blackwell predicted in a press briefing. "I think this will offer a very important therapeutic option for patients with HER2-positive metastatic breast cancer."

The manufacturer is preparing a filing with the Food and Drug Administration for approval of T-DM1 that will likely cover use in the same population eligible for the trial, namely, women in the first, second, and third lines of treatment, she added.

“I congratulate Dr. Blackwell and her colleagues for designing, implementing, and analyzing a phase III clinical trial that convincingly demonstrates the superiority of T-DM1 therapy compared to a standard reference regimen of capecitabine plus lapatinib in women with HER2-positive metastatic breast cancer that is refractory to trastuzumab,” said discussant Dr. Louis M. Weiner, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington. “Stated simply, T-DM1 really works in this patient population. The improved survival is particularly notable since effective palliative treatment of metastatic breast cancer has rarely been associated with substantially improved survival in the refractory setting.”

“Like any significant new finding, the success of the EMILIA trial raises many new avenues for further exploration,” Dr. Weiner added. “It will be important to define new clinical niches for T-DM1 therapy in metastatic HER2-positive breast cancer with an additional emphasis on defining effective T-DM1–based drug combinations; such combinations might include chemotherapy agents, other antibodies, targeted agents against the epidermal growth factor receptor network components or other targets, or even immune therapies that liberate nascent antitumor immune responses. While it is perhaps still early, future studies to determine the value of T-DM1 use in the adjuvant setting will be warranted.”

In an interview Dr. Andrew D. Seidman of the Memorial Sloan-Kettering Cancer Center in New York praised the drug’s mechanism of action, saying, “this is a way to teach an old dog new tricks, so to speak. We have a smart bomb: We have trained trastuzumab to deliver a toxic moiety to cancer cells. It’s precision medicine, and it’s superior to the combination of two oral medications that are the current standard of treatment.”

T-DM1 "keeps breast cancer from progressing and, at least in an early analysis, appears likely to prolong survival in HER2-positive metastatic breast cancer," Dr. Seidman added. "So this is, for me, good news. I’ve had hands-on experience with the drug in our own clinical trials at Memorial Sloan-Kettering. It’s kind and gentle. So it’s very welcome."

The investigators enrolled in EMILIA 991 women with locally advanced or metastatic HER2-positive breast cancer that had been previously treated with a taxane and trastuzumab (Herceptin).

They were assigned evenly to intravenous T-DM1 (also known as trastuzumab emtansine) once every 3 weeks, or to oral, standard-dose capecitabine (Xeloda) and lapatinib (Tykerb), currently the only approved combination for trastuzumab-refractory HER2-positive metastatic breast cancer. There was no planned cross-over at progression.

Median progression-free survival, one of the trial’s primary efficacy end points, was 9.6 months with T-DM1, compared with 6.4 months with capecitabine-lapatinib (hazard ratio, 0.65; P less than .0001). Results were largely the same across patient subgroups, except for an apparent lack of benefit among women aged 65 years or older.

The progression-free survival findings triggered an interim analysis of overall survival, the trial’s other primary efficacy end point, according to Dr. Blackwell, who is a professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University, Durham, N.C.

Although T-DM1 also improved median overall survival (not reached vs. 23.3 months; hazard ratio, 0.62; P less than .0005), the difference fell just short of the predefined statistical threshold for stopping the trial.

In addition, T-DM1 was superior to capecitabine-lapatinib in terms of the overall response rate and the duration of response.

T-DM1 was associated with higher rates of grade 3 or worse thrombocytopenia (12.9% vs. 0.2%) and elevations of aspartate aminotransferase (4.3% vs. 0.8%) and alanine aminotransferase (2.9% vs. 1.4%); notably, however, cardiac toxicity (an adverse effect seen with trastuzumab) was not elevated with T-DM1. On the other hand, capecitabine-lapatinib was associated with higher rates of diarrhea (20.7% vs. 1.6%), hand-foot syndrome (16.4% vs. 0%), and vomiting (4.5% vs. 0.8%).

Patients given capecitabine-lapatinib were significantly more likely to discontinue treatment because of toxicity, according to Dr. Blackwell.

"We would hope that these data would support the availability of the drug for patients faced with HER2-positive breast cancer," she concluded.

Dr. Blackwell disclosed no relevant conflicts of interest. The trial was sponsored by Genentech, manufacturer of T-DM1. Dr. Seidman disclosed that he is a consultant to Enzon and Wyeth, and receives honoraria from Celgene, Genentech, and Genomic Health. Dr. Weiner disclosed that he is a consultant to Abbott Laboratories, Celldex, Johnson and Johnson, Merrimack, Samsung Advanced Institute of Technology, and Symphogen; owns stock in Celldex and Merrimack; receives honoraria from Bristol-Myers Squibb; and receives research funding from Samsung Advanced Institute of Technology.

*This article was updated June 4, 2012.

CHICAGO – T-DM1, an investigational antibody-drug conjugate, is more efficacious and less toxic than standard treatment for advanced HER2-positive breast cancer, finds the randomized phase III EMILIA trial.

In the nearly 1,000 women studied, all of whom had previously received a taxane and trastuzumab, T-DM1 reduced the risk of progression-free survival events by 35% and the risk of death by 38% when compared with capecitabine plus lapatinib, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In addition, the rate of grade 3 or higher adverse events was about one-third lower with T-DM1 than with the combination therapy (41% vs. 57%).

"T-DM1 is a brand new way of treating HER2-positive breast cancer. I think it’s the first of many antibody-drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody," lead investigator Dr. Kimberly L. Blackwell predicted in a press briefing. "I think this will offer a very important therapeutic option for patients with HER2-positive metastatic breast cancer."

The manufacturer is preparing a filing with the Food and Drug Administration for approval of T-DM1 that will likely cover use in the same population eligible for the trial, namely, women in the first, second, and third lines of treatment, she added.

“I congratulate Dr. Blackwell and her colleagues for designing, implementing, and analyzing a phase III clinical trial that convincingly demonstrates the superiority of T-DM1 therapy compared to a standard reference regimen of capecitabine plus lapatinib in women with HER2-positive metastatic breast cancer that is refractory to trastuzumab,” said discussant Dr. Louis M. Weiner, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington. “Stated simply, T-DM1 really works in this patient population. The improved survival is particularly notable since effective palliative treatment of metastatic breast cancer has rarely been associated with substantially improved survival in the refractory setting.”

“Like any significant new finding, the success of the EMILIA trial raises many new avenues for further exploration,” Dr. Weiner added. “It will be important to define new clinical niches for T-DM1 therapy in metastatic HER2-positive breast cancer with an additional emphasis on defining effective T-DM1–based drug combinations; such combinations might include chemotherapy agents, other antibodies, targeted agents against the epidermal growth factor receptor network components or other targets, or even immune therapies that liberate nascent antitumor immune responses. While it is perhaps still early, future studies to determine the value of T-DM1 use in the adjuvant setting will be warranted.”

In an interview Dr. Andrew D. Seidman of the Memorial Sloan-Kettering Cancer Center in New York praised the drug’s mechanism of action, saying, “this is a way to teach an old dog new tricks, so to speak. We have a smart bomb: We have trained trastuzumab to deliver a toxic moiety to cancer cells. It’s precision medicine, and it’s superior to the combination of two oral medications that are the current standard of treatment.”

T-DM1 "keeps breast cancer from progressing and, at least in an early analysis, appears likely to prolong survival in HER2-positive metastatic breast cancer," Dr. Seidman added. "So this is, for me, good news. I’ve had hands-on experience with the drug in our own clinical trials at Memorial Sloan-Kettering. It’s kind and gentle. So it’s very welcome."

The investigators enrolled in EMILIA 991 women with locally advanced or metastatic HER2-positive breast cancer that had been previously treated with a taxane and trastuzumab (Herceptin).

They were assigned evenly to intravenous T-DM1 (also known as trastuzumab emtansine) once every 3 weeks, or to oral, standard-dose capecitabine (Xeloda) and lapatinib (Tykerb), currently the only approved combination for trastuzumab-refractory HER2-positive metastatic breast cancer. There was no planned cross-over at progression.

Median progression-free survival, one of the trial’s primary efficacy end points, was 9.6 months with T-DM1, compared with 6.4 months with capecitabine-lapatinib (hazard ratio, 0.65; P less than .0001). Results were largely the same across patient subgroups, except for an apparent lack of benefit among women aged 65 years or older.

The progression-free survival findings triggered an interim analysis of overall survival, the trial’s other primary efficacy end point, according to Dr. Blackwell, who is a professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University, Durham, N.C.

Although T-DM1 also improved median overall survival (not reached vs. 23.3 months; hazard ratio, 0.62; P less than .0005), the difference fell just short of the predefined statistical threshold for stopping the trial.

In addition, T-DM1 was superior to capecitabine-lapatinib in terms of the overall response rate and the duration of response.

T-DM1 was associated with higher rates of grade 3 or worse thrombocytopenia (12.9% vs. 0.2%) and elevations of aspartate aminotransferase (4.3% vs. 0.8%) and alanine aminotransferase (2.9% vs. 1.4%); notably, however, cardiac toxicity (an adverse effect seen with trastuzumab) was not elevated with T-DM1. On the other hand, capecitabine-lapatinib was associated with higher rates of diarrhea (20.7% vs. 1.6%), hand-foot syndrome (16.4% vs. 0%), and vomiting (4.5% vs. 0.8%).

Patients given capecitabine-lapatinib were significantly more likely to discontinue treatment because of toxicity, according to Dr. Blackwell.

"We would hope that these data would support the availability of the drug for patients faced with HER2-positive breast cancer," she concluded.

Dr. Blackwell disclosed no relevant conflicts of interest. The trial was sponsored by Genentech, manufacturer of T-DM1. Dr. Seidman disclosed that he is a consultant to Enzon and Wyeth, and receives honoraria from Celgene, Genentech, and Genomic Health. Dr. Weiner disclosed that he is a consultant to Abbott Laboratories, Celldex, Johnson and Johnson, Merrimack, Samsung Advanced Institute of Technology, and Symphogen; owns stock in Celldex and Merrimack; receives honoraria from Bristol-Myers Squibb; and receives research funding from Samsung Advanced Institute of Technology.

*This article was updated June 4, 2012.

The American College of Radiology’s Imaging Network and the Eastern Cooperative Oncology Group have completed their merger, which was first announced in March 2011.

As of May 17, the two groups will be known as the ECOG-ACRIN Cancer Research Group. The merger became official when they completed and approved a constitution that fully integrates the governance, administrative, and scientific components of both groups.

The new ECOG-ACRIN group comprises nearly 650 institutions and 6,000 individuals from a variety of disciplines.

The Eastern Cooperative Oncology Group was one of the first clinical trial cooperative groups sponsored by the National Cancer Institute. Now, it claims to be one of the largest cancer research organizations in the United States.

The American College of Radiology’s Imaging Network has a network of investigators from 100 academic and community-based facilities in the United States and overseas.

The merger is part of an ongoing process to streamline and consolidate the NCI cooperative groups. The overhaul was spurred by a 2010 Institute of Medicine report that found the NCI clinical trials enterprise had become unwieldy. Cooperative groups also were finding themselves increasingly in the position of competing for the same limited amount of resources for cancer research.

In a joint statement issued upon completion of the merger, ECOG-ACRIN cochairs Dr. Robert L. Comis of Drexel University and Dr. Mitchell L. Schnall of the University of Pennsylvania, both in Philadelphia, said that the new group "establishes for the public and private sectors one organizational structure capable of studying the entire cancer care pathway – prevention and screening, surveillance, early detection, staging, diagnosis, treatment, follow-up, and survivorship."

The two groups also believe that they will be stronger together than they would have been individually, said the joint statement. "For example, our core pathology and imaging scientists, and their associated laboratories and extensive IT infrastructures, make it entirely possible for the Group to integrate large data sets required for biomarker-driven science," the statement said.

Dr. Comis is also chairman of the Coalition of Cancer Cooperative Groups.

When the merger was announced in 2011, the two groups said that the new entity would focus on three main areas: early detection and diagnosis; biomarker-driven phase II and phase III therapeutic studies; and "genetic, molecular, and imaging marker research to predict and monitor treatment response."

The newly merged group said that it expects to start enrolling patients in joint clinical trials soon.

The American College of Radiology’s Imaging Network and the Eastern Cooperative Oncology Group have completed their merger, which was first announced in March 2011.

As of May 17, the two groups will be known as the ECOG-ACRIN Cancer Research Group. The merger became official when they completed and approved a constitution that fully integrates the governance, administrative, and scientific components of both groups.

The new ECOG-ACRIN group comprises nearly 650 institutions and 6,000 individuals from a variety of disciplines.

The Eastern Cooperative Oncology Group was one of the first clinical trial cooperative groups sponsored by the National Cancer Institute. Now, it claims to be one of the largest cancer research organizations in the United States.

The American College of Radiology’s Imaging Network has a network of investigators from 100 academic and community-based facilities in the United States and overseas.

The merger is part of an ongoing process to streamline and consolidate the NCI cooperative groups. The overhaul was spurred by a 2010 Institute of Medicine report that found the NCI clinical trials enterprise had become unwieldy. Cooperative groups also were finding themselves increasingly in the position of competing for the same limited amount of resources for cancer research.

In a joint statement issued upon completion of the merger, ECOG-ACRIN cochairs Dr. Robert L. Comis of Drexel University and Dr. Mitchell L. Schnall of the University of Pennsylvania, both in Philadelphia, said that the new group "establishes for the public and private sectors one organizational structure capable of studying the entire cancer care pathway – prevention and screening, surveillance, early detection, staging, diagnosis, treatment, follow-up, and survivorship."

The two groups also believe that they will be stronger together than they would have been individually, said the joint statement. "For example, our core pathology and imaging scientists, and their associated laboratories and extensive IT infrastructures, make it entirely possible for the Group to integrate large data sets required for biomarker-driven science," the statement said.

Dr. Comis is also chairman of the Coalition of Cancer Cooperative Groups.

When the merger was announced in 2011, the two groups said that the new entity would focus on three main areas: early detection and diagnosis; biomarker-driven phase II and phase III therapeutic studies; and "genetic, molecular, and imaging marker research to predict and monitor treatment response."

The newly merged group said that it expects to start enrolling patients in joint clinical trials soon.

The American College of Radiology’s Imaging Network and the Eastern Cooperative Oncology Group have completed their merger, which was first announced in March 2011.

As of May 17, the two groups will be known as the ECOG-ACRIN Cancer Research Group. The merger became official when they completed and approved a constitution that fully integrates the governance, administrative, and scientific components of both groups.

The new ECOG-ACRIN group comprises nearly 650 institutions and 6,000 individuals from a variety of disciplines.

The Eastern Cooperative Oncology Group was one of the first clinical trial cooperative groups sponsored by the National Cancer Institute. Now, it claims to be one of the largest cancer research organizations in the United States.

The American College of Radiology’s Imaging Network has a network of investigators from 100 academic and community-based facilities in the United States and overseas.

The merger is part of an ongoing process to streamline and consolidate the NCI cooperative groups. The overhaul was spurred by a 2010 Institute of Medicine report that found the NCI clinical trials enterprise had become unwieldy. Cooperative groups also were finding themselves increasingly in the position of competing for the same limited amount of resources for cancer research.

In a joint statement issued upon completion of the merger, ECOG-ACRIN cochairs Dr. Robert L. Comis of Drexel University and Dr. Mitchell L. Schnall of the University of Pennsylvania, both in Philadelphia, said that the new group "establishes for the public and private sectors one organizational structure capable of studying the entire cancer care pathway – prevention and screening, surveillance, early detection, staging, diagnosis, treatment, follow-up, and survivorship."

The two groups also believe that they will be stronger together than they would have been individually, said the joint statement. "For example, our core pathology and imaging scientists, and their associated laboratories and extensive IT infrastructures, make it entirely possible for the Group to integrate large data sets required for biomarker-driven science," the statement said.

Dr. Comis is also chairman of the Coalition of Cancer Cooperative Groups.

When the merger was announced in 2011, the two groups said that the new entity would focus on three main areas: early detection and diagnosis; biomarker-driven phase II and phase III therapeutic studies; and "genetic, molecular, and imaging marker research to predict and monitor treatment response."

The newly merged group said that it expects to start enrolling patients in joint clinical trials soon.