SABCS 2012

SAN ANTONIO – A lower-dose, briefer radiotherapy regimen than is standard for early-stage breast cancer in the U.S. demonstrated comparable efficacy with fewer side effects at 10 years of follow-up in a pair of landmark U.K. studies.

"Long-term follow-up confirms that a lower total dose of radiation in fewer, slightly larger fractions delivered over a shorter treatment time is at least as safe and effective as standard 5-week schedules of curative radiotherapy in women with early breast cancer," Dr. John R. Yarnold declared in presenting the latest data from the U.K. START (Standardization of Breast Radiotherapy) trials at the annual San Antonio Breast Cancer Symposium.

The historical standard of care for radiotherapy in patients with surgically excised early breast cancer is 50 Gy delivered in 25 fractions of 2.0 Gy each over the course of 5 weeks. That’s still standard practice in the United States.

In the United Kingdom, however, the standard nationwide is 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Radiologists term this "hypofractionation": delivering a lower total dose of radiation using fewer but larger fractions. Hypofractionation has standard practice in the United Kingdom since the National Institute for Health and Clinical Excellence–issued guidelines to that effect in 2009. Those guidelines were based in large part on the earlier, highly favorable 5-year outcomes of START A (Lancet Oncology 2008;9:331-41) and START B (Lancet 2008;371:1098-107).

The START investigators deemed it essential to conduct the new 10-year analysis because adverse effects of radiotherapy given for breast cancer can arise after the 5-year mark. Also, it was important to learn whether the early antitumor effects of hypofractionated radiotherapy persisted, explained Dr. Yarnold, professor of clinical oncology at the Institute of Cancer Research, London.

The two key findings at the 10-year mark of START are, first, that both breast cancer and the dose-limiting normal tissues respond similarly to fraction size, so there’s no advantage in continuing the 2 Gy fractions that have historically been the international standard; and, second, that a 15-fraction/3-week schedule is gentler on normal tissues and comparable in antitumor efficacy to a 25-fraction/5-week regimen.

The clinical implications are clear, Dr. Yarnold emphasized: "Patients can safely be treated to a lower total dose with fewer fractions than the historical standard of 50 Gy and 25 fractions. There are no detrimental effects of hypofractionation noted in any of the subgroups studied."

The 10-year rate of moderate to marked adverse treatment effects on normal tissues in START A survivors who received 39 Gy in 13 fractions over 5 weeks was 43.9% compared with 50.4% in those randomized to 50 Gy in 25 fractions over 5 weeks. The resultant 20% relative risk reduction with a lower total radiation dose delivered in fewer fractions was statistically significant. In contrast, the 10-year locoregional tumor relapse rates in the two groups were similarly low.

At 10 years in START B, patients who received 40 Gy in 15 fractions over 3 weeks had a 37.9% rate of moderate-to-marked adverse effects on normal tissues, compared with a 45.3% rate in those who got 50 Gy in 25 fractions over 5 weeks, for a highly significant 23% risk reduction. The relapse rate was 4.3% after 40 Gy and 5.5% after 50 Gy, a nonsignificant difference.

In both trials, all types of side effects involving normal tissues were significantly less common in the lower-total-dose, fewer-fraction groups. That includes brachial plexus injury, which has been a concern expressed by supporters of the historical standard regimen, Dr. Yarnold added.

Radiologists and surgeons in the audience called the 10-year START results "very, very important" and likely to be practice changing.

Canada has already switched from the historical standard to 42.5 Gy delivered in 16 fractions over the course of 22 days. Asked if he thinks U.S. radiologists, too, should change their practice in light of the START findings, Dr. Yarnold was diplomatic. "I foresee no scientific reasons why they should not consider that very carefully," he replied.

Follow-up will continue in the START trials, which are funded by the Institute for Cancer Research, Cancer Research UK, the Medical Research Council, and the National Cancer Research Institute. Dr. Yarnold reported having no financial conflicts.

[email protected]

SAN ANTONIO – A lower-dose, briefer radiotherapy regimen than is standard for early-stage breast cancer in the U.S. demonstrated comparable efficacy with fewer side effects at 10 years of follow-up in a pair of landmark U.K. studies.

"Long-term follow-up confirms that a lower total dose of radiation in fewer, slightly larger fractions delivered over a shorter treatment time is at least as safe and effective as standard 5-week schedules of curative radiotherapy in women with early breast cancer," Dr. John R. Yarnold declared in presenting the latest data from the U.K. START (Standardization of Breast Radiotherapy) trials at the annual San Antonio Breast Cancer Symposium.

The historical standard of care for radiotherapy in patients with surgically excised early breast cancer is 50 Gy delivered in 25 fractions of 2.0 Gy each over the course of 5 weeks. That’s still standard practice in the United States.

In the United Kingdom, however, the standard nationwide is 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Radiologists term this "hypofractionation": delivering a lower total dose of radiation using fewer but larger fractions. Hypofractionation has standard practice in the United Kingdom since the National Institute for Health and Clinical Excellence–issued guidelines to that effect in 2009. Those guidelines were based in large part on the earlier, highly favorable 5-year outcomes of START A (Lancet Oncology 2008;9:331-41) and START B (Lancet 2008;371:1098-107).

The START investigators deemed it essential to conduct the new 10-year analysis because adverse effects of radiotherapy given for breast cancer can arise after the 5-year mark. Also, it was important to learn whether the early antitumor effects of hypofractionated radiotherapy persisted, explained Dr. Yarnold, professor of clinical oncology at the Institute of Cancer Research, London.

The two key findings at the 10-year mark of START are, first, that both breast cancer and the dose-limiting normal tissues respond similarly to fraction size, so there’s no advantage in continuing the 2 Gy fractions that have historically been the international standard; and, second, that a 15-fraction/3-week schedule is gentler on normal tissues and comparable in antitumor efficacy to a 25-fraction/5-week regimen.

The clinical implications are clear, Dr. Yarnold emphasized: "Patients can safely be treated to a lower total dose with fewer fractions than the historical standard of 50 Gy and 25 fractions. There are no detrimental effects of hypofractionation noted in any of the subgroups studied."

The 10-year rate of moderate to marked adverse treatment effects on normal tissues in START A survivors who received 39 Gy in 13 fractions over 5 weeks was 43.9% compared with 50.4% in those randomized to 50 Gy in 25 fractions over 5 weeks. The resultant 20% relative risk reduction with a lower total radiation dose delivered in fewer fractions was statistically significant. In contrast, the 10-year locoregional tumor relapse rates in the two groups were similarly low.

At 10 years in START B, patients who received 40 Gy in 15 fractions over 3 weeks had a 37.9% rate of moderate-to-marked adverse effects on normal tissues, compared with a 45.3% rate in those who got 50 Gy in 25 fractions over 5 weeks, for a highly significant 23% risk reduction. The relapse rate was 4.3% after 40 Gy and 5.5% after 50 Gy, a nonsignificant difference.

In both trials, all types of side effects involving normal tissues were significantly less common in the lower-total-dose, fewer-fraction groups. That includes brachial plexus injury, which has been a concern expressed by supporters of the historical standard regimen, Dr. Yarnold added.

Radiologists and surgeons in the audience called the 10-year START results "very, very important" and likely to be practice changing.

Canada has already switched from the historical standard to 42.5 Gy delivered in 16 fractions over the course of 22 days. Asked if he thinks U.S. radiologists, too, should change their practice in light of the START findings, Dr. Yarnold was diplomatic. "I foresee no scientific reasons why they should not consider that very carefully," he replied.

Follow-up will continue in the START trials, which are funded by the Institute for Cancer Research, Cancer Research UK, the Medical Research Council, and the National Cancer Research Institute. Dr. Yarnold reported having no financial conflicts.

[email protected]

SAN ANTONIO – A lower-dose, briefer radiotherapy regimen than is standard for early-stage breast cancer in the U.S. demonstrated comparable efficacy with fewer side effects at 10 years of follow-up in a pair of landmark U.K. studies.

"Long-term follow-up confirms that a lower total dose of radiation in fewer, slightly larger fractions delivered over a shorter treatment time is at least as safe and effective as standard 5-week schedules of curative radiotherapy in women with early breast cancer," Dr. John R. Yarnold declared in presenting the latest data from the U.K. START (Standardization of Breast Radiotherapy) trials at the annual San Antonio Breast Cancer Symposium.

The historical standard of care for radiotherapy in patients with surgically excised early breast cancer is 50 Gy delivered in 25 fractions of 2.0 Gy each over the course of 5 weeks. That’s still standard practice in the United States.

In the United Kingdom, however, the standard nationwide is 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Radiologists term this "hypofractionation": delivering a lower total dose of radiation using fewer but larger fractions. Hypofractionation has standard practice in the United Kingdom since the National Institute for Health and Clinical Excellence–issued guidelines to that effect in 2009. Those guidelines were based in large part on the earlier, highly favorable 5-year outcomes of START A (Lancet Oncology 2008;9:331-41) and START B (Lancet 2008;371:1098-107).

The START investigators deemed it essential to conduct the new 10-year analysis because adverse effects of radiotherapy given for breast cancer can arise after the 5-year mark. Also, it was important to learn whether the early antitumor effects of hypofractionated radiotherapy persisted, explained Dr. Yarnold, professor of clinical oncology at the Institute of Cancer Research, London.

The two key findings at the 10-year mark of START are, first, that both breast cancer and the dose-limiting normal tissues respond similarly to fraction size, so there’s no advantage in continuing the 2 Gy fractions that have historically been the international standard; and, second, that a 15-fraction/3-week schedule is gentler on normal tissues and comparable in antitumor efficacy to a 25-fraction/5-week regimen.

The clinical implications are clear, Dr. Yarnold emphasized: "Patients can safely be treated to a lower total dose with fewer fractions than the historical standard of 50 Gy and 25 fractions. There are no detrimental effects of hypofractionation noted in any of the subgroups studied."

The 10-year rate of moderate to marked adverse treatment effects on normal tissues in START A survivors who received 39 Gy in 13 fractions over 5 weeks was 43.9% compared with 50.4% in those randomized to 50 Gy in 25 fractions over 5 weeks. The resultant 20% relative risk reduction with a lower total radiation dose delivered in fewer fractions was statistically significant. In contrast, the 10-year locoregional tumor relapse rates in the two groups were similarly low.

At 10 years in START B, patients who received 40 Gy in 15 fractions over 3 weeks had a 37.9% rate of moderate-to-marked adverse effects on normal tissues, compared with a 45.3% rate in those who got 50 Gy in 25 fractions over 5 weeks, for a highly significant 23% risk reduction. The relapse rate was 4.3% after 40 Gy and 5.5% after 50 Gy, a nonsignificant difference.

In both trials, all types of side effects involving normal tissues were significantly less common in the lower-total-dose, fewer-fraction groups. That includes brachial plexus injury, which has been a concern expressed by supporters of the historical standard regimen, Dr. Yarnold added.

Radiologists and surgeons in the audience called the 10-year START results "very, very important" and likely to be practice changing.

Canada has already switched from the historical standard to 42.5 Gy delivered in 16 fractions over the course of 22 days. Asked if he thinks U.S. radiologists, too, should change their practice in light of the START findings, Dr. Yarnold was diplomatic. "I foresee no scientific reasons why they should not consider that very carefully," he replied.

Follow-up will continue in the START trials, which are funded by the Institute for Cancer Research, Cancer Research UK, the Medical Research Council, and the National Cancer Research Institute. Dr. Yarnold reported having no financial conflicts.

[email protected]

SAN ANTONIO – It’s back!

At a median follow-up of 8 years in the landmark HERA trial, patients randomized to 1 year of trastuzumab (Herceptin) once again displayed a significantly greater overall survival rate than did a control group assigned to observation, Dr. Martine J. Piccart reported at the annual San Antonio Breast Cancer Symposium.

Bruce Jancin/IMNG Medical Media

This updated analysis is cause for celebration. At 2 years of follow-up, HERA (HERceptin Adjuvant) participants who’d received a year of trastuzumab had a 34% reduction in risk of all-cause mortality compared with controls (P = .0115). This survival advantage had vanished at 4 years, however. An intention-to-treat analysis at a median 4 years of follow-up (Lancet Oncology 2011;12:236-44) showed 89.3% survival in the trastuzumab group and 87.7% in controls, a nonsignificant difference (P = .1).

"As you can imagine, there was some concern in 2008 because it looked like the survival benefit had disappeared. So it’s very good news that now, with a very mature follow-up, we see a robust reduction in the risk of death with 1 year of trastuzumab given sequentially after chemotherapy and/or radiotherapy," declared Dr. Piccart, chief of the department of medicine at the Jules Bordet Institute in Brussels and president of the European Society for Medical Oncology.

New data show 24% reduction in relative risk

Indeed, at 8 years follow-up, a cumulative 278 deaths had occurred in the trastuzumab group compared with 350 in controls, for an adjusted 24% relative risk reduction (P = .0005).

The same pattern was seen for disease-free survival: a decrease in the benefit of 1 year of trastuzumab between years 2 and 4 of follow-up, with the relative risk reduction sliding somewhat ominously from 36% to 24%, albeit still significantly significant. Gratifyingly, however, the new 8-year analysis showed no further erosion in the disease-free survival benefit. It remained steady at a 24% relative risk reduction, with 471 events in the trastuzumab group and 570 in controls (P less than .0001).

The explanation for the dicey findings at a median 4-year follow-up is twofold: The results were less stable than at 8 years because considerably fewer events had occurred at that point; plus, fully 52% of women in the observation group elected to start taking trastuzumab once they received the opportunity following the 2005 initial report of favorable early benefits. Thus, the HERA intention-to-treat analyses underestimate by a considerable margin the true benefits of 1 year of trastuzumab because more than half of the patients listed as being in the control arm have actually taken the drug, Dr. Piccart noted.

At 8 years of follow-up, the disease-free survival benefit favoring 1 year of trastuzumab over observation was significant whether patients had hormone receptor–positive or negative tumors.

HERA is an international, multicenter, phase III randomized trial involving 5,102 women with HER2-positive early-stage breast cancer. They were randomly assigned to 1 year of trastuzumab, 2 years of the drug, or to observation following adjuvant chemotherapy and/or radiotherapy.

One year trumps 2 years of adjuvant trastuzumab

HERA is the only randomized trial investigating whether 2 years of trastuzumab is better than 1. And as Dr. Piccart declared in San Antonio, the answer is no. Longer therapy brought no advantage in terms of disease-free or overall survival, and it was associated with a significantly greater incidence of asymptomatic left ventricular dysfunction: 7.2% compared with 4.1% in women who received 1 year of trastuzumab. Fortunately, most of these cardiac abnormalities were reversible upon discontinuation of the drug, she observed.

"HERA confirms that 1 year of adjuvant trastuzumab should remain the standard of care in women with HER2-positive breast cancer," Dr. Piccart said.

"I think the HERA trial is an extremely important one," said conference codirector Dr. C. Kent Osborne.

"The reason is, you can imagine the cost to the health care system if we have to give trastuzumab for 2 years rather than 1. So I was really gratified to see that 1 year seemed just as good. Although the drug is not terribly toxic to people, still, the practicality of it and the expense of it are a problem.

"So I think HERA sets the standard at 1 year going forward with future studies," said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston.

The HERA trial is being conducted by the Breast International Group (BIG) with funding from Roche. Dr. Piccart, who chairs BIG, is a consultant to the pharmaceutical company.

SAN ANTONIO – It’s back!

At a median follow-up of 8 years in the landmark HERA trial, patients randomized to 1 year of trastuzumab (Herceptin) once again displayed a significantly greater overall survival rate than did a control group assigned to observation, Dr. Martine J. Piccart reported at the annual San Antonio Breast Cancer Symposium.

Bruce Jancin/IMNG Medical Media

This updated analysis is cause for celebration. At 2 years of follow-up, HERA (HERceptin Adjuvant) participants who’d received a year of trastuzumab had a 34% reduction in risk of all-cause mortality compared with controls (P = .0115). This survival advantage had vanished at 4 years, however. An intention-to-treat analysis at a median 4 years of follow-up (Lancet Oncology 2011;12:236-44) showed 89.3% survival in the trastuzumab group and 87.7% in controls, a nonsignificant difference (P = .1).

"As you can imagine, there was some concern in 2008 because it looked like the survival benefit had disappeared. So it’s very good news that now, with a very mature follow-up, we see a robust reduction in the risk of death with 1 year of trastuzumab given sequentially after chemotherapy and/or radiotherapy," declared Dr. Piccart, chief of the department of medicine at the Jules Bordet Institute in Brussels and president of the European Society for Medical Oncology.

New data show 24% reduction in relative risk

Indeed, at 8 years follow-up, a cumulative 278 deaths had occurred in the trastuzumab group compared with 350 in controls, for an adjusted 24% relative risk reduction (P = .0005).

The same pattern was seen for disease-free survival: a decrease in the benefit of 1 year of trastuzumab between years 2 and 4 of follow-up, with the relative risk reduction sliding somewhat ominously from 36% to 24%, albeit still significantly significant. Gratifyingly, however, the new 8-year analysis showed no further erosion in the disease-free survival benefit. It remained steady at a 24% relative risk reduction, with 471 events in the trastuzumab group and 570 in controls (P less than .0001).

The explanation for the dicey findings at a median 4-year follow-up is twofold: The results were less stable than at 8 years because considerably fewer events had occurred at that point; plus, fully 52% of women in the observation group elected to start taking trastuzumab once they received the opportunity following the 2005 initial report of favorable early benefits. Thus, the HERA intention-to-treat analyses underestimate by a considerable margin the true benefits of 1 year of trastuzumab because more than half of the patients listed as being in the control arm have actually taken the drug, Dr. Piccart noted.

At 8 years of follow-up, the disease-free survival benefit favoring 1 year of trastuzumab over observation was significant whether patients had hormone receptor–positive or negative tumors.

HERA is an international, multicenter, phase III randomized trial involving 5,102 women with HER2-positive early-stage breast cancer. They were randomly assigned to 1 year of trastuzumab, 2 years of the drug, or to observation following adjuvant chemotherapy and/or radiotherapy.

One year trumps 2 years of adjuvant trastuzumab

HERA is the only randomized trial investigating whether 2 years of trastuzumab is better than 1. And as Dr. Piccart declared in San Antonio, the answer is no. Longer therapy brought no advantage in terms of disease-free or overall survival, and it was associated with a significantly greater incidence of asymptomatic left ventricular dysfunction: 7.2% compared with 4.1% in women who received 1 year of trastuzumab. Fortunately, most of these cardiac abnormalities were reversible upon discontinuation of the drug, she observed.

"HERA confirms that 1 year of adjuvant trastuzumab should remain the standard of care in women with HER2-positive breast cancer," Dr. Piccart said.

"I think the HERA trial is an extremely important one," said conference codirector Dr. C. Kent Osborne.

"The reason is, you can imagine the cost to the health care system if we have to give trastuzumab for 2 years rather than 1. So I was really gratified to see that 1 year seemed just as good. Although the drug is not terribly toxic to people, still, the practicality of it and the expense of it are a problem.

"So I think HERA sets the standard at 1 year going forward with future studies," said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston.

The HERA trial is being conducted by the Breast International Group (BIG) with funding from Roche. Dr. Piccart, who chairs BIG, is a consultant to the pharmaceutical company.

SAN ANTONIO – It’s back!

At a median follow-up of 8 years in the landmark HERA trial, patients randomized to 1 year of trastuzumab (Herceptin) once again displayed a significantly greater overall survival rate than did a control group assigned to observation, Dr. Martine J. Piccart reported at the annual San Antonio Breast Cancer Symposium.

Bruce Jancin/IMNG Medical Media

This updated analysis is cause for celebration. At 2 years of follow-up, HERA (HERceptin Adjuvant) participants who’d received a year of trastuzumab had a 34% reduction in risk of all-cause mortality compared with controls (P = .0115). This survival advantage had vanished at 4 years, however. An intention-to-treat analysis at a median 4 years of follow-up (Lancet Oncology 2011;12:236-44) showed 89.3% survival in the trastuzumab group and 87.7% in controls, a nonsignificant difference (P = .1).

"As you can imagine, there was some concern in 2008 because it looked like the survival benefit had disappeared. So it’s very good news that now, with a very mature follow-up, we see a robust reduction in the risk of death with 1 year of trastuzumab given sequentially after chemotherapy and/or radiotherapy," declared Dr. Piccart, chief of the department of medicine at the Jules Bordet Institute in Brussels and president of the European Society for Medical Oncology.

New data show 24% reduction in relative risk

Indeed, at 8 years follow-up, a cumulative 278 deaths had occurred in the trastuzumab group compared with 350 in controls, for an adjusted 24% relative risk reduction (P = .0005).

The same pattern was seen for disease-free survival: a decrease in the benefit of 1 year of trastuzumab between years 2 and 4 of follow-up, with the relative risk reduction sliding somewhat ominously from 36% to 24%, albeit still significantly significant. Gratifyingly, however, the new 8-year analysis showed no further erosion in the disease-free survival benefit. It remained steady at a 24% relative risk reduction, with 471 events in the trastuzumab group and 570 in controls (P less than .0001).

The explanation for the dicey findings at a median 4-year follow-up is twofold: The results were less stable than at 8 years because considerably fewer events had occurred at that point; plus, fully 52% of women in the observation group elected to start taking trastuzumab once they received the opportunity following the 2005 initial report of favorable early benefits. Thus, the HERA intention-to-treat analyses underestimate by a considerable margin the true benefits of 1 year of trastuzumab because more than half of the patients listed as being in the control arm have actually taken the drug, Dr. Piccart noted.

At 8 years of follow-up, the disease-free survival benefit favoring 1 year of trastuzumab over observation was significant whether patients had hormone receptor–positive or negative tumors.

HERA is an international, multicenter, phase III randomized trial involving 5,102 women with HER2-positive early-stage breast cancer. They were randomly assigned to 1 year of trastuzumab, 2 years of the drug, or to observation following adjuvant chemotherapy and/or radiotherapy.

One year trumps 2 years of adjuvant trastuzumab

HERA is the only randomized trial investigating whether 2 years of trastuzumab is better than 1. And as Dr. Piccart declared in San Antonio, the answer is no. Longer therapy brought no advantage in terms of disease-free or overall survival, and it was associated with a significantly greater incidence of asymptomatic left ventricular dysfunction: 7.2% compared with 4.1% in women who received 1 year of trastuzumab. Fortunately, most of these cardiac abnormalities were reversible upon discontinuation of the drug, she observed.

"HERA confirms that 1 year of adjuvant trastuzumab should remain the standard of care in women with HER2-positive breast cancer," Dr. Piccart said.

"I think the HERA trial is an extremely important one," said conference codirector Dr. C. Kent Osborne.

"The reason is, you can imagine the cost to the health care system if we have to give trastuzumab for 2 years rather than 1. So I was really gratified to see that 1 year seemed just as good. Although the drug is not terribly toxic to people, still, the practicality of it and the expense of it are a problem.

"So I think HERA sets the standard at 1 year going forward with future studies," said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston.

The HERA trial is being conducted by the Breast International Group (BIG) with funding from Roche. Dr. Piccart, who chairs BIG, is a consultant to the pharmaceutical company.

SAN ANTONIO – Adding adjuvant bevacizumab to chemotherapy failed to improve outcomes over chemotherapy alone in women with early-stage triple-negative breast cancer in the phase III BEATRICE trial.

The BEATRICE findings come on the heels of another negative bevacizumab (Avastin) trial, also unveiled at the annual San Antonio Breast Cancer Symposium. In the LEA (Letrozole/Fulvestrant and Avastin) trial, use of the angiogenesis inhibitor in combination with conventional hormone therapy had no benefit over hormone therapy alone in women with advanced breast cancer. These studies may well be the final two nails driven into the coffin containing the once-lively prospects for bevacizumab as an important therapy in breast cancer.

"The results, I would say, are disappointing, and they suggest that bevacizumab is going to have a very limited, if any, role in breast cancer," conference codirector Dr. C. Kent Osborne observed in commenting on the studies.

BEATRICE (Bevacizumab Adjuvant Therapy in Triple-Negative Breast Cancer) is an open-label study of 2,591 women with surgically resected early-stage disease. Participants were randomized to adjuvant chemotherapy plus or minus 1 year of bevacizumab. The chemotherapy regimen was left to the discretion of the patient’s oncologist but had to include a taxane and/or anthracycline for four to eight cycles total. Bevacizumab was dosed at 5 mg/kg per week for 1 year.

Dr. David Cameron reported that during a median follow up of 32 months the primary study endpoint, invasive disease-free survival, was achieved in 85.5% of the bevacizumab-plus-chemotherapy group and 84.1% of the chemotherapy-only group. This translated to a 13% relative risk reduction, which was not statistically significant (P = .18).

Invasive disease-free survival differs from disease-free survival, a more common outcome measure, in that it’s designed to capture any cancers bevacizumab might possibly be inducing at sites other than the breast, explained Dr. Cameron, professor of oncology at Edinburgh University.

All-cause mortality, a key secondary endpoint, occurred in 7.1% of the bevacizumab group compared to 8.3% of controls. The resultant 16% reduction in relative risk favoring the angiogenesis inhibitor was nonsignificant (P = .23); however, this analysis was underpowered. A more definitive analysis of overall survival will be conducted in late 2013, he continued.

Adverse events associated with bevacizumab were as seen in earlier trials: a relatively mild toxicity profile, with no increased risk of bone marrow suppression, a 2% incidence of proteinuria, 5% hypertension, and a 1.1% incidence of NYHA class III or IV heart failure.

A bright spot in BEATRICE was the overall 84% 3-year invasive disease-free survival rate.

"That was actually much better than we had originally planned. So when women go on the Web and look up what is a very negative image of triple-negative breast cancer, we can at least say that based on a big, worldwide, phase-III trial, outcomes actually may not be as bad as the older literature suggests," according to Dr. Cameron. "To me, this is a reflection of what we would see now in our clinics: yes, some of the women do badly, but generally they perhaps don’t do as badly as we’ve learned from the historical literature."

Dr. Osborne agreed, adding that the same phenomenon of control groups in more recent clinical trials doing better than projected is "being seen pretty much across the board" in breast cancer.

"It may reflect gradual improvements through the years in our basic, backbone treatments," he explained.

BEATRICE was the first study looking at bevacizumab in the adjuvant setting, where it really ought to shine, said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston. "If it’s going to work, you’d think it would work in that situation. What we’re dealing with at that stage are microscopic metastases that haven’t developed a sufficient blood supply yet – and if you can prevent that blood supply from forming you might have a more dramatic effect than in an already established tumor, like in metastatic breast cancer."

BEATRICE was sponsored by Roche. Dr. Cameron is a consultant to the company.

SAN ANTONIO – Adding adjuvant bevacizumab to chemotherapy failed to improve outcomes over chemotherapy alone in women with early-stage triple-negative breast cancer in the phase III BEATRICE trial.

The BEATRICE findings come on the heels of another negative bevacizumab (Avastin) trial, also unveiled at the annual San Antonio Breast Cancer Symposium. In the LEA (Letrozole/Fulvestrant and Avastin) trial, use of the angiogenesis inhibitor in combination with conventional hormone therapy had no benefit over hormone therapy alone in women with advanced breast cancer. These studies may well be the final two nails driven into the coffin containing the once-lively prospects for bevacizumab as an important therapy in breast cancer.

"The results, I would say, are disappointing, and they suggest that bevacizumab is going to have a very limited, if any, role in breast cancer," conference codirector Dr. C. Kent Osborne observed in commenting on the studies.

BEATRICE (Bevacizumab Adjuvant Therapy in Triple-Negative Breast Cancer) is an open-label study of 2,591 women with surgically resected early-stage disease. Participants were randomized to adjuvant chemotherapy plus or minus 1 year of bevacizumab. The chemotherapy regimen was left to the discretion of the patient’s oncologist but had to include a taxane and/or anthracycline for four to eight cycles total. Bevacizumab was dosed at 5 mg/kg per week for 1 year.

Dr. David Cameron reported that during a median follow up of 32 months the primary study endpoint, invasive disease-free survival, was achieved in 85.5% of the bevacizumab-plus-chemotherapy group and 84.1% of the chemotherapy-only group. This translated to a 13% relative risk reduction, which was not statistically significant (P = .18).

Invasive disease-free survival differs from disease-free survival, a more common outcome measure, in that it’s designed to capture any cancers bevacizumab might possibly be inducing at sites other than the breast, explained Dr. Cameron, professor of oncology at Edinburgh University.

All-cause mortality, a key secondary endpoint, occurred in 7.1% of the bevacizumab group compared to 8.3% of controls. The resultant 16% reduction in relative risk favoring the angiogenesis inhibitor was nonsignificant (P = .23); however, this analysis was underpowered. A more definitive analysis of overall survival will be conducted in late 2013, he continued.

Adverse events associated with bevacizumab were as seen in earlier trials: a relatively mild toxicity profile, with no increased risk of bone marrow suppression, a 2% incidence of proteinuria, 5% hypertension, and a 1.1% incidence of NYHA class III or IV heart failure.

A bright spot in BEATRICE was the overall 84% 3-year invasive disease-free survival rate.

"That was actually much better than we had originally planned. So when women go on the Web and look up what is a very negative image of triple-negative breast cancer, we can at least say that based on a big, worldwide, phase-III trial, outcomes actually may not be as bad as the older literature suggests," according to Dr. Cameron. "To me, this is a reflection of what we would see now in our clinics: yes, some of the women do badly, but generally they perhaps don’t do as badly as we’ve learned from the historical literature."

Dr. Osborne agreed, adding that the same phenomenon of control groups in more recent clinical trials doing better than projected is "being seen pretty much across the board" in breast cancer.

"It may reflect gradual improvements through the years in our basic, backbone treatments," he explained.

BEATRICE was the first study looking at bevacizumab in the adjuvant setting, where it really ought to shine, said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston. "If it’s going to work, you’d think it would work in that situation. What we’re dealing with at that stage are microscopic metastases that haven’t developed a sufficient blood supply yet – and if you can prevent that blood supply from forming you might have a more dramatic effect than in an already established tumor, like in metastatic breast cancer."

BEATRICE was sponsored by Roche. Dr. Cameron is a consultant to the company.

SAN ANTONIO – Adding adjuvant bevacizumab to chemotherapy failed to improve outcomes over chemotherapy alone in women with early-stage triple-negative breast cancer in the phase III BEATRICE trial.

The BEATRICE findings come on the heels of another negative bevacizumab (Avastin) trial, also unveiled at the annual San Antonio Breast Cancer Symposium. In the LEA (Letrozole/Fulvestrant and Avastin) trial, use of the angiogenesis inhibitor in combination with conventional hormone therapy had no benefit over hormone therapy alone in women with advanced breast cancer. These studies may well be the final two nails driven into the coffin containing the once-lively prospects for bevacizumab as an important therapy in breast cancer.

"The results, I would say, are disappointing, and they suggest that bevacizumab is going to have a very limited, if any, role in breast cancer," conference codirector Dr. C. Kent Osborne observed in commenting on the studies.

BEATRICE (Bevacizumab Adjuvant Therapy in Triple-Negative Breast Cancer) is an open-label study of 2,591 women with surgically resected early-stage disease. Participants were randomized to adjuvant chemotherapy plus or minus 1 year of bevacizumab. The chemotherapy regimen was left to the discretion of the patient’s oncologist but had to include a taxane and/or anthracycline for four to eight cycles total. Bevacizumab was dosed at 5 mg/kg per week for 1 year.

Dr. David Cameron reported that during a median follow up of 32 months the primary study endpoint, invasive disease-free survival, was achieved in 85.5% of the bevacizumab-plus-chemotherapy group and 84.1% of the chemotherapy-only group. This translated to a 13% relative risk reduction, which was not statistically significant (P = .18).

Invasive disease-free survival differs from disease-free survival, a more common outcome measure, in that it’s designed to capture any cancers bevacizumab might possibly be inducing at sites other than the breast, explained Dr. Cameron, professor of oncology at Edinburgh University.

All-cause mortality, a key secondary endpoint, occurred in 7.1% of the bevacizumab group compared to 8.3% of controls. The resultant 16% reduction in relative risk favoring the angiogenesis inhibitor was nonsignificant (P = .23); however, this analysis was underpowered. A more definitive analysis of overall survival will be conducted in late 2013, he continued.

Adverse events associated with bevacizumab were as seen in earlier trials: a relatively mild toxicity profile, with no increased risk of bone marrow suppression, a 2% incidence of proteinuria, 5% hypertension, and a 1.1% incidence of NYHA class III or IV heart failure.

A bright spot in BEATRICE was the overall 84% 3-year invasive disease-free survival rate.

"That was actually much better than we had originally planned. So when women go on the Web and look up what is a very negative image of triple-negative breast cancer, we can at least say that based on a big, worldwide, phase-III trial, outcomes actually may not be as bad as the older literature suggests," according to Dr. Cameron. "To me, this is a reflection of what we would see now in our clinics: yes, some of the women do badly, but generally they perhaps don’t do as badly as we’ve learned from the historical literature."

Dr. Osborne agreed, adding that the same phenomenon of control groups in more recent clinical trials doing better than projected is "being seen pretty much across the board" in breast cancer.

"It may reflect gradual improvements through the years in our basic, backbone treatments," he explained.

BEATRICE was the first study looking at bevacizumab in the adjuvant setting, where it really ought to shine, said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston. "If it’s going to work, you’d think it would work in that situation. What we’re dealing with at that stage are microscopic metastases that haven’t developed a sufficient blood supply yet – and if you can prevent that blood supply from forming you might have a more dramatic effect than in an already established tumor, like in metastatic breast cancer."

BEATRICE was sponsored by Roche. Dr. Cameron is a consultant to the company.

SAN ANTONIO – Women who received paclitaxel and trastuzumab after anthracycline chemotherapy for HER2-positive breast cancer were almost 40% less likely to die by 10 years than were those given only paclitaxel in a pair of landmark clinical trials.

"This means that 80% of these patients – most of whom had node-positive disease – were alive at 10 years after their diagnosis of breast cancer." said Dr. Edward H. Romond, reporting long-term findings at the annual San Antonio Breast Cancer Symposium.

The regimen also reduced the risk of a 10-year disease-free survival event by 40% in the definitive survival analysis of the two pivotal trastuzumab (Herceptin) studies – the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 protocol and the North Central Cancer Treatment Group (NCCTG) N9831 trial.

Both studies compared the paclitaxel/trastuzumab combination with paclitaxel alone in women with invasive HER2-positive breast cancers. All patients had undergone a lumpectomy or mastectomy with pathologically clear margins, and had axillary nodes that were initially pathologically involved.

Outcomes of both trials have been separately reported. However, because of their similar structure, treatment regimens, and patient populations, the Food and Drug Administration agreed to combine them to allow for a definite survival analysis, said Dr. Romond of the University of Kentucky, Lexington.

The combined analysis comprised 4,046 patients, 2,028 of whom took the paclitaxel/trastuzumab combination and 2,018 of whom took paclitaxel alone. The median follow-up in the combined analysis was 8.4 years, with data available for up to 10 years.

About half of the patients were younger than 50 years. Most had node positive disease; slightly more than half had hormone receptor positive–breast cancer. The tumor was T1 in 40%, T2 in 50%, and T3 in 10%.

By the end of the follow-up period, 680 disease-free survival events had occurred in the paclitaxel-only group vs. 473 in the combination therapy group (hazard ratio, 0.60; P less than .0001).

The disease-free survival curve began to separate shortly before year 2. The difference became significant around year 5; by year 6, 81% of the combination group and 69% of the single-therapy group were without an event. By year 10, the rates of disease-free survival were 74% and 62% - an absolute difference of 11.5%.

Most events in each group were distant recurrences (227 with the combination and 391 with single-therapy). Local or regional recurrence was seen in 84 and 124, respectively, and contralateral breast disease in 46 and 40. About 4% of women in each group developed a second primary cancer, and about 2% in each group died without a recurrence of their breast cancer.

There were 286 deaths in the combination group and 418 in the paclitaxel-only group. Women in the combination-therapy group were 37% less likely to die than were those who took paclitaxel alone – a significant difference (HR, 0.63; P less than .0001)

The survival curves began to diverge around year 2 and continued to separate throughout the follow-up period. By year 10, 84% of those in the combination group and 75% of those in the single therapy group were still alive, an absolute difference of 9%.

The survival advantage was apparent whether women had hormone receptor positive or negative disease, Dr. Romond noted (HR, 0.61 and 0.64, respectively).

Most deaths in both groups were due to the original breast cancer (209 in the combination group and 340 in the paclitaxel-only group). Other causes of death were a second primary cancer (25 and 41, respectively), or other or unknown causes.

The combination treatment was especially helpful for women with high risk factors, conferring a significant survival advantage over paclitaxel alone to women aged 60 years and older (14%), women with 10 more positive nodes (16%), and women with tumors larger than 5 cm (12%).

Dr. Romond had no financial disclosures.

SAN ANTONIO – Women who received paclitaxel and trastuzumab after anthracycline chemotherapy for HER2-positive breast cancer were almost 40% less likely to die by 10 years than were those given only paclitaxel in a pair of landmark clinical trials.

"This means that 80% of these patients – most of whom had node-positive disease – were alive at 10 years after their diagnosis of breast cancer." said Dr. Edward H. Romond, reporting long-term findings at the annual San Antonio Breast Cancer Symposium.

The regimen also reduced the risk of a 10-year disease-free survival event by 40% in the definitive survival analysis of the two pivotal trastuzumab (Herceptin) studies – the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 protocol and the North Central Cancer Treatment Group (NCCTG) N9831 trial.

Both studies compared the paclitaxel/trastuzumab combination with paclitaxel alone in women with invasive HER2-positive breast cancers. All patients had undergone a lumpectomy or mastectomy with pathologically clear margins, and had axillary nodes that were initially pathologically involved.

Outcomes of both trials have been separately reported. However, because of their similar structure, treatment regimens, and patient populations, the Food and Drug Administration agreed to combine them to allow for a definite survival analysis, said Dr. Romond of the University of Kentucky, Lexington.

The combined analysis comprised 4,046 patients, 2,028 of whom took the paclitaxel/trastuzumab combination and 2,018 of whom took paclitaxel alone. The median follow-up in the combined analysis was 8.4 years, with data available for up to 10 years.

About half of the patients were younger than 50 years. Most had node positive disease; slightly more than half had hormone receptor positive–breast cancer. The tumor was T1 in 40%, T2 in 50%, and T3 in 10%.

By the end of the follow-up period, 680 disease-free survival events had occurred in the paclitaxel-only group vs. 473 in the combination therapy group (hazard ratio, 0.60; P less than .0001).

The disease-free survival curve began to separate shortly before year 2. The difference became significant around year 5; by year 6, 81% of the combination group and 69% of the single-therapy group were without an event. By year 10, the rates of disease-free survival were 74% and 62% - an absolute difference of 11.5%.

Most events in each group were distant recurrences (227 with the combination and 391 with single-therapy). Local or regional recurrence was seen in 84 and 124, respectively, and contralateral breast disease in 46 and 40. About 4% of women in each group developed a second primary cancer, and about 2% in each group died without a recurrence of their breast cancer.

There were 286 deaths in the combination group and 418 in the paclitaxel-only group. Women in the combination-therapy group were 37% less likely to die than were those who took paclitaxel alone – a significant difference (HR, 0.63; P less than .0001)

The survival curves began to diverge around year 2 and continued to separate throughout the follow-up period. By year 10, 84% of those in the combination group and 75% of those in the single therapy group were still alive, an absolute difference of 9%.

The survival advantage was apparent whether women had hormone receptor positive or negative disease, Dr. Romond noted (HR, 0.61 and 0.64, respectively).

Most deaths in both groups were due to the original breast cancer (209 in the combination group and 340 in the paclitaxel-only group). Other causes of death were a second primary cancer (25 and 41, respectively), or other or unknown causes.

The combination treatment was especially helpful for women with high risk factors, conferring a significant survival advantage over paclitaxel alone to women aged 60 years and older (14%), women with 10 more positive nodes (16%), and women with tumors larger than 5 cm (12%).

Dr. Romond had no financial disclosures.

SAN ANTONIO – Women who received paclitaxel and trastuzumab after anthracycline chemotherapy for HER2-positive breast cancer were almost 40% less likely to die by 10 years than were those given only paclitaxel in a pair of landmark clinical trials.

"This means that 80% of these patients – most of whom had node-positive disease – were alive at 10 years after their diagnosis of breast cancer." said Dr. Edward H. Romond, reporting long-term findings at the annual San Antonio Breast Cancer Symposium.

The regimen also reduced the risk of a 10-year disease-free survival event by 40% in the definitive survival analysis of the two pivotal trastuzumab (Herceptin) studies – the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 protocol and the North Central Cancer Treatment Group (NCCTG) N9831 trial.

Both studies compared the paclitaxel/trastuzumab combination with paclitaxel alone in women with invasive HER2-positive breast cancers. All patients had undergone a lumpectomy or mastectomy with pathologically clear margins, and had axillary nodes that were initially pathologically involved.

Outcomes of both trials have been separately reported. However, because of their similar structure, treatment regimens, and patient populations, the Food and Drug Administration agreed to combine them to allow for a definite survival analysis, said Dr. Romond of the University of Kentucky, Lexington.

The combined analysis comprised 4,046 patients, 2,028 of whom took the paclitaxel/trastuzumab combination and 2,018 of whom took paclitaxel alone. The median follow-up in the combined analysis was 8.4 years, with data available for up to 10 years.

About half of the patients were younger than 50 years. Most had node positive disease; slightly more than half had hormone receptor positive–breast cancer. The tumor was T1 in 40%, T2 in 50%, and T3 in 10%.

By the end of the follow-up period, 680 disease-free survival events had occurred in the paclitaxel-only group vs. 473 in the combination therapy group (hazard ratio, 0.60; P less than .0001).

The disease-free survival curve began to separate shortly before year 2. The difference became significant around year 5; by year 6, 81% of the combination group and 69% of the single-therapy group were without an event. By year 10, the rates of disease-free survival were 74% and 62% - an absolute difference of 11.5%.

Most events in each group were distant recurrences (227 with the combination and 391 with single-therapy). Local or regional recurrence was seen in 84 and 124, respectively, and contralateral breast disease in 46 and 40. About 4% of women in each group developed a second primary cancer, and about 2% in each group died without a recurrence of their breast cancer.

There were 286 deaths in the combination group and 418 in the paclitaxel-only group. Women in the combination-therapy group were 37% less likely to die than were those who took paclitaxel alone – a significant difference (HR, 0.63; P less than .0001)

The survival curves began to diverge around year 2 and continued to separate throughout the follow-up period. By year 10, 84% of those in the combination group and 75% of those in the single therapy group were still alive, an absolute difference of 9%.

The survival advantage was apparent whether women had hormone receptor positive or negative disease, Dr. Romond noted (HR, 0.61 and 0.64, respectively).

Most deaths in both groups were due to the original breast cancer (209 in the combination group and 340 in the paclitaxel-only group). Other causes of death were a second primary cancer (25 and 41, respectively), or other or unknown causes.

The combination treatment was especially helpful for women with high risk factors, conferring a significant survival advantage over paclitaxel alone to women aged 60 years and older (14%), women with 10 more positive nodes (16%), and women with tumors larger than 5 cm (12%).

Dr. Romond had no financial disclosures.

SAN ANTONIO – Patients with locally advanced or metastatic breast cancer did not fare better if given eribulin instead of capecitabine in a randomized phase III trial. But results suggest eribulin may have an edge in certain subgroups, including women with triple-negative breast cancer.

Investigators led by Dr. Peter A. Kaufman studied more than 1,000 such patients who had had up to three prior treatments, assigning them evenly to eribulin (Halaven) or capecitabine (Xeloda). Trial results, reported at the San Antonio Breast Cancer Symposium, showed only a nonsignificant trend in overall survival in favor of eribulin, amounting to a gain of about 1.5 months, and essentially no difference in progression-free survival.

However, preplanned subgroup analyses hinted at a potential overall survival benefit among patients having the notoriously hard-to-treat triple-negative disease, as well as those with estrogen receptor–negative or HER2-negative disease.

"Eribulin and capecitabine have similar overall activity in this trial that included patients in the first-, second-, and third-line settings," Dr. Kaufman commented in a press briefing. "Our findings, I want to emphasize, are not definitive but interesting in terms of certain subsets and suggest that the triple-negative subgroup perhaps may be doing better with eribulin."

The reason for the unusual combination of a trend toward overall survival benefit in the absence of a progression-free survival benefit is unknown, he said. "This is not typical of what one sees in metastatic breast cancer, but the data are what the data are."

Given the trial’s findings, what are clinicians to do?

"I think eribulin is a reasonable option to consider therapeutically now for women. It compares reasonably to capecitabine," maintained Dr. Kaufman of the Geisel School of Medicine at Dartmouth and the Norris Cotton Cancer Center in Lebanon, N.H. "Our primary objective was to demonstrate superiority, which we did not meet. But the results are reasonably encouraging."

HER2 Therapy Questioned

In the session where the results were presented, attendee Dr. Daniel F. Hayes of the University of Michigan, Ann Arbor said, "I’m assuming that everyone who was HER2-positive received trastuzumab or some other anti-HER2 therapy, which might affect your subgroup analysis for HER2."

"A large proportion of the study population was enrolled in eastern Europe or South America, parts of the world where trastuzumab and other HER2-targeted therapies were not routinely used at the time of enrollment for this study," Dr. Kaufman replied. "We are sorting out those results and will present them at a further date."

Dr. Hayes also wondered about crossover on the trial and its possible impact on overall survival.

Although there was no planned crossover, about half of patients in the eribulin arm did switch to capecitabine, and that may have affected the results, Dr. Kaufman acknowledged. "We are pulling the data together on post-progression treatments to try to analyze that further."

FDA Requested Bone Scans

Attendee Dr. Steven Vogl of Montefiore Medical Center in the Bronx, New York, took issue with the objective response rates with both eribulin and capecitabine, which were 16% and 20%, respectively, by local investigator assessment but just 11% and 12% on independent review.

"The objective response rate on radiologic review is sort of distressing," he said. "Did someone decide that if the bone scan didn’t get better, that wasn’t a response, even though the node shrank 70%?"

"Correct. So this is one of the reasons why the response rate on the independent analysis is lower," Dr. Kaufman replied. "If the bone scan did not confirm it, those patients were not scored as having responding disease; additionally, if the confirmatory bone scan was not performed, those patients were not scored as having an objective response.

"We are still pulling all this together, but I think that is a large piece of why the independent analysis response rates were lower than the local investigator assessment. But I will highlight also that ... only about 20% of the patients were in the first-line setting, so it’s not a pure first-line trial."

"The 20% response rate in a third-line trial is credible, but the 10% response rate – some of us don’t think that’s worth pursuing," Dr. Vogl added. "I think bone scans shouldn’t be done on studies like this because they take forever to get better."

"Bone scan was actually included at the request of the FDA," Dr. Kaufman noted.

Results Not Statistically Different

Patients were eligible for the trial, formally known as Study 301, if they had locally advanced or metastatic breast cancer and had a received up to three prior regimens (up to two for their advanced disease), which must have included a taxane and an anthracycline.

In all, 1,102 patients were randomized to eribulin – the only chemotherapeutic agent shown to have a survival benefit in heavily pretreated metastatic breast cancer – or capecitabine. The former is approved by the FDA for treatment of metastatic breast cancer after at least two treatment regimens with an anthracycline and a taxane; the latter is approved for treatment of pretreated metastatic breast cancer, as well as stage III colon cancer.

Demographically, the patients had a median age of 53 years. The majority had received one or two prior chemotherapy regimens for advanced disease. More than 85% had visceral involvement.

In terms of drug exposure, the two groups had almost identical median durations of treatment and relative dose intensities.

Main results showed that median overall survival achieved with eribulin was numerically but not statistically better than that with capecitabine (15.9 vs. 14.5 months; hazard ratio, 0.88; P = .056), Dr. Kaufman reported.

In preplanned subgroup analyses, there were trends favoring eribulin over capecitabine in patients who had triple-negative disease (hazard ratio, 0.70), as well as those with HER2-negative disease (0.84) and estrogen receptor–negative disease (0.78).

The 1-, 2-, and 3-year rates of overall survival were statistically indistinguishable between groups.

There was also no significant difference in progression-free survival, with the value standing at about 4 months in each group (P = .31), and no significant difference in response rates.

The eribulin and capecitabine groups were similarly likely to experience treatment-related adverse events (85% and 77%) and serious adverse events (18% and 21%).

"The side effect profiles are consistent with previous data on the side effects of these medications," Dr. Kaufman said.

Eribulin was associated with higher rates of grade 3/4 neutropenia and leukopenia, whereas capecitabine was associated with higher rates of grade 3/4 hand-foot syndrome and diarrhea.

The investigators have not yet performed comparative cost analyses in the trial.

Dr. Kaufman disclosed that he receives research support from and is a consultant to Eisai. The trial was sponsored by Eisai.

SAN ANTONIO – Patients with locally advanced or metastatic breast cancer did not fare better if given eribulin instead of capecitabine in a randomized phase III trial. But results suggest eribulin may have an edge in certain subgroups, including women with triple-negative breast cancer.

Investigators led by Dr. Peter A. Kaufman studied more than 1,000 such patients who had had up to three prior treatments, assigning them evenly to eribulin (Halaven) or capecitabine (Xeloda). Trial results, reported at the San Antonio Breast Cancer Symposium, showed only a nonsignificant trend in overall survival in favor of eribulin, amounting to a gain of about 1.5 months, and essentially no difference in progression-free survival.

However, preplanned subgroup analyses hinted at a potential overall survival benefit among patients having the notoriously hard-to-treat triple-negative disease, as well as those with estrogen receptor–negative or HER2-negative disease.

"Eribulin and capecitabine have similar overall activity in this trial that included patients in the first-, second-, and third-line settings," Dr. Kaufman commented in a press briefing. "Our findings, I want to emphasize, are not definitive but interesting in terms of certain subsets and suggest that the triple-negative subgroup perhaps may be doing better with eribulin."

The reason for the unusual combination of a trend toward overall survival benefit in the absence of a progression-free survival benefit is unknown, he said. "This is not typical of what one sees in metastatic breast cancer, but the data are what the data are."

Given the trial’s findings, what are clinicians to do?

"I think eribulin is a reasonable option to consider therapeutically now for women. It compares reasonably to capecitabine," maintained Dr. Kaufman of the Geisel School of Medicine at Dartmouth and the Norris Cotton Cancer Center in Lebanon, N.H. "Our primary objective was to demonstrate superiority, which we did not meet. But the results are reasonably encouraging."

HER2 Therapy Questioned

In the session where the results were presented, attendee Dr. Daniel F. Hayes of the University of Michigan, Ann Arbor said, "I’m assuming that everyone who was HER2-positive received trastuzumab or some other anti-HER2 therapy, which might affect your subgroup analysis for HER2."

"A large proportion of the study population was enrolled in eastern Europe or South America, parts of the world where trastuzumab and other HER2-targeted therapies were not routinely used at the time of enrollment for this study," Dr. Kaufman replied. "We are sorting out those results and will present them at a further date."

Dr. Hayes also wondered about crossover on the trial and its possible impact on overall survival.

Although there was no planned crossover, about half of patients in the eribulin arm did switch to capecitabine, and that may have affected the results, Dr. Kaufman acknowledged. "We are pulling the data together on post-progression treatments to try to analyze that further."

FDA Requested Bone Scans

Attendee Dr. Steven Vogl of Montefiore Medical Center in the Bronx, New York, took issue with the objective response rates with both eribulin and capecitabine, which were 16% and 20%, respectively, by local investigator assessment but just 11% and 12% on independent review.

"The objective response rate on radiologic review is sort of distressing," he said. "Did someone decide that if the bone scan didn’t get better, that wasn’t a response, even though the node shrank 70%?"

"Correct. So this is one of the reasons why the response rate on the independent analysis is lower," Dr. Kaufman replied. "If the bone scan did not confirm it, those patients were not scored as having responding disease; additionally, if the confirmatory bone scan was not performed, those patients were not scored as having an objective response.

"We are still pulling all this together, but I think that is a large piece of why the independent analysis response rates were lower than the local investigator assessment. But I will highlight also that ... only about 20% of the patients were in the first-line setting, so it’s not a pure first-line trial."

"The 20% response rate in a third-line trial is credible, but the 10% response rate – some of us don’t think that’s worth pursuing," Dr. Vogl added. "I think bone scans shouldn’t be done on studies like this because they take forever to get better."

"Bone scan was actually included at the request of the FDA," Dr. Kaufman noted.

Results Not Statistically Different

Patients were eligible for the trial, formally known as Study 301, if they had locally advanced or metastatic breast cancer and had a received up to three prior regimens (up to two for their advanced disease), which must have included a taxane and an anthracycline.

In all, 1,102 patients were randomized to eribulin – the only chemotherapeutic agent shown to have a survival benefit in heavily pretreated metastatic breast cancer – or capecitabine. The former is approved by the FDA for treatment of metastatic breast cancer after at least two treatment regimens with an anthracycline and a taxane; the latter is approved for treatment of pretreated metastatic breast cancer, as well as stage III colon cancer.

Demographically, the patients had a median age of 53 years. The majority had received one or two prior chemotherapy regimens for advanced disease. More than 85% had visceral involvement.

In terms of drug exposure, the two groups had almost identical median durations of treatment and relative dose intensities.

Main results showed that median overall survival achieved with eribulin was numerically but not statistically better than that with capecitabine (15.9 vs. 14.5 months; hazard ratio, 0.88; P = .056), Dr. Kaufman reported.

In preplanned subgroup analyses, there were trends favoring eribulin over capecitabine in patients who had triple-negative disease (hazard ratio, 0.70), as well as those with HER2-negative disease (0.84) and estrogen receptor–negative disease (0.78).

The 1-, 2-, and 3-year rates of overall survival were statistically indistinguishable between groups.

There was also no significant difference in progression-free survival, with the value standing at about 4 months in each group (P = .31), and no significant difference in response rates.

The eribulin and capecitabine groups were similarly likely to experience treatment-related adverse events (85% and 77%) and serious adverse events (18% and 21%).

"The side effect profiles are consistent with previous data on the side effects of these medications," Dr. Kaufman said.

Eribulin was associated with higher rates of grade 3/4 neutropenia and leukopenia, whereas capecitabine was associated with higher rates of grade 3/4 hand-foot syndrome and diarrhea.

The investigators have not yet performed comparative cost analyses in the trial.

Dr. Kaufman disclosed that he receives research support from and is a consultant to Eisai. The trial was sponsored by Eisai.

SAN ANTONIO – Patients with locally advanced or metastatic breast cancer did not fare better if given eribulin instead of capecitabine in a randomized phase III trial. But results suggest eribulin may have an edge in certain subgroups, including women with triple-negative breast cancer.

Investigators led by Dr. Peter A. Kaufman studied more than 1,000 such patients who had had up to three prior treatments, assigning them evenly to eribulin (Halaven) or capecitabine (Xeloda). Trial results, reported at the San Antonio Breast Cancer Symposium, showed only a nonsignificant trend in overall survival in favor of eribulin, amounting to a gain of about 1.5 months, and essentially no difference in progression-free survival.

However, preplanned subgroup analyses hinted at a potential overall survival benefit among patients having the notoriously hard-to-treat triple-negative disease, as well as those with estrogen receptor–negative or HER2-negative disease.

"Eribulin and capecitabine have similar overall activity in this trial that included patients in the first-, second-, and third-line settings," Dr. Kaufman commented in a press briefing. "Our findings, I want to emphasize, are not definitive but interesting in terms of certain subsets and suggest that the triple-negative subgroup perhaps may be doing better with eribulin."

The reason for the unusual combination of a trend toward overall survival benefit in the absence of a progression-free survival benefit is unknown, he said. "This is not typical of what one sees in metastatic breast cancer, but the data are what the data are."

Given the trial’s findings, what are clinicians to do?

"I think eribulin is a reasonable option to consider therapeutically now for women. It compares reasonably to capecitabine," maintained Dr. Kaufman of the Geisel School of Medicine at Dartmouth and the Norris Cotton Cancer Center in Lebanon, N.H. "Our primary objective was to demonstrate superiority, which we did not meet. But the results are reasonably encouraging."

HER2 Therapy Questioned

In the session where the results were presented, attendee Dr. Daniel F. Hayes of the University of Michigan, Ann Arbor said, "I’m assuming that everyone who was HER2-positive received trastuzumab or some other anti-HER2 therapy, which might affect your subgroup analysis for HER2."

"A large proportion of the study population was enrolled in eastern Europe or South America, parts of the world where trastuzumab and other HER2-targeted therapies were not routinely used at the time of enrollment for this study," Dr. Kaufman replied. "We are sorting out those results and will present them at a further date."

Dr. Hayes also wondered about crossover on the trial and its possible impact on overall survival.

Although there was no planned crossover, about half of patients in the eribulin arm did switch to capecitabine, and that may have affected the results, Dr. Kaufman acknowledged. "We are pulling the data together on post-progression treatments to try to analyze that further."

FDA Requested Bone Scans

Attendee Dr. Steven Vogl of Montefiore Medical Center in the Bronx, New York, took issue with the objective response rates with both eribulin and capecitabine, which were 16% and 20%, respectively, by local investigator assessment but just 11% and 12% on independent review.

"The objective response rate on radiologic review is sort of distressing," he said. "Did someone decide that if the bone scan didn’t get better, that wasn’t a response, even though the node shrank 70%?"

"Correct. So this is one of the reasons why the response rate on the independent analysis is lower," Dr. Kaufman replied. "If the bone scan did not confirm it, those patients were not scored as having responding disease; additionally, if the confirmatory bone scan was not performed, those patients were not scored as having an objective response.

"We are still pulling all this together, but I think that is a large piece of why the independent analysis response rates were lower than the local investigator assessment. But I will highlight also that ... only about 20% of the patients were in the first-line setting, so it’s not a pure first-line trial."

"The 20% response rate in a third-line trial is credible, but the 10% response rate – some of us don’t think that’s worth pursuing," Dr. Vogl added. "I think bone scans shouldn’t be done on studies like this because they take forever to get better."

"Bone scan was actually included at the request of the FDA," Dr. Kaufman noted.

Results Not Statistically Different

Patients were eligible for the trial, formally known as Study 301, if they had locally advanced or metastatic breast cancer and had a received up to three prior regimens (up to two for their advanced disease), which must have included a taxane and an anthracycline.

In all, 1,102 patients were randomized to eribulin – the only chemotherapeutic agent shown to have a survival benefit in heavily pretreated metastatic breast cancer – or capecitabine. The former is approved by the FDA for treatment of metastatic breast cancer after at least two treatment regimens with an anthracycline and a taxane; the latter is approved for treatment of pretreated metastatic breast cancer, as well as stage III colon cancer.

Demographically, the patients had a median age of 53 years. The majority had received one or two prior chemotherapy regimens for advanced disease. More than 85% had visceral involvement.

In terms of drug exposure, the two groups had almost identical median durations of treatment and relative dose intensities.

Main results showed that median overall survival achieved with eribulin was numerically but not statistically better than that with capecitabine (15.9 vs. 14.5 months; hazard ratio, 0.88; P = .056), Dr. Kaufman reported.

In preplanned subgroup analyses, there were trends favoring eribulin over capecitabine in patients who had triple-negative disease (hazard ratio, 0.70), as well as those with HER2-negative disease (0.84) and estrogen receptor–negative disease (0.78).

The 1-, 2-, and 3-year rates of overall survival were statistically indistinguishable between groups.

There was also no significant difference in progression-free survival, with the value standing at about 4 months in each group (P = .31), and no significant difference in response rates.

The eribulin and capecitabine groups were similarly likely to experience treatment-related adverse events (85% and 77%) and serious adverse events (18% and 21%).

"The side effect profiles are consistent with previous data on the side effects of these medications," Dr. Kaufman said.

Eribulin was associated with higher rates of grade 3/4 neutropenia and leukopenia, whereas capecitabine was associated with higher rates of grade 3/4 hand-foot syndrome and diarrhea.

The investigators have not yet performed comparative cost analyses in the trial.

Dr. Kaufman disclosed that he receives research support from and is a consultant to Eisai. The trial was sponsored by Eisai.

SAN ANTONIO – New data from the Women’s Health Initiative dash cold water on the idea that statin therapy reduces breast cancer risk.

The updated WHI findings showed no association between prior statin use and breast cancer risk in nearly 155,000 postmenopausal study participants followed prospectively for an average of 10.8 years.

Indeed, the annualized rate of breast cancer was 0.42% in 11,584 statin users and 0.42% in nonusers in this analysis of 7,430 first cases of invasive breast cancer, Dr. Pinkal Desai reported at the San Antonio Breast Cancer Symposium.

Statin potency, duration of use, lipophilicity versus hydrophilicity – none of those factors had any impact, added Dr. Desai of Providence Hospital Medical Center in Southfield, Mich.

In commenting on Dr. Desai’s WHI update at a session on statins and breast cancer risk, Dr. Vered Stearns noted that the new data represent quite a turnabout, since an earlier report from the WHI was one of the major initial triggers of interest in the notion that statins might protect against breast cancer.

That report (J. Natl. Cancer Inst. 2006;98:700-7) analyzed 4,383 cases of invasive breast cancer among study participants followed for a median of 6.7 years. It showed no reduction in breast cancer risk in association with statins overall; however, there was an 18% reduction in risk (P = .02) among users of lipophilic statins, including simvastatin, lovastatin, and fluvastatin. With longer follow-up and more cases, however, that earlier benefit is gone, observed Dr. Stearns of Johns Hopkins University, Baltimore.

Moreover, a new meta-analysis has put a further damper on the hypothesis that statins protect against breast cancer, she continued. The meta-analysis included 13 published cohort and 11 case-control studies with more than 2.4 million participants, including 76,759 breast cancer patients. The investigators, from the National Institute of Pharmaceutical Education and Research in Punjab, India, found that neither statin use overall nor long-term statin therapy affected breast cancer risk (Breast Cancer Res. Treat. 2012;135:261-9).

Dr. Desai noted that the latest WHI findings do contain one glimmer of hope regarding statins and breast cancer: In a multivariate analysis, women on simvastatin were 13% less likely to develop breast cancer than statin nonusers after adjustment for demographic factors, body mass index, smoking, alcohol intake, family history, age at menarche and at first birth, NSAID use, dietary fat, physical activity, and mammography within the past 2 years. However, this trend toward reduced breast cancer risk with simvastatin therapy didn’t achieve statistical significance.

Statins are safe and cheap, and multiple products are readily available. But in light of the discouraging new epidemiologic data, Dr. Stearns declared "I think that the effects of statins as single agents are modest at best. There’s quite a good rationale, though, for prospective studies of them in combination with standard hormonal therapy, chemotherapy, and radiation therapy, as well as with novel cancer treatment agents."

She added that the statins remain worthy of research interest because many of their pleomorphic cellular effects are antineoplastic. The drugs inhibit the mevalonate pathway, down-regulate metalloproteinases, inhibit Rho and Ras activation, decrease CD44 cells, and increase PTEN antibodies, all of which are salutary from an anticarcinogenesis standpoint.

Dr. Desai and Dr. Stearns reported having no financial conflicts of interest.

SAN ANTONIO – New data from the Women’s Health Initiative dash cold water on the idea that statin therapy reduces breast cancer risk.

The updated WHI findings showed no association between prior statin use and breast cancer risk in nearly 155,000 postmenopausal study participants followed prospectively for an average of 10.8 years.

Indeed, the annualized rate of breast cancer was 0.42% in 11,584 statin users and 0.42% in nonusers in this analysis of 7,430 first cases of invasive breast cancer, Dr. Pinkal Desai reported at the San Antonio Breast Cancer Symposium.

Statin potency, duration of use, lipophilicity versus hydrophilicity – none of those factors had any impact, added Dr. Desai of Providence Hospital Medical Center in Southfield, Mich.

In commenting on Dr. Desai’s WHI update at a session on statins and breast cancer risk, Dr. Vered Stearns noted that the new data represent quite a turnabout, since an earlier report from the WHI was one of the major initial triggers of interest in the notion that statins might protect against breast cancer.

That report (J. Natl. Cancer Inst. 2006;98:700-7) analyzed 4,383 cases of invasive breast cancer among study participants followed for a median of 6.7 years. It showed no reduction in breast cancer risk in association with statins overall; however, there was an 18% reduction in risk (P = .02) among users of lipophilic statins, including simvastatin, lovastatin, and fluvastatin. With longer follow-up and more cases, however, that earlier benefit is gone, observed Dr. Stearns of Johns Hopkins University, Baltimore.

Moreover, a new meta-analysis has put a further damper on the hypothesis that statins protect against breast cancer, she continued. The meta-analysis included 13 published cohort and 11 case-control studies with more than 2.4 million participants, including 76,759 breast cancer patients. The investigators, from the National Institute of Pharmaceutical Education and Research in Punjab, India, found that neither statin use overall nor long-term statin therapy affected breast cancer risk (Breast Cancer Res. Treat. 2012;135:261-9).

Dr. Desai noted that the latest WHI findings do contain one glimmer of hope regarding statins and breast cancer: In a multivariate analysis, women on simvastatin were 13% less likely to develop breast cancer than statin nonusers after adjustment for demographic factors, body mass index, smoking, alcohol intake, family history, age at menarche and at first birth, NSAID use, dietary fat, physical activity, and mammography within the past 2 years. However, this trend toward reduced breast cancer risk with simvastatin therapy didn’t achieve statistical significance.

Statins are safe and cheap, and multiple products are readily available. But in light of the discouraging new epidemiologic data, Dr. Stearns declared "I think that the effects of statins as single agents are modest at best. There’s quite a good rationale, though, for prospective studies of them in combination with standard hormonal therapy, chemotherapy, and radiation therapy, as well as with novel cancer treatment agents."

She added that the statins remain worthy of research interest because many of their pleomorphic cellular effects are antineoplastic. The drugs inhibit the mevalonate pathway, down-regulate metalloproteinases, inhibit Rho and Ras activation, decrease CD44 cells, and increase PTEN antibodies, all of which are salutary from an anticarcinogenesis standpoint.

Dr. Desai and Dr. Stearns reported having no financial conflicts of interest.

SAN ANTONIO – New data from the Women’s Health Initiative dash cold water on the idea that statin therapy reduces breast cancer risk.

The updated WHI findings showed no association between prior statin use and breast cancer risk in nearly 155,000 postmenopausal study participants followed prospectively for an average of 10.8 years.

Indeed, the annualized rate of breast cancer was 0.42% in 11,584 statin users and 0.42% in nonusers in this analysis of 7,430 first cases of invasive breast cancer, Dr. Pinkal Desai reported at the San Antonio Breast Cancer Symposium.

Statin potency, duration of use, lipophilicity versus hydrophilicity – none of those factors had any impact, added Dr. Desai of Providence Hospital Medical Center in Southfield, Mich.

In commenting on Dr. Desai’s WHI update at a session on statins and breast cancer risk, Dr. Vered Stearns noted that the new data represent quite a turnabout, since an earlier report from the WHI was one of the major initial triggers of interest in the notion that statins might protect against breast cancer.

That report (J. Natl. Cancer Inst. 2006;98:700-7) analyzed 4,383 cases of invasive breast cancer among study participants followed for a median of 6.7 years. It showed no reduction in breast cancer risk in association with statins overall; however, there was an 18% reduction in risk (P = .02) among users of lipophilic statins, including simvastatin, lovastatin, and fluvastatin. With longer follow-up and more cases, however, that earlier benefit is gone, observed Dr. Stearns of Johns Hopkins University, Baltimore.

Moreover, a new meta-analysis has put a further damper on the hypothesis that statins protect against breast cancer, she continued. The meta-analysis included 13 published cohort and 11 case-control studies with more than 2.4 million participants, including 76,759 breast cancer patients. The investigators, from the National Institute of Pharmaceutical Education and Research in Punjab, India, found that neither statin use overall nor long-term statin therapy affected breast cancer risk (Breast Cancer Res. Treat. 2012;135:261-9).

Dr. Desai noted that the latest WHI findings do contain one glimmer of hope regarding statins and breast cancer: In a multivariate analysis, women on simvastatin were 13% less likely to develop breast cancer than statin nonusers after adjustment for demographic factors, body mass index, smoking, alcohol intake, family history, age at menarche and at first birth, NSAID use, dietary fat, physical activity, and mammography within the past 2 years. However, this trend toward reduced breast cancer risk with simvastatin therapy didn’t achieve statistical significance.

Statins are safe and cheap, and multiple products are readily available. But in light of the discouraging new epidemiologic data, Dr. Stearns declared "I think that the effects of statins as single agents are modest at best. There’s quite a good rationale, though, for prospective studies of them in combination with standard hormonal therapy, chemotherapy, and radiation therapy, as well as with novel cancer treatment agents."

She added that the statins remain worthy of research interest because many of their pleomorphic cellular effects are antineoplastic. The drugs inhibit the mevalonate pathway, down-regulate metalloproteinases, inhibit Rho and Ras activation, decrease CD44 cells, and increase PTEN antibodies, all of which are salutary from an anticarcinogenesis standpoint.

Dr. Desai and Dr. Stearns reported having no financial conflicts of interest.

SAN ANTONIO – Adjuvant chemotherapy in women with completely resected locoregional recurrence of breast cancer improved disease-free and overall survival in the randomized CALOR trial.

Indeed, adjuvant chemotherapy reduced the risk of recurrent disease by 41% during 5 years of follow-up in CALOR (Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer) while cutting the risk of all-cause mortality by 59%, Dr. Stefan Aebi reported at the annual San Antonio Breast Cancer Symposium.

Thus, CALOR helps resolve a longstanding controversy regarding the appropriate treatment of patients with isolated local or regional recurrence of breast cancer. But the trial provides only a partial resolution. That’s because while adjuvant chemotherapy had a huge benefit in patients with estrogen receptor–negative locoregional recurrences, in estrogen receptor–positive recurrences it had no significant effect.

"Decisions regarding ER-positive recurrent tumors remain a struggle. But events are very few so far. We consider this analysis premature. We will need longer follow-up for patients with ER-positive recurrences to see if there is a benefit for chemotherapy," said Dr. Aebi, head of the division of medical oncology at Lucerne Canton Hospital in Switzerland.

CALOR included 162 patients with isolated local and/or regional recurrence of breast cancer. After complete excisional surgery, they were randomized to chemotherapy or no chemotherapy. The choice of chemotherapy regimen was left to the patient’s oncologists, with a recommendation from CALOR investigators to use at least two drugs for 3-6 months. Radiation therapy was recommended for all patients, but only about 40% received it.

The 5-year disease-free survival rate – the primary endpoint – was 69% in the chemotherapy group compared with 57% with no adjuvant chemotherapy. This translates to a 41% relative risk reduction (P = .045). The 5-year overall survival rate was 88% in the chemotherapy group vs. 76% in controls, for a 59% reduction in risk (P = .02).

These benefits were driven by the outstanding effectiveness of chemotherapy in patients with ER-negative recurrences. Their 5-year disease-free survival rate was 67% with adjuvant chemotherapy compared with 35% without it, for a 68% reduction in risk (P = .007). Overall survival in the ER-negative recurrence subgroup was 79% with chemotherapy and 69% without. In contrast, the 5-year disease-free survival rate in the ER-positive group was 70% with chemotherapy and 69% without.

In a multivariate analysis controlling for ER status, location of the isolated recurrence, and prior chemotherapy, adjunctive chemotherapy was associated with a 50% reduction in recurrent disease during 5 years of follow-up (P = .01). The only other independent predictor of disease-free survival was time since primary surgery: The risk of recurrent disease during 5 years of follow-up dropped by 9% for each year since primary surgery.

This was a difficult study to conduct. The original plans called for recruitment of nearly 1,000 patients, but enrollment was so slow that Dr. Aebi and coinvestigators had to scale back their ambitions, eventually closing the trial with 162 participants.

"There were many colleagues with preconceived ideas. We had colleagues who just knew that chemotherapy was not needed and others who just knew that it was needed. And if you know, why should you randomize your patients?" he explained.

Dr. Carlos L. Arteaga called CALOR "a very important contribution to what has been an ongoing controversy in this field."

"Some surgeons feel very strongly that resection is enough in treating local recurrences, while many of our medical oncologists feel chemotherapy is also required. I have a lot more impetus to give adjuvant chemotherapy based on the CALOR findings," said Dr. Arteaga, director of the breast cancer program at Vanderbilt-Ingram Cancer Center, Nashville, Tenn.

The CALOR trial was sponsored by several major cancer research organizations. Dr. Aebi reported having no financial conflicts.

SAN ANTONIO – Adjuvant chemotherapy in women with completely resected locoregional recurrence of breast cancer improved disease-free and overall survival in the randomized CALOR trial.

Indeed, adjuvant chemotherapy reduced the risk of recurrent disease by 41% during 5 years of follow-up in CALOR (Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer) while cutting the risk of all-cause mortality by 59%, Dr. Stefan Aebi reported at the annual San Antonio Breast Cancer Symposium.

Thus, CALOR helps resolve a longstanding controversy regarding the appropriate treatment of patients with isolated local or regional recurrence of breast cancer. But the trial provides only a partial resolution. That’s because while adjuvant chemotherapy had a huge benefit in patients with estrogen receptor–negative locoregional recurrences, in estrogen receptor–positive recurrences it had no significant effect.

"Decisions regarding ER-positive recurrent tumors remain a struggle. But events are very few so far. We consider this analysis premature. We will need longer follow-up for patients with ER-positive recurrences to see if there is a benefit for chemotherapy," said Dr. Aebi, head of the division of medical oncology at Lucerne Canton Hospital in Switzerland.

CALOR included 162 patients with isolated local and/or regional recurrence of breast cancer. After complete excisional surgery, they were randomized to chemotherapy or no chemotherapy. The choice of chemotherapy regimen was left to the patient’s oncologists, with a recommendation from CALOR investigators to use at least two drugs for 3-6 months. Radiation therapy was recommended for all patients, but only about 40% received it.

The 5-year disease-free survival rate – the primary endpoint – was 69% in the chemotherapy group compared with 57% with no adjuvant chemotherapy. This translates to a 41% relative risk reduction (P = .045). The 5-year overall survival rate was 88% in the chemotherapy group vs. 76% in controls, for a 59% reduction in risk (P = .02).

These benefits were driven by the outstanding effectiveness of chemotherapy in patients with ER-negative recurrences. Their 5-year disease-free survival rate was 67% with adjuvant chemotherapy compared with 35% without it, for a 68% reduction in risk (P = .007). Overall survival in the ER-negative recurrence subgroup was 79% with chemotherapy and 69% without. In contrast, the 5-year disease-free survival rate in the ER-positive group was 70% with chemotherapy and 69% without.

In a multivariate analysis controlling for ER status, location of the isolated recurrence, and prior chemotherapy, adjunctive chemotherapy was associated with a 50% reduction in recurrent disease during 5 years of follow-up (P = .01). The only other independent predictor of disease-free survival was time since primary surgery: The risk of recurrent disease during 5 years of follow-up dropped by 9% for each year since primary surgery.

This was a difficult study to conduct. The original plans called for recruitment of nearly 1,000 patients, but enrollment was so slow that Dr. Aebi and coinvestigators had to scale back their ambitions, eventually closing the trial with 162 participants.

"There were many colleagues with preconceived ideas. We had colleagues who just knew that chemotherapy was not needed and others who just knew that it was needed. And if you know, why should you randomize your patients?" he explained.

Dr. Carlos L. Arteaga called CALOR "a very important contribution to what has been an ongoing controversy in this field."

"Some surgeons feel very strongly that resection is enough in treating local recurrences, while many of our medical oncologists feel chemotherapy is also required. I have a lot more impetus to give adjuvant chemotherapy based on the CALOR findings," said Dr. Arteaga, director of the breast cancer program at Vanderbilt-Ingram Cancer Center, Nashville, Tenn.

The CALOR trial was sponsored by several major cancer research organizations. Dr. Aebi reported having no financial conflicts.

SAN ANTONIO – Adjuvant chemotherapy in women with completely resected locoregional recurrence of breast cancer improved disease-free and overall survival in the randomized CALOR trial.

Indeed, adjuvant chemotherapy reduced the risk of recurrent disease by 41% during 5 years of follow-up in CALOR (Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer) while cutting the risk of all-cause mortality by 59%, Dr. Stefan Aebi reported at the annual San Antonio Breast Cancer Symposium.

Thus, CALOR helps resolve a longstanding controversy regarding the appropriate treatment of patients with isolated local or regional recurrence of breast cancer. But the trial provides only a partial resolution. That’s because while adjuvant chemotherapy had a huge benefit in patients with estrogen receptor–negative locoregional recurrences, in estrogen receptor–positive recurrences it had no significant effect.

"Decisions regarding ER-positive recurrent tumors remain a struggle. But events are very few so far. We consider this analysis premature. We will need longer follow-up for patients with ER-positive recurrences to see if there is a benefit for chemotherapy," said Dr. Aebi, head of the division of medical oncology at Lucerne Canton Hospital in Switzerland.

CALOR included 162 patients with isolated local and/or regional recurrence of breast cancer. After complete excisional surgery, they were randomized to chemotherapy or no chemotherapy. The choice of chemotherapy regimen was left to the patient’s oncologists, with a recommendation from CALOR investigators to use at least two drugs for 3-6 months. Radiation therapy was recommended for all patients, but only about 40% received it.

The 5-year disease-free survival rate – the primary endpoint – was 69% in the chemotherapy group compared with 57% with no adjuvant chemotherapy. This translates to a 41% relative risk reduction (P = .045). The 5-year overall survival rate was 88% in the chemotherapy group vs. 76% in controls, for a 59% reduction in risk (P = .02).

These benefits were driven by the outstanding effectiveness of chemotherapy in patients with ER-negative recurrences. Their 5-year disease-free survival rate was 67% with adjuvant chemotherapy compared with 35% without it, for a 68% reduction in risk (P = .007). Overall survival in the ER-negative recurrence subgroup was 79% with chemotherapy and 69% without. In contrast, the 5-year disease-free survival rate in the ER-positive group was 70% with chemotherapy and 69% without.

In a multivariate analysis controlling for ER status, location of the isolated recurrence, and prior chemotherapy, adjunctive chemotherapy was associated with a 50% reduction in recurrent disease during 5 years of follow-up (P = .01). The only other independent predictor of disease-free survival was time since primary surgery: The risk of recurrent disease during 5 years of follow-up dropped by 9% for each year since primary surgery.

This was a difficult study to conduct. The original plans called for recruitment of nearly 1,000 patients, but enrollment was so slow that Dr. Aebi and coinvestigators had to scale back their ambitions, eventually closing the trial with 162 participants.

"There were many colleagues with preconceived ideas. We had colleagues who just knew that chemotherapy was not needed and others who just knew that it was needed. And if you know, why should you randomize your patients?" he explained.

Dr. Carlos L. Arteaga called CALOR "a very important contribution to what has been an ongoing controversy in this field."

"Some surgeons feel very strongly that resection is enough in treating local recurrences, while many of our medical oncologists feel chemotherapy is also required. I have a lot more impetus to give adjuvant chemotherapy based on the CALOR findings," said Dr. Arteaga, director of the breast cancer program at Vanderbilt-Ingram Cancer Center, Nashville, Tenn.

The CALOR trial was sponsored by several major cancer research organizations. Dr. Aebi reported having no financial conflicts.

SAN ANTONIO – The 10-year incidence of leukemia after adjuvant chemotherapy for breast cancer appears to hover around 0.5%, twice as high as previously reported.

A review of more than 20,000 patient records included in the National Comprehensive Cancer Network (NCCN) database found 51 cases of leukemia that developed within 10 years of treatment. Women who had only chemotherapy were at the greatest risk – almost six times more likely to develop the disease than the surgery-only control group, Dr. Antonio Wolff said at that annual San Antonio Breast Cancer Symposium.

"We know that the observed survival benefit with adjuvant therapy does take into account the potential mortality associated with leukemia," said Dr. Wolff of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore. "But often we are in the situation where we make the decision to give chemotherapy ‘just because.’ We need to be very careful here, because some of those patients will potentially derive none of the benefits of chemo, and be at risk of its toxicities."

Dr. Wolff and colleagues examined the 1997-2008 data from eight facilities in the NCCN database – a total of 20,533 women with a first diagnosis of breast cancer. The median follow-up was 5 years, but some data were available for up to 15 years after treatment.

About half of the cohort had stage I disease; in most, the cancer was invasive ductal. Slightly more than half had hormone receptor–positive/HER2 negative disease.

The only baseline characteristic significantly different between the groups was age. Women who developed leukemia were significantly older at the time of their cancer treatment (60 vs. 54 years; P = .02); 78% of those with leukemia were older than 50 years.

Of the 51 cases, 44 were acute myeloid leukemia (AML), with a median onset time of 3.5 years after treatment. One-third of these occurred in women with a family history of breast or ovarian cancer. The median time to onset in the AML cases was 2 years.

None of the tumor characteristics were significantly associated with the development of leukemia. There were no significant differences among those who had breast-conserving surgery, mastectomy, or no surgery; or between those who had no radiation therapy, radiation without surgery, radiation after breast-conserving surgery, or radiation after mastectomy, though larger numbers of patients are needed for some of these smaller subset analyses.

The overall rate of leukemia per 1,000 patient/years was 0.46; in the surgery-only group, the rate was 0.16 per 1,000 patient-years. "Of interest is that the rates in each of the treatment groups were similar to the overall rate," – 0.43 in the radiation-only group, 0.52 in the chemotherapy-only group, and 0.54 in the combination therapy group.

At 5 years, the cumulative incidence of leukemia was 0.05% in the surgery-only group; 0.19% in the radiation-only group; 0.30% in the chemotherapy-only group; and 0.32% in the combination therapy group.

But the onset accelerated over the study period, Dr. Wolff noted, with the bulk of cases developing from years 6 to 10. .By the end of the 10-year period, the incidence was 0.2% in the surgery-only group; 0.44% in the radiation-only group; 0.52% in the chemotherapy group; and 0.51% in the combination group.

In a risk analysis using surgery as the control, the overall hazard ratio of leukemia was 2.7 in the radiation-only group; 5.68 in the chemotherapy only group; and 5.64 in the combination group.

Radiation appeared to confer no significant additional risk when it was combined with chemotherapy, Dr. Wolff added.

The findings are strikingly different than previously identified. The largest study of the association was published in 2003, when researchers from the National Surgical Adjuvant Breast and Bowel Project Operations Center reviewed six trials that examined rates of acute myeloid leukemia and myelodysplastic syndrome after doxorubicin and cyclophosphamide therapy (Clin. Breast Cancer 2003;4:273-9).

The subgroup that received anthracycline/cyclophosphamide in that review had a cumulative 8-year incidence of 0.24%. In Dr. Wolff’s chemotherapy subgroup, the cumulative 8-year incidence was 0.52%.

"It’s very important to keep in mind that the known leukemia latency period for anthracycline is 1-3 years, but that of alkylating drugs like cyclophosphamide is 4-6 years and there are case reports of it developing after 10 years," he said. "We need to be very careful when we talk about survival at 5 years vs. 10 years in exposed patients, because they could be at risk for a decade and, potentially, even longer."

SAN ANTONIO – The 10-year incidence of leukemia after adjuvant chemotherapy for breast cancer appears to hover around 0.5%, twice as high as previously reported.

A review of more than 20,000 patient records included in the National Comprehensive Cancer Network (NCCN) database found 51 cases of leukemia that developed within 10 years of treatment. Women who had only chemotherapy were at the greatest risk – almost six times more likely to develop the disease than the surgery-only control group, Dr. Antonio Wolff said at that annual San Antonio Breast Cancer Symposium.

"We know that the observed survival benefit with adjuvant therapy does take into account the potential mortality associated with leukemia," said Dr. Wolff of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore. "But often we are in the situation where we make the decision to give chemotherapy ‘just because.’ We need to be very careful here, because some of those patients will potentially derive none of the benefits of chemo, and be at risk of its toxicities."

Dr. Wolff and colleagues examined the 1997-2008 data from eight facilities in the NCCN database – a total of 20,533 women with a first diagnosis of breast cancer. The median follow-up was 5 years, but some data were available for up to 15 years after treatment.

About half of the cohort had stage I disease; in most, the cancer was invasive ductal. Slightly more than half had hormone receptor–positive/HER2 negative disease.

The only baseline characteristic significantly different between the groups was age. Women who developed leukemia were significantly older at the time of their cancer treatment (60 vs. 54 years; P = .02); 78% of those with leukemia were older than 50 years.

Of the 51 cases, 44 were acute myeloid leukemia (AML), with a median onset time of 3.5 years after treatment. One-third of these occurred in women with a family history of breast or ovarian cancer. The median time to onset in the AML cases was 2 years.

None of the tumor characteristics were significantly associated with the development of leukemia. There were no significant differences among those who had breast-conserving surgery, mastectomy, or no surgery; or between those who had no radiation therapy, radiation without surgery, radiation after breast-conserving surgery, or radiation after mastectomy, though larger numbers of patients are needed for some of these smaller subset analyses.

The overall rate of leukemia per 1,000 patient/years was 0.46; in the surgery-only group, the rate was 0.16 per 1,000 patient-years. "Of interest is that the rates in each of the treatment groups were similar to the overall rate," – 0.43 in the radiation-only group, 0.52 in the chemotherapy-only group, and 0.54 in the combination therapy group.

At 5 years, the cumulative incidence of leukemia was 0.05% in the surgery-only group; 0.19% in the radiation-only group; 0.30% in the chemotherapy-only group; and 0.32% in the combination therapy group.

But the onset accelerated over the study period, Dr. Wolff noted, with the bulk of cases developing from years 6 to 10. .By the end of the 10-year period, the incidence was 0.2% in the surgery-only group; 0.44% in the radiation-only group; 0.52% in the chemotherapy group; and 0.51% in the combination group.

In a risk analysis using surgery as the control, the overall hazard ratio of leukemia was 2.7 in the radiation-only group; 5.68 in the chemotherapy only group; and 5.64 in the combination group.

Radiation appeared to confer no significant additional risk when it was combined with chemotherapy, Dr. Wolff added.

The findings are strikingly different than previously identified. The largest study of the association was published in 2003, when researchers from the National Surgical Adjuvant Breast and Bowel Project Operations Center reviewed six trials that examined rates of acute myeloid leukemia and myelodysplastic syndrome after doxorubicin and cyclophosphamide therapy (Clin. Breast Cancer 2003;4:273-9).

The subgroup that received anthracycline/cyclophosphamide in that review had a cumulative 8-year incidence of 0.24%. In Dr. Wolff’s chemotherapy subgroup, the cumulative 8-year incidence was 0.52%.

"It’s very important to keep in mind that the known leukemia latency period for anthracycline is 1-3 years, but that of alkylating drugs like cyclophosphamide is 4-6 years and there are case reports of it developing after 10 years," he said. "We need to be very careful when we talk about survival at 5 years vs. 10 years in exposed patients, because they could be at risk for a decade and, potentially, even longer."

SAN ANTONIO – The 10-year incidence of leukemia after adjuvant chemotherapy for breast cancer appears to hover around 0.5%, twice as high as previously reported.

A review of more than 20,000 patient records included in the National Comprehensive Cancer Network (NCCN) database found 51 cases of leukemia that developed within 10 years of treatment. Women who had only chemotherapy were at the greatest risk – almost six times more likely to develop the disease than the surgery-only control group, Dr. Antonio Wolff said at that annual San Antonio Breast Cancer Symposium.

"We know that the observed survival benefit with adjuvant therapy does take into account the potential mortality associated with leukemia," said Dr. Wolff of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore. "But often we are in the situation where we make the decision to give chemotherapy ‘just because.’ We need to be very careful here, because some of those patients will potentially derive none of the benefits of chemo, and be at risk of its toxicities."

Dr. Wolff and colleagues examined the 1997-2008 data from eight facilities in the NCCN database – a total of 20,533 women with a first diagnosis of breast cancer. The median follow-up was 5 years, but some data were available for up to 15 years after treatment.

About half of the cohort had stage I disease; in most, the cancer was invasive ductal. Slightly more than half had hormone receptor–positive/HER2 negative disease.

The only baseline characteristic significantly different between the groups was age. Women who developed leukemia were significantly older at the time of their cancer treatment (60 vs. 54 years; P = .02); 78% of those with leukemia were older than 50 years.

Of the 51 cases, 44 were acute myeloid leukemia (AML), with a median onset time of 3.5 years after treatment. One-third of these occurred in women with a family history of breast or ovarian cancer. The median time to onset in the AML cases was 2 years.

None of the tumor characteristics were significantly associated with the development of leukemia. There were no significant differences among those who had breast-conserving surgery, mastectomy, or no surgery; or between those who had no radiation therapy, radiation without surgery, radiation after breast-conserving surgery, or radiation after mastectomy, though larger numbers of patients are needed for some of these smaller subset analyses.

The overall rate of leukemia per 1,000 patient/years was 0.46; in the surgery-only group, the rate was 0.16 per 1,000 patient-years. "Of interest is that the rates in each of the treatment groups were similar to the overall rate," – 0.43 in the radiation-only group, 0.52 in the chemotherapy-only group, and 0.54 in the combination therapy group.

At 5 years, the cumulative incidence of leukemia was 0.05% in the surgery-only group; 0.19% in the radiation-only group; 0.30% in the chemotherapy-only group; and 0.32% in the combination therapy group.

But the onset accelerated over the study period, Dr. Wolff noted, with the bulk of cases developing from years 6 to 10. .By the end of the 10-year period, the incidence was 0.2% in the surgery-only group; 0.44% in the radiation-only group; 0.52% in the chemotherapy group; and 0.51% in the combination group.

In a risk analysis using surgery as the control, the overall hazard ratio of leukemia was 2.7 in the radiation-only group; 5.68 in the chemotherapy only group; and 5.64 in the combination group.

Radiation appeared to confer no significant additional risk when it was combined with chemotherapy, Dr. Wolff added.

The findings are strikingly different than previously identified. The largest study of the association was published in 2003, when researchers from the National Surgical Adjuvant Breast and Bowel Project Operations Center reviewed six trials that examined rates of acute myeloid leukemia and myelodysplastic syndrome after doxorubicin and cyclophosphamide therapy (Clin. Breast Cancer 2003;4:273-9).

The subgroup that received anthracycline/cyclophosphamide in that review had a cumulative 8-year incidence of 0.24%. In Dr. Wolff’s chemotherapy subgroup, the cumulative 8-year incidence was 0.52%.

"It’s very important to keep in mind that the known leukemia latency period for anthracycline is 1-3 years, but that of alkylating drugs like cyclophosphamide is 4-6 years and there are case reports of it developing after 10 years," he said. "We need to be very careful when we talk about survival at 5 years vs. 10 years in exposed patients, because they could be at risk for a decade and, potentially, even longer."

SAN ANTONIO – In the not-too-distant future, triple-negative breast cancer that persists after neoadjuvant chemotherapy could potentially be treated with targeted therapies, new data suggest.

At the time of resection performed after neoadjuvant chemotherapy, about 90% of residual tumors have alterations in pathways that could potentially be targeted by agents that are already on the market or in the pipeline, researchers reported at the San Antonio Breast Cancer Symposium. Thus, targeted adjuvant treatment might ultimately reduce the risk of recurrence.

"We believe (these cells) likely mirror the molecular profiles present in the clinically silent micrometastases that are ultimately destined to recur in such patients. If we had knowledge of these molecular alterations, it could provide us some therapeutic impetus to treat patients after surgical resection," according to lead investigator Justin M. Balko, Pharm.D., Ph.D., a research faculty member at the Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

Additional study results suggested that some residual triple-negative breast cancers might be treated effectively with two emerging classes of agents, inhibitors of janus kinase 2 (JAK2) and MEK. Both proteins are involved in cell growth and proliferation.

"These data provide a targetable catalogue of the alterations present in the residual disease of triple-negative breast cancer after neoadjuvant chemotherapy, and we believe that they support genomically driven adjuvant trials in this patient population," Dr. Balko maintained.

"This study is a discovery exercise that to me suggests nothing has changed in clinical care, but it is a strong direction for discovery and research," commented Dr. Carlos Arteaga, moderator of a related press briefing and associate director for clinical research and director of the breast cancer program at Vanderbilt-Ingram Cancer Center.

"If you have patients who have residual disease in the breast after chemotherapy, the standard of care is just to observe those patients. But many of them are going to recur and die from their metastases," noted Dr. Arteaga, who was also a researcher on the study. "The reason we don’t treat them is because we don’t know how to treat them. So this study suggests that there are actionable molecular lesions that we may one day be able to act upon early and potentially change the natural history of that micrometastatic disease that is waiting there to recur in a few months or years."

The investigators obtained residual tumor samples from 114 patients who had completed neoadjuvant chemotherapy for triple-negative breast cancer. They measured immunohistochemical protein expression in 112 tumors and nanostring gene expression in 89 tumors, and performed next-generation sequencing in 81 tumors.

The patients were 48 years old, on average, and most had stage III disease. About half of them had received a taxane as part of their neoadjuvant chemotherapy and were postmenopausal.

The genes most commonly showing amplifications, deletions, or mutations of known or implied functional significance were p53 (altered in about 90% of tumors), MCL1 (an antiapoptotic gene, altered in 55%), and MYC (altered in 30%). But alterations were found, albeit less commonly, in more than 15 other genes as well.

"This heterogeneity highlights a need for personalized medicine in this subgroup" of patients, Dr. Balko commented.

When the altered genes were grouped into pathways, 90% of patients had tumors with at least one affected pathway that could potentially be targeted by agents that are already available or in clinical trials.

The most commonly affected pathways were the PI3 kinase and mammalian target of rapamycin (PI3K/mTOR) pathway (potentially targeted by PI3K/mTOR inhibitors) and the cell cycle pathways (potentially targeted by cell cycle or mitotic spindle inhibitors).

Additionally, alterations were found in the DNA repair pathway (potentially targeted by DNA repair–targeting agents), the Ras/MAPK pathway (potentially targeted by RAF/MEK inhibitors), and growth factor receptor pathways (potentially targeted with receptor tyrosine kinase inhibitors).

Patients whose tumors had high MEK activation and MYC amplification had poorer recurrence-free survival than others (P = .03). In vitro treatment of MYC-overexpressing cells with two MEK inhibitors in clinical trials – selumetinib and trametinib – indeed reduced colony formation.

"This may provide some justification for exploring MEK inhibition within MYC-amplified tumors," Dr. Balko proposed.

In a novel finding, 11% of tumors had amplification of JAK2, which is thought to contribute to cancer cells’ stem cell–like behavior. Compared to others, patients with these tumors also had poorer recurrence-free survival (P = .005) and overall survival (P = .002). They also had higher levels of gene expression of interleukin 6, one of the main cytokines activating this pathway.

"We would like to propose that these JAK2 amplifications may represent a biomarker for clinical trials exploring JAK2 inhibitors that are currently in clinical trials for inflammatory diseases," Dr. Balko said.

As for future research, "efforts to determine whether lesions present in the residual disease mirror those in the recurrence and whether they are selected during neoadjuvant treatment are under way," he concluded.

The research was funded by the Susan G. Komen for the Cure Foundation, the National Institutes of Health, and the Lee Jeans/Entertainment Industry Foundation Translational Breast Cancer Research Program. Dr. Balko disclosed no relevant conflicts of interest. Dr. Arteaga disclosed he is a consultant/adviser for Roche, Monogram Biosciences, AstraZeneca, GlaxoSmithKline, and Genentech, and that he receives research grants from Amgen, AstraZeneca, and Exelixis.

SAN ANTONIO – In the not-too-distant future, triple-negative breast cancer that persists after neoadjuvant chemotherapy could potentially be treated with targeted therapies, new data suggest.

At the time of resection performed after neoadjuvant chemotherapy, about 90% of residual tumors have alterations in pathways that could potentially be targeted by agents that are already on the market or in the pipeline, researchers reported at the San Antonio Breast Cancer Symposium. Thus, targeted adjuvant treatment might ultimately reduce the risk of recurrence.

"We believe (these cells) likely mirror the molecular profiles present in the clinically silent micrometastases that are ultimately destined to recur in such patients. If we had knowledge of these molecular alterations, it could provide us some therapeutic impetus to treat patients after surgical resection," according to lead investigator Justin M. Balko, Pharm.D., Ph.D., a research faculty member at the Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

Additional study results suggested that some residual triple-negative breast cancers might be treated effectively with two emerging classes of agents, inhibitors of janus kinase 2 (JAK2) and MEK. Both proteins are involved in cell growth and proliferation.

"These data provide a targetable catalogue of the alterations present in the residual disease of triple-negative breast cancer after neoadjuvant chemotherapy, and we believe that they support genomically driven adjuvant trials in this patient population," Dr. Balko maintained.

"This study is a discovery exercise that to me suggests nothing has changed in clinical care, but it is a strong direction for discovery and research," commented Dr. Carlos Arteaga, moderator of a related press briefing and associate director for clinical research and director of the breast cancer program at Vanderbilt-Ingram Cancer Center.

"If you have patients who have residual disease in the breast after chemotherapy, the standard of care is just to observe those patients. But many of them are going to recur and die from their metastases," noted Dr. Arteaga, who was also a researcher on the study. "The reason we don’t treat them is because we don’t know how to treat them. So this study suggests that there are actionable molecular lesions that we may one day be able to act upon early and potentially change the natural history of that micrometastatic disease that is waiting there to recur in a few months or years."

The investigators obtained residual tumor samples from 114 patients who had completed neoadjuvant chemotherapy for triple-negative breast cancer. They measured immunohistochemical protein expression in 112 tumors and nanostring gene expression in 89 tumors, and performed next-generation sequencing in 81 tumors.

The patients were 48 years old, on average, and most had stage III disease. About half of them had received a taxane as part of their neoadjuvant chemotherapy and were postmenopausal.

The genes most commonly showing amplifications, deletions, or mutations of known or implied functional significance were p53 (altered in about 90% of tumors), MCL1 (an antiapoptotic gene, altered in 55%), and MYC (altered in 30%). But alterations were found, albeit less commonly, in more than 15 other genes as well.

"This heterogeneity highlights a need for personalized medicine in this subgroup" of patients, Dr. Balko commented.

When the altered genes were grouped into pathways, 90% of patients had tumors with at least one affected pathway that could potentially be targeted by agents that are already available or in clinical trials.

The most commonly affected pathways were the PI3 kinase and mammalian target of rapamycin (PI3K/mTOR) pathway (potentially targeted by PI3K/mTOR inhibitors) and the cell cycle pathways (potentially targeted by cell cycle or mitotic spindle inhibitors).

Additionally, alterations were found in the DNA repair pathway (potentially targeted by DNA repair–targeting agents), the Ras/MAPK pathway (potentially targeted by RAF/MEK inhibitors), and growth factor receptor pathways (potentially targeted with receptor tyrosine kinase inhibitors).

Patients whose tumors had high MEK activation and MYC amplification had poorer recurrence-free survival than others (P = .03). In vitro treatment of MYC-overexpressing cells with two MEK inhibitors in clinical trials – selumetinib and trametinib – indeed reduced colony formation.

"This may provide some justification for exploring MEK inhibition within MYC-amplified tumors," Dr. Balko proposed.

In a novel finding, 11% of tumors had amplification of JAK2, which is thought to contribute to cancer cells’ stem cell–like behavior. Compared to others, patients with these tumors also had poorer recurrence-free survival (P = .005) and overall survival (P = .002). They also had higher levels of gene expression of interleukin 6, one of the main cytokines activating this pathway.

"We would like to propose that these JAK2 amplifications may represent a biomarker for clinical trials exploring JAK2 inhibitors that are currently in clinical trials for inflammatory diseases," Dr. Balko said.

As for future research, "efforts to determine whether lesions present in the residual disease mirror those in the recurrence and whether they are selected during neoadjuvant treatment are under way," he concluded.

The research was funded by the Susan G. Komen for the Cure Foundation, the National Institutes of Health, and the Lee Jeans/Entertainment Industry Foundation Translational Breast Cancer Research Program. Dr. Balko disclosed no relevant conflicts of interest. Dr. Arteaga disclosed he is a consultant/adviser for Roche, Monogram Biosciences, AstraZeneca, GlaxoSmithKline, and Genentech, and that he receives research grants from Amgen, AstraZeneca, and Exelixis.

SAN ANTONIO – In the not-too-distant future, triple-negative breast cancer that persists after neoadjuvant chemotherapy could potentially be treated with targeted therapies, new data suggest.

At the time of resection performed after neoadjuvant chemotherapy, about 90% of residual tumors have alterations in pathways that could potentially be targeted by agents that are already on the market or in the pipeline, researchers reported at the San Antonio Breast Cancer Symposium. Thus, targeted adjuvant treatment might ultimately reduce the risk of recurrence.

"We believe (these cells) likely mirror the molecular profiles present in the clinically silent micrometastases that are ultimately destined to recur in such patients. If we had knowledge of these molecular alterations, it could provide us some therapeutic impetus to treat patients after surgical resection," according to lead investigator Justin M. Balko, Pharm.D., Ph.D., a research faculty member at the Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

Additional study results suggested that some residual triple-negative breast cancers might be treated effectively with two emerging classes of agents, inhibitors of janus kinase 2 (JAK2) and MEK. Both proteins are involved in cell growth and proliferation.

"These data provide a targetable catalogue of the alterations present in the residual disease of triple-negative breast cancer after neoadjuvant chemotherapy, and we believe that they support genomically driven adjuvant trials in this patient population," Dr. Balko maintained.

"This study is a discovery exercise that to me suggests nothing has changed in clinical care, but it is a strong direction for discovery and research," commented Dr. Carlos Arteaga, moderator of a related press briefing and associate director for clinical research and director of the breast cancer program at Vanderbilt-Ingram Cancer Center.

"If you have patients who have residual disease in the breast after chemotherapy, the standard of care is just to observe those patients. But many of them are going to recur and die from their metastases," noted Dr. Arteaga, who was also a researcher on the study. "The reason we don’t treat them is because we don’t know how to treat them. So this study suggests that there are actionable molecular lesions that we may one day be able to act upon early and potentially change the natural history of that micrometastatic disease that is waiting there to recur in a few months or years."

The investigators obtained residual tumor samples from 114 patients who had completed neoadjuvant chemotherapy for triple-negative breast cancer. They measured immunohistochemical protein expression in 112 tumors and nanostring gene expression in 89 tumors, and performed next-generation sequencing in 81 tumors.

The patients were 48 years old, on average, and most had stage III disease. About half of them had received a taxane as part of their neoadjuvant chemotherapy and were postmenopausal.

The genes most commonly showing amplifications, deletions, or mutations of known or implied functional significance were p53 (altered in about 90% of tumors), MCL1 (an antiapoptotic gene, altered in 55%), and MYC (altered in 30%). But alterations were found, albeit less commonly, in more than 15 other genes as well.

"This heterogeneity highlights a need for personalized medicine in this subgroup" of patients, Dr. Balko commented.

When the altered genes were grouped into pathways, 90% of patients had tumors with at least one affected pathway that could potentially be targeted by agents that are already available or in clinical trials.

The most commonly affected pathways were the PI3 kinase and mammalian target of rapamycin (PI3K/mTOR) pathway (potentially targeted by PI3K/mTOR inhibitors) and the cell cycle pathways (potentially targeted by cell cycle or mitotic spindle inhibitors).

Additionally, alterations were found in the DNA repair pathway (potentially targeted by DNA repair–targeting agents), the Ras/MAPK pathway (potentially targeted by RAF/MEK inhibitors), and growth factor receptor pathways (potentially targeted with receptor tyrosine kinase inhibitors).

Patients whose tumors had high MEK activation and MYC amplification had poorer recurrence-free survival than others (P = .03). In vitro treatment of MYC-overexpressing cells with two MEK inhibitors in clinical trials – selumetinib and trametinib – indeed reduced colony formation.

"This may provide some justification for exploring MEK inhibition within MYC-amplified tumors," Dr. Balko proposed.

In a novel finding, 11% of tumors had amplification of JAK2, which is thought to contribute to cancer cells’ stem cell–like behavior. Compared to others, patients with these tumors also had poorer recurrence-free survival (P = .005) and overall survival (P = .002). They also had higher levels of gene expression of interleukin 6, one of the main cytokines activating this pathway.

"We would like to propose that these JAK2 amplifications may represent a biomarker for clinical trials exploring JAK2 inhibitors that are currently in clinical trials for inflammatory diseases," Dr. Balko said.

As for future research, "efforts to determine whether lesions present in the residual disease mirror those in the recurrence and whether they are selected during neoadjuvant treatment are under way," he concluded.

The research was funded by the Susan G. Komen for the Cure Foundation, the National Institutes of Health, and the Lee Jeans/Entertainment Industry Foundation Translational Breast Cancer Research Program. Dr. Balko disclosed no relevant conflicts of interest. Dr. Arteaga disclosed he is a consultant/adviser for Roche, Monogram Biosciences, AstraZeneca, GlaxoSmithKline, and Genentech, and that he receives research grants from Amgen, AstraZeneca, and Exelixis.

SAN ANTONIO – When given along with conventional hormone therapy, bevacizumab improved neither disease-free progression times nor mortality, compared with conventional treatment alone in patients with advanced breast cancer.

The median progression-free survival time for the combination regimen was 18.4 months, compared with 13.8 months for standard estrogen therapy alone – a nonsignificant 17% risk reduction in the phase III LEA trial (hazard ratio, 0.83; P = .14)

© SABCS/Todd Buchanan 2012

Median overall survival was 41 months with bevacizumab (Avastin) added and 42 months with standard therapy (HR, 1.18; P = .469), Dr. Miguel Martin reported at the San Antonio Breast Cancer Symposium. There were 42 deaths in each group.

"Adding bevacizumab to estrogen therapy as a first-line treatment had no impact on progression-free survival or overall survival," said Dr. Martin of the Instituto de Investigación Sanitaria Gregorio Marañón, Madrid.

The phase III LEA (letrozole/fulvestrant and Avastin) trial included 380 patients with unresectable locally advanced or metastatic breast cancer that was hormone receptor–positive and HER2 negative. They were randomized to one of two treatment regimens: conventional hormone therapy of letrozole (Femara, 2.5 mg daily) or fulvestrant (Faslodex, 250 mg monthly) or to one of those drugs with concomitant bevacizumab (15 mg/kg every 3 weeks). Most patients in both trial arms received letrozole (89%-92%).

All of the patients were postmenopausal. Although previous treatment with adjuvant aromatase inhibitors was allowed, the patients had no prior therapy for advanced disease, said Dr. Martin.

The patients’ median age was 65 years (38-86 years). Most (72%) were fully active, with an Eastern Cooperative Oncology Group score of 0. About 80% were metastatic, with 48% having visceral disease and 65% measurable bone lesions.

Almost all patients had received some form of adjuvant therapy, including 44% who had undergone adjuvant chemotherapy and 51% who had taken adjuvant endocrine therapy.

Anemia occurred in virtually all patients, but neutropenia was seen in just 6% of the standard therapy group and 11% of the combination group – not a significant difference. Both leukopenia and thrombocytopenia were significantly more common in the combination group (leukopenia, 25% vs. 11%; P = less than .001; and thrombocytopenia 19% vs. 9%; P = .006).

Nonhematologic toxicities were significantly more common among patients taking the combination treatment. Fatigue was present in 51% of the combination group vs. 29% of the standard therapy group, hypertension in 59% vs. 16%, hemorrhage in 19% vs. 2%, liver enzyme elevation in 47% vs. 28%, and proteinuria in 30% vs. 3%, respectively. All of these differences were highly significant statistically (P less than .001).

There was no significant between-group difference in the occurrence of thromboembolic events (2% vs. 0%; P = .373).

Dr. Martin said that the control group did much better than was expected. However, he suggested that biomarker studies might be able to pinpoint a select population that could benefit from the addition of bevacizumab to standard hormonal therapy.

Dr. Martin is on the speakers bureau and a consultant for Roche.

SAN ANTONIO – When given along with conventional hormone therapy, bevacizumab improved neither disease-free progression times nor mortality, compared with conventional treatment alone in patients with advanced breast cancer.

The median progression-free survival time for the combination regimen was 18.4 months, compared with 13.8 months for standard estrogen therapy alone – a nonsignificant 17% risk reduction in the phase III LEA trial (hazard ratio, 0.83; P = .14)

© SABCS/Todd Buchanan 2012

Median overall survival was 41 months with bevacizumab (Avastin) added and 42 months with standard therapy (HR, 1.18; P = .469), Dr. Miguel Martin reported at the San Antonio Breast Cancer Symposium. There were 42 deaths in each group.

"Adding bevacizumab to estrogen therapy as a first-line treatment had no impact on progression-free survival or overall survival," said Dr. Martin of the Instituto de Investigación Sanitaria Gregorio Marañón, Madrid.

The phase III LEA (letrozole/fulvestrant and Avastin) trial included 380 patients with unresectable locally advanced or metastatic breast cancer that was hormone receptor–positive and HER2 negative. They were randomized to one of two treatment regimens: conventional hormone therapy of letrozole (Femara, 2.5 mg daily) or fulvestrant (Faslodex, 250 mg monthly) or to one of those drugs with concomitant bevacizumab (15 mg/kg every 3 weeks). Most patients in both trial arms received letrozole (89%-92%).

All of the patients were postmenopausal. Although previous treatment with adjuvant aromatase inhibitors was allowed, the patients had no prior therapy for advanced disease, said Dr. Martin.

The patients’ median age was 65 years (38-86 years). Most (72%) were fully active, with an Eastern Cooperative Oncology Group score of 0. About 80% were metastatic, with 48% having visceral disease and 65% measurable bone lesions.

Almost all patients had received some form of adjuvant therapy, including 44% who had undergone adjuvant chemotherapy and 51% who had taken adjuvant endocrine therapy.

Anemia occurred in virtually all patients, but neutropenia was seen in just 6% of the standard therapy group and 11% of the combination group – not a significant difference. Both leukopenia and thrombocytopenia were significantly more common in the combination group (leukopenia, 25% vs. 11%; P = less than .001; and thrombocytopenia 19% vs. 9%; P = .006).

Nonhematologic toxicities were significantly more common among patients taking the combination treatment. Fatigue was present in 51% of the combination group vs. 29% of the standard therapy group, hypertension in 59% vs. 16%, hemorrhage in 19% vs. 2%, liver enzyme elevation in 47% vs. 28%, and proteinuria in 30% vs. 3%, respectively. All of these differences were highly significant statistically (P less than .001).

There was no significant between-group difference in the occurrence of thromboembolic events (2% vs. 0%; P = .373).

Dr. Martin said that the control group did much better than was expected. However, he suggested that biomarker studies might be able to pinpoint a select population that could benefit from the addition of bevacizumab to standard hormonal therapy.

Dr. Martin is on the speakers bureau and a consultant for Roche.

SAN ANTONIO – When given along with conventional hormone therapy, bevacizumab improved neither disease-free progression times nor mortality, compared with conventional treatment alone in patients with advanced breast cancer.

The median progression-free survival time for the combination regimen was 18.4 months, compared with 13.8 months for standard estrogen therapy alone – a nonsignificant 17% risk reduction in the phase III LEA trial (hazard ratio, 0.83; P = .14)

© SABCS/Todd Buchanan 2012

Median overall survival was 41 months with bevacizumab (Avastin) added and 42 months with standard therapy (HR, 1.18; P = .469), Dr. Miguel Martin reported at the San Antonio Breast Cancer Symposium. There were 42 deaths in each group.

"Adding bevacizumab to estrogen therapy as a first-line treatment had no impact on progression-free survival or overall survival," said Dr. Martin of the Instituto de Investigación Sanitaria Gregorio Marañón, Madrid.

The phase III LEA (letrozole/fulvestrant and Avastin) trial included 380 patients with unresectable locally advanced or metastatic breast cancer that was hormone receptor–positive and HER2 negative. They were randomized to one of two treatment regimens: conventional hormone therapy of letrozole (Femara, 2.5 mg daily) or fulvestrant (Faslodex, 250 mg monthly) or to one of those drugs with concomitant bevacizumab (15 mg/kg every 3 weeks). Most patients in both trial arms received letrozole (89%-92%).

All of the patients were postmenopausal. Although previous treatment with adjuvant aromatase inhibitors was allowed, the patients had no prior therapy for advanced disease, said Dr. Martin.

The patients’ median age was 65 years (38-86 years). Most (72%) were fully active, with an Eastern Cooperative Oncology Group score of 0. About 80% were metastatic, with 48% having visceral disease and 65% measurable bone lesions.

Almost all patients had received some form of adjuvant therapy, including 44% who had undergone adjuvant chemotherapy and 51% who had taken adjuvant endocrine therapy.

Anemia occurred in virtually all patients, but neutropenia was seen in just 6% of the standard therapy group and 11% of the combination group – not a significant difference. Both leukopenia and thrombocytopenia were significantly more common in the combination group (leukopenia, 25% vs. 11%; P = less than .001; and thrombocytopenia 19% vs. 9%; P = .006).

Nonhematologic toxicities were significantly more common among patients taking the combination treatment. Fatigue was present in 51% of the combination group vs. 29% of the standard therapy group, hypertension in 59% vs. 16%, hemorrhage in 19% vs. 2%, liver enzyme elevation in 47% vs. 28%, and proteinuria in 30% vs. 3%, respectively. All of these differences were highly significant statistically (P less than .001).

There was no significant between-group difference in the occurrence of thromboembolic events (2% vs. 0%; P = .373).

Dr. Martin said that the control group did much better than was expected. However, he suggested that biomarker studies might be able to pinpoint a select population that could benefit from the addition of bevacizumab to standard hormonal therapy.

Dr. Martin is on the speakers bureau and a consultant for Roche.