Breast Cancer

The following reports are based on presentations at the 2011 Breast Cancer Symposium, held September 8–10 in San Francisco. The symposium was sponsored in part by the American Society of Clinical Oncology.

Taxane-induced neuropathy gives no clue to breast cancer outcome
The development of taxaneinduced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data demonstrate.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial of 4,554 women, 13%–22% developed peripheral neuropathy, depending on which of four taxane regimens they received. Women who developed peripheral neuropathy did not have better recurrence- free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups.

Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received. The findings are important given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

“Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome,” he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that “at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points.”

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted. “The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients,” concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grades 2–4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio [HR], 1.47), and were marginally more likely if they were black, obese, or postmenopausal. Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel versus paclitaxel every 3 weeks (HR, 1.52), paclitaxel every 3 weeks versus weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks versus docetaxel every 3 weeks (HR, 1.91). In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence- free, disease-free, or overall survival.

The findings contrast with an earlier study in which women receiving paclitaxel-containing therapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

Chemotherapy timing does not affect breast cancer recurrence

Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of The University of Texas MD Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987–2005. Results showed that with a median follow-up of 7–8 years, the rate of freedom from locoregional recurrence was high (≥ 90% at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

“For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy,” Dr. Mittendorf, a surgical oncologist, commented, adding, “It is important to obtain a negative margin at the time of surgery.”

“It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy,” she said. However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of “oversimplification of [a] complex issue … especially in the era of personalized therapy.”

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

“The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important,” commented Dr. Fowble. “Initial stage, molecular subtype, and response to therapy will impact on outcome.”

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor-negative disease, and to have multifocal disease.

Median durations of follow-up were 7.2 and 7.9 years. In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%; P < 0.001).

“Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy,” Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P < 0.001). For example, the 10-year rate was 90% with the former and 94% with the latter.

“Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors,” she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence. Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (HR, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor-negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor-positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence- free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

In the pipeline: entinostat may overcome AI resistance

Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase II trial suggest.

Investigators studied 130 women with estrogen receptor-positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.

“The combination…is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy,” principal investigator Dr. Denise A. Yardley reported.

“These results support our plans for a global, pivotal phase III study due to begin enrollment in 2012,” added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.

In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy.

These data reveal “for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes,” she noted.

Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as “very, very promising,” saying, “I agree that it’s time for a phase III” trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.

The randomized phase II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor-positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.

The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values < 0.1 were considered statistically significant. Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.

With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs 2.27 months; HR, 0.73; P = 0.06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.

In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an abovemedian percent change in lysines that were acetylated during the first cycle of treatment.

These findings “suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment,” said Dr. Yardley.

In an analysis that was exploratory because follow-up is still short, entinostat was also associated with better overall survival (26.9 vs 20.3 months; HR, 0.56; P = 0.027). Additional data with longer follow-up will be reported at the San Antonio Breast Cancer Symposium later this year.

The combination of entinostat and exemestane was well tolerated, with no unexpected safety signals. The most common grade 3/4 adverse events in the entinostat group were fatigue (13%), neutropenia (13%), nausea (5%), and vomiting (5%). The rate of discontinuation because of adverse events was 1% in the placebo group and 11% in the entinostat group.

Dr. Yardley reported no relevant conflicts of interest. Syndax Pharmaceuticals, developer of entinostat, was not among Dr. O’Shaughnessy’s disclosures.

Measure of bone metastases predicts breast cancer survival

The more metabolically active a woman’s bone metastases of breast cancer are on imaging, the greater her risk of death, researchers reported at the symposium.

In a retrospective cohort study of 269 women with newly diagnosed metastatic breast cancer, those whose bone metastases were “hotter” on a PET/CT—as assessed from maximum standardized uptake value (SUV-max)— had poorer overall survival. Compared with their counterparts with values in the bottom tertile of SUV-max values, women with values in the middle and top tertiles were roughly two to three times more likely to die after other prognostic factors were taken into account.

“To our understanding, this is the first large retrospective series to correlate SUV-max at metastatic breast cancer diagnosis with overall survival,” said lead author Dr. Komal Jhaveri of Memorial Sloan-Kettering Cancer Center, New York.

The risk of death also rose with increasing tertile of SUV-max in liver, lung, and lymph node metastases, but those associations were not signifycant. Their nonsignificance may have been due to the smaller numbers of patients having metastases in those sites, she said.

Session chair Dr. Robert R. Kuske, a radiation oncologist with Arizona Breast Cancer Specialists in Scottsdale, noted that SUV-max is a surrogate for how rapidly the tumor cells are proliferating and, hence, the tumor’s aggressiveness.

“So there should be a strong correlation between this SUV on the PET and the Ki-67 [histologic proliferation index],” he said. “This gives us another tool to evaluate how patients are going to do,” he commented. “Now [oncologists] can look at a metastasis on PET, measure the SUV, and get a handle on what the future of that patient is going to be—is it going to be a rapid slide to death, or is it going to be a very slow, indolent progression maybe over 10 or 15 years. And they can tailor the therapy based on the aggressiveness of the disease.” The PET/CT is usually done to determine whether the patient has metastases, so this additional prognostic information “is a little something extra you get from the test.”

Will these new findings be practice changing?

“I’ll start looking at SUV values in my patients with newly diagnosed metastasis,” said Dr. Kuske. “Yes, it will change my practice.”

In the study, Dr. Jhaveri and her coinvestigators reviewed records for women with metastatic breast cancer diagnosed between 2001 and 2008 who had a PET/CT scan performed within 60 days of the detection of metastases; had at least one avid metastasis in bone, liver, lung, or lymph node; and had not received chemotherapy in the month before the scan. Prior or current hormonal therapy was permitted.

The investigators determined the SUV-max for individual metastatic sites. They compared values only within a given site because of known variation across sites such as liver and lung, Dr. Jhaveri explained. The women had a median age of 58 years. The median time elapsed between primary breast cancer diagnosis and PET/CT was 2.3 years. A fifth each had triple-negative disease and HER2-positive disease. The median duration of followup was 40 months.

In a multivariate analysis that included other prognostic factors (grade, tumor phenotype, and visceral metastases), overall survival differed across tertiles of SUV-max for bone metastases (P = 0.006). Women with values in the middle and top tertiles were 1.87 and 2.67 times more likely to die, respectively, than their counterparts with values in the bottom tertile.

“Given the variation in SUV and the differential impact on survival by site, it is possible that SUV-max may not be the most optimal PET variable,” Dr. Jhaveri commented. She proposed that an alternate variable, called total lesion glycolysis (TLG), which incorporates tumor lesion size, might perform better and be more informative.

“Ultimately, prospective studies are required to further delineate the role of PET/CT as a prognostic tool in metastatic breast cancer,” she concluded.

Dr. Jhaveri and Dr. Kuske reported having no relevant conflicts of interest.

Score predicts late recurrence in ER-positive breast cancer

A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor-positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor-positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole or placebo.

Study results, reported at the meeting, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled. The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor-positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

“If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component,” he explained.

“If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy,” he continued. “For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials.

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase- polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL- 17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

“We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually,” he noted. “In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence.”

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = 0.014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = 0.019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported.

In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = 0.037).

“Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = 0.02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I,” he said. “These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy.”

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

The following reports are based on presentations at the 2011 Breast Cancer Symposium, held September 8–10 in San Francisco. The symposium was sponsored in part by the American Society of Clinical Oncology.

Taxane-induced neuropathy gives no clue to breast cancer outcome
The development of taxaneinduced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data demonstrate.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial of 4,554 women, 13%–22% developed peripheral neuropathy, depending on which of four taxane regimens they received. Women who developed peripheral neuropathy did not have better recurrence- free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups.

Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received. The findings are important given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

“Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome,” he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that “at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points.”

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted. “The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients,” concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grades 2–4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio [HR], 1.47), and were marginally more likely if they were black, obese, or postmenopausal. Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel versus paclitaxel every 3 weeks (HR, 1.52), paclitaxel every 3 weeks versus weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks versus docetaxel every 3 weeks (HR, 1.91). In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence- free, disease-free, or overall survival.

The findings contrast with an earlier study in which women receiving paclitaxel-containing therapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

Chemotherapy timing does not affect breast cancer recurrence

Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of The University of Texas MD Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987–2005. Results showed that with a median follow-up of 7–8 years, the rate of freedom from locoregional recurrence was high (≥ 90% at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

“For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy,” Dr. Mittendorf, a surgical oncologist, commented, adding, “It is important to obtain a negative margin at the time of surgery.”

“It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy,” she said. However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of “oversimplification of [a] complex issue … especially in the era of personalized therapy.”

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

“The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important,” commented Dr. Fowble. “Initial stage, molecular subtype, and response to therapy will impact on outcome.”

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor-negative disease, and to have multifocal disease.

Median durations of follow-up were 7.2 and 7.9 years. In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%; P < 0.001).

“Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy,” Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P < 0.001). For example, the 10-year rate was 90% with the former and 94% with the latter.

“Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors,” she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence. Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (HR, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor-negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor-positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence- free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

In the pipeline: entinostat may overcome AI resistance

Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase II trial suggest.

Investigators studied 130 women with estrogen receptor-positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.

“The combination…is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy,” principal investigator Dr. Denise A. Yardley reported.

“These results support our plans for a global, pivotal phase III study due to begin enrollment in 2012,” added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.

In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy.

These data reveal “for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes,” she noted.

Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as “very, very promising,” saying, “I agree that it’s time for a phase III” trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.

The randomized phase II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor-positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.

The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values < 0.1 were considered statistically significant. Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.

With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs 2.27 months; HR, 0.73; P = 0.06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.

In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an abovemedian percent change in lysines that were acetylated during the first cycle of treatment.

These findings “suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment,” said Dr. Yardley.

In an analysis that was exploratory because follow-up is still short, entinostat was also associated with better overall survival (26.9 vs 20.3 months; HR, 0.56; P = 0.027). Additional data with longer follow-up will be reported at the San Antonio Breast Cancer Symposium later this year.

The combination of entinostat and exemestane was well tolerated, with no unexpected safety signals. The most common grade 3/4 adverse events in the entinostat group were fatigue (13%), neutropenia (13%), nausea (5%), and vomiting (5%). The rate of discontinuation because of adverse events was 1% in the placebo group and 11% in the entinostat group.

Dr. Yardley reported no relevant conflicts of interest. Syndax Pharmaceuticals, developer of entinostat, was not among Dr. O’Shaughnessy’s disclosures.

Measure of bone metastases predicts breast cancer survival

The more metabolically active a woman’s bone metastases of breast cancer are on imaging, the greater her risk of death, researchers reported at the symposium.

In a retrospective cohort study of 269 women with newly diagnosed metastatic breast cancer, those whose bone metastases were “hotter” on a PET/CT—as assessed from maximum standardized uptake value (SUV-max)— had poorer overall survival. Compared with their counterparts with values in the bottom tertile of SUV-max values, women with values in the middle and top tertiles were roughly two to three times more likely to die after other prognostic factors were taken into account.

“To our understanding, this is the first large retrospective series to correlate SUV-max at metastatic breast cancer diagnosis with overall survival,” said lead author Dr. Komal Jhaveri of Memorial Sloan-Kettering Cancer Center, New York.

The risk of death also rose with increasing tertile of SUV-max in liver, lung, and lymph node metastases, but those associations were not signifycant. Their nonsignificance may have been due to the smaller numbers of patients having metastases in those sites, she said.

Session chair Dr. Robert R. Kuske, a radiation oncologist with Arizona Breast Cancer Specialists in Scottsdale, noted that SUV-max is a surrogate for how rapidly the tumor cells are proliferating and, hence, the tumor’s aggressiveness.

“So there should be a strong correlation between this SUV on the PET and the Ki-67 [histologic proliferation index],” he said. “This gives us another tool to evaluate how patients are going to do,” he commented. “Now [oncologists] can look at a metastasis on PET, measure the SUV, and get a handle on what the future of that patient is going to be—is it going to be a rapid slide to death, or is it going to be a very slow, indolent progression maybe over 10 or 15 years. And they can tailor the therapy based on the aggressiveness of the disease.” The PET/CT is usually done to determine whether the patient has metastases, so this additional prognostic information “is a little something extra you get from the test.”

Will these new findings be practice changing?

“I’ll start looking at SUV values in my patients with newly diagnosed metastasis,” said Dr. Kuske. “Yes, it will change my practice.”

In the study, Dr. Jhaveri and her coinvestigators reviewed records for women with metastatic breast cancer diagnosed between 2001 and 2008 who had a PET/CT scan performed within 60 days of the detection of metastases; had at least one avid metastasis in bone, liver, lung, or lymph node; and had not received chemotherapy in the month before the scan. Prior or current hormonal therapy was permitted.

The investigators determined the SUV-max for individual metastatic sites. They compared values only within a given site because of known variation across sites such as liver and lung, Dr. Jhaveri explained. The women had a median age of 58 years. The median time elapsed between primary breast cancer diagnosis and PET/CT was 2.3 years. A fifth each had triple-negative disease and HER2-positive disease. The median duration of followup was 40 months.

In a multivariate analysis that included other prognostic factors (grade, tumor phenotype, and visceral metastases), overall survival differed across tertiles of SUV-max for bone metastases (P = 0.006). Women with values in the middle and top tertiles were 1.87 and 2.67 times more likely to die, respectively, than their counterparts with values in the bottom tertile.

“Given the variation in SUV and the differential impact on survival by site, it is possible that SUV-max may not be the most optimal PET variable,” Dr. Jhaveri commented. She proposed that an alternate variable, called total lesion glycolysis (TLG), which incorporates tumor lesion size, might perform better and be more informative.

“Ultimately, prospective studies are required to further delineate the role of PET/CT as a prognostic tool in metastatic breast cancer,” she concluded.

Dr. Jhaveri and Dr. Kuske reported having no relevant conflicts of interest.

Score predicts late recurrence in ER-positive breast cancer

A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor-positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor-positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole or placebo.

Study results, reported at the meeting, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled. The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor-positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

“If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component,” he explained.

“If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy,” he continued. “For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials.

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase- polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL- 17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

“We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually,” he noted. “In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence.”

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = 0.014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = 0.019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported.

In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = 0.037).

“Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = 0.02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I,” he said. “These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy.”

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

The following reports are based on presentations at the 2011 Breast Cancer Symposium, held September 8–10 in San Francisco. The symposium was sponsored in part by the American Society of Clinical Oncology.

Taxane-induced neuropathy gives no clue to breast cancer outcome
The development of taxaneinduced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data demonstrate.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial of 4,554 women, 13%–22% developed peripheral neuropathy, depending on which of four taxane regimens they received. Women who developed peripheral neuropathy did not have better recurrence- free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups.

Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received. The findings are important given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

“Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome,” he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that “at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points.”

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted. “The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients,” concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grades 2–4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio [HR], 1.47), and were marginally more likely if they were black, obese, or postmenopausal. Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel versus paclitaxel every 3 weeks (HR, 1.52), paclitaxel every 3 weeks versus weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks versus docetaxel every 3 weeks (HR, 1.91). In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence- free, disease-free, or overall survival.

The findings contrast with an earlier study in which women receiving paclitaxel-containing therapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

Chemotherapy timing does not affect breast cancer recurrence

Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of The University of Texas MD Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987–2005. Results showed that with a median follow-up of 7–8 years, the rate of freedom from locoregional recurrence was high (≥ 90% at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

“For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy,” Dr. Mittendorf, a surgical oncologist, commented, adding, “It is important to obtain a negative margin at the time of surgery.”

“It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy,” she said. However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of “oversimplification of [a] complex issue … especially in the era of personalized therapy.”

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

“The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important,” commented Dr. Fowble. “Initial stage, molecular subtype, and response to therapy will impact on outcome.”

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor-negative disease, and to have multifocal disease.

Median durations of follow-up were 7.2 and 7.9 years. In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%; P < 0.001).

“Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy,” Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P < 0.001). For example, the 10-year rate was 90% with the former and 94% with the latter.

“Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors,” she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence. Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (HR, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor-negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor-positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence- free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

In the pipeline: entinostat may overcome AI resistance

Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase II trial suggest.

Investigators studied 130 women with estrogen receptor-positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.

“The combination…is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy,” principal investigator Dr. Denise A. Yardley reported.

“These results support our plans for a global, pivotal phase III study due to begin enrollment in 2012,” added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.

In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy.

These data reveal “for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes,” she noted.

Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as “very, very promising,” saying, “I agree that it’s time for a phase III” trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.

The randomized phase II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor-positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.

The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values < 0.1 were considered statistically significant. Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.

With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs 2.27 months; HR, 0.73; P = 0.06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.

In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an abovemedian percent change in lysines that were acetylated during the first cycle of treatment.

These findings “suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment,” said Dr. Yardley.

In an analysis that was exploratory because follow-up is still short, entinostat was also associated with better overall survival (26.9 vs 20.3 months; HR, 0.56; P = 0.027). Additional data with longer follow-up will be reported at the San Antonio Breast Cancer Symposium later this year.

The combination of entinostat and exemestane was well tolerated, with no unexpected safety signals. The most common grade 3/4 adverse events in the entinostat group were fatigue (13%), neutropenia (13%), nausea (5%), and vomiting (5%). The rate of discontinuation because of adverse events was 1% in the placebo group and 11% in the entinostat group.

Dr. Yardley reported no relevant conflicts of interest. Syndax Pharmaceuticals, developer of entinostat, was not among Dr. O’Shaughnessy’s disclosures.

Measure of bone metastases predicts breast cancer survival

The more metabolically active a woman’s bone metastases of breast cancer are on imaging, the greater her risk of death, researchers reported at the symposium.

In a retrospective cohort study of 269 women with newly diagnosed metastatic breast cancer, those whose bone metastases were “hotter” on a PET/CT—as assessed from maximum standardized uptake value (SUV-max)— had poorer overall survival. Compared with their counterparts with values in the bottom tertile of SUV-max values, women with values in the middle and top tertiles were roughly two to three times more likely to die after other prognostic factors were taken into account.

“To our understanding, this is the first large retrospective series to correlate SUV-max at metastatic breast cancer diagnosis with overall survival,” said lead author Dr. Komal Jhaveri of Memorial Sloan-Kettering Cancer Center, New York.

The risk of death also rose with increasing tertile of SUV-max in liver, lung, and lymph node metastases, but those associations were not signifycant. Their nonsignificance may have been due to the smaller numbers of patients having metastases in those sites, she said.

Session chair Dr. Robert R. Kuske, a radiation oncologist with Arizona Breast Cancer Specialists in Scottsdale, noted that SUV-max is a surrogate for how rapidly the tumor cells are proliferating and, hence, the tumor’s aggressiveness.

“So there should be a strong correlation between this SUV on the PET and the Ki-67 [histologic proliferation index],” he said. “This gives us another tool to evaluate how patients are going to do,” he commented. “Now [oncologists] can look at a metastasis on PET, measure the SUV, and get a handle on what the future of that patient is going to be—is it going to be a rapid slide to death, or is it going to be a very slow, indolent progression maybe over 10 or 15 years. And they can tailor the therapy based on the aggressiveness of the disease.” The PET/CT is usually done to determine whether the patient has metastases, so this additional prognostic information “is a little something extra you get from the test.”

Will these new findings be practice changing?

“I’ll start looking at SUV values in my patients with newly diagnosed metastasis,” said Dr. Kuske. “Yes, it will change my practice.”

In the study, Dr. Jhaveri and her coinvestigators reviewed records for women with metastatic breast cancer diagnosed between 2001 and 2008 who had a PET/CT scan performed within 60 days of the detection of metastases; had at least one avid metastasis in bone, liver, lung, or lymph node; and had not received chemotherapy in the month before the scan. Prior or current hormonal therapy was permitted.

The investigators determined the SUV-max for individual metastatic sites. They compared values only within a given site because of known variation across sites such as liver and lung, Dr. Jhaveri explained. The women had a median age of 58 years. The median time elapsed between primary breast cancer diagnosis and PET/CT was 2.3 years. A fifth each had triple-negative disease and HER2-positive disease. The median duration of followup was 40 months.

In a multivariate analysis that included other prognostic factors (grade, tumor phenotype, and visceral metastases), overall survival differed across tertiles of SUV-max for bone metastases (P = 0.006). Women with values in the middle and top tertiles were 1.87 and 2.67 times more likely to die, respectively, than their counterparts with values in the bottom tertile.

“Given the variation in SUV and the differential impact on survival by site, it is possible that SUV-max may not be the most optimal PET variable,” Dr. Jhaveri commented. She proposed that an alternate variable, called total lesion glycolysis (TLG), which incorporates tumor lesion size, might perform better and be more informative.

“Ultimately, prospective studies are required to further delineate the role of PET/CT as a prognostic tool in metastatic breast cancer,” she concluded.

Dr. Jhaveri and Dr. Kuske reported having no relevant conflicts of interest.

Score predicts late recurrence in ER-positive breast cancer

A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor-positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor-positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole or placebo.

Study results, reported at the meeting, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled. The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor-positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

“If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component,” he explained.

“If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy,” he continued. “For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials.

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase- polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL- 17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

“We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually,” he noted. “In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence.”

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = 0.014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = 0.019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported.

In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = 0.037).

“Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = 0.02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I,” he said. “These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy.”

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

MIAMI BEACH – Adding radiotherapy and tamoxifen to breast-conserving surgery significantly reduces the local recurrence rate and the breast cancer–specific death rate in women with ductal carcinoma in situ, according to a systematic review and meta-analysis.

The review of 22 studies with a minimum of 10-year follow-up data showed that surgery plus radiation therapy nearly halved the rate of ipsilateral local recurrence from 23.5% with surgery alone to 13.5%, and the addition of tamoxifen cut the rate even further, to 9.2%.

The addition of tamoxifen to surgery and radiation also reduced breast cancer death rates from 3.1% without the drug to 1.5% with it, reported Dr. Kirsty Stuart of the Westmead Breast Cancer Institute at Westmead Hospital in Sydney, Australia.

"DCIS [ductal carcinoma in situ] treatment, however, will ultimately depend on the individual patient, their general condition, their tumor, and their fears," she told attendees at the annual meeting of the American Society for Radiation Oncology.

Dr. Stuart and colleagues conducted a meta-analysis of published randomized or nonrandomized trials of long-term outcomes in DCIS to determine the benefits of adjuvant radiotherapy and tamoxifen, a selective estrogen receptor modulator. The subjects all had pure DCIS with a minimum of 10-years’ follow-up, with data on treatment type and local recurrence. All studies were peer reviewed.

The investigators defined local recurrence as subsequent ipsilateral breast or chest wall disease (DCIS or invasive), and calculated the breast cancer death rate as the number of deaths from breast cancer divided by the total number of DCIS cases.

They identified a total of 22 qualifying studies dating from 1974 through 2011 with 6,167 patients. In all, 4.9% of patients had mastectomies, 51.8% had conservative surgery plus radiation, 41.2% had conservative surgery alone, and 2.1% had biopsy alone.

Among all cases, ipsilateral local recurrence was seen in 3.3% of mastectomy patients, 13.5% of patients who had surgery and radiation, 23.5% of surgery only patients, and 35.1% of biopsy only patients. Between-treatment comparisons showed that mastectomy was significantly better than each of the forms of therapy, both at preventing all cases of ipsilateral local recurrences and all cases of invasive local recurrence.

Looking at the addition of tamoxifen to surgery with or without radiation, the authors found that the drug significantly reduced the rate of local recurrence, from 24.1% with surgery alone to 19.8% with surgery and tamoxifen, and from 14.9% for the surgery/radiation combination to 9.2% for the two modalities plus tamoxifen.

Between-treatment comparisons showed that adding tamoxifen to radiation and surgery significantly improved recurrence rates over surgery plus radiation (P = .037), surgery plus tamoxifen (P = .0086), or surgery alone (P less than .000001). Compared with surgery only, the relative risk for invasive local recurrence was 0.71 for surgery plus tamoxifen, 0.63 for surgery plus radiotherapy, and 0.35 for all three treatments.

Invasive breast cancer death rates were also significantly lower when tamoxifen was added to surgery and radiation, decreasing from 8.4% without the drug to 4.3% with it.

"From the pooled data, conservative surgery alone for DCIS has a high recurrence rate that is partly reduced with tamoxifen," Dr. Stuart said.

"DCIS treatment will ultimately depend on the individual patient, their general condition, their tumor, and their fears."

"Conservative surgery plus radiation therapy almost halves the ipsilateral recurrence rate, and has a breast cancer death rate that is equivalent to that of the mastectomy population.

"Conservative surgery and radiation therapy plus tamoxifen halves the invasive local recurrence rate, from 8% to 4%, and halves the breast cancer death rate, from 3% to 1.5%."

In a separate study Dr. Julia Wong of the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, both in Boston, presented 8-year follow-up data on wide-area excision alone in 132 patients treated for DCIS. The investigators found that 19 patients had a local recurrence. The cumulative 8-year local recurrence rate was 14.4%. A total of 13 of the recurrences were DCIS, and 6 were invasive disease. All but one of the recurrences was detectable by mammogram, and one was palpable.

A total of 14 of the recurrences were in the same quadrant as the original tumor, and 5 were elsewhere in the same breast. Of the six patients with invasive disease, none had axillary involvement, and no patients developed distant metastases.

Other events seen in the study included 13 contralateral breast cancers (4 DCIS, 9 invasive), 1 other cancer, and 3 deaths from other causes.

"Even in this highly selected group of patients with small grade 1 or 2 DCIS treated with wide excision alone and margins 1 cm or greater, there is a substantial local recurrence rate, especially in the same quadrant," Dr. Wong said.

The meta-analysis was internally funded. Dr. Stuart reported having no relevant financial disclosures. Dr. Wong’s study was funded by participating institutions. Dr. Wong reported no other relevant financial disclosures.

MIAMI BEACH – Adding radiotherapy and tamoxifen to breast-conserving surgery significantly reduces the local recurrence rate and the breast cancer–specific death rate in women with ductal carcinoma in situ, according to a systematic review and meta-analysis.

The review of 22 studies with a minimum of 10-year follow-up data showed that surgery plus radiation therapy nearly halved the rate of ipsilateral local recurrence from 23.5% with surgery alone to 13.5%, and the addition of tamoxifen cut the rate even further, to 9.2%.

The addition of tamoxifen to surgery and radiation also reduced breast cancer death rates from 3.1% without the drug to 1.5% with it, reported Dr. Kirsty Stuart of the Westmead Breast Cancer Institute at Westmead Hospital in Sydney, Australia.

"DCIS [ductal carcinoma in situ] treatment, however, will ultimately depend on the individual patient, their general condition, their tumor, and their fears," she told attendees at the annual meeting of the American Society for Radiation Oncology.

Dr. Stuart and colleagues conducted a meta-analysis of published randomized or nonrandomized trials of long-term outcomes in DCIS to determine the benefits of adjuvant radiotherapy and tamoxifen, a selective estrogen receptor modulator. The subjects all had pure DCIS with a minimum of 10-years’ follow-up, with data on treatment type and local recurrence. All studies were peer reviewed.

The investigators defined local recurrence as subsequent ipsilateral breast or chest wall disease (DCIS or invasive), and calculated the breast cancer death rate as the number of deaths from breast cancer divided by the total number of DCIS cases.

They identified a total of 22 qualifying studies dating from 1974 through 2011 with 6,167 patients. In all, 4.9% of patients had mastectomies, 51.8% had conservative surgery plus radiation, 41.2% had conservative surgery alone, and 2.1% had biopsy alone.

Among all cases, ipsilateral local recurrence was seen in 3.3% of mastectomy patients, 13.5% of patients who had surgery and radiation, 23.5% of surgery only patients, and 35.1% of biopsy only patients. Between-treatment comparisons showed that mastectomy was significantly better than each of the forms of therapy, both at preventing all cases of ipsilateral local recurrences and all cases of invasive local recurrence.

Looking at the addition of tamoxifen to surgery with or without radiation, the authors found that the drug significantly reduced the rate of local recurrence, from 24.1% with surgery alone to 19.8% with surgery and tamoxifen, and from 14.9% for the surgery/radiation combination to 9.2% for the two modalities plus tamoxifen.

Between-treatment comparisons showed that adding tamoxifen to radiation and surgery significantly improved recurrence rates over surgery plus radiation (P = .037), surgery plus tamoxifen (P = .0086), or surgery alone (P less than .000001). Compared with surgery only, the relative risk for invasive local recurrence was 0.71 for surgery plus tamoxifen, 0.63 for surgery plus radiotherapy, and 0.35 for all three treatments.

Invasive breast cancer death rates were also significantly lower when tamoxifen was added to surgery and radiation, decreasing from 8.4% without the drug to 4.3% with it.

"From the pooled data, conservative surgery alone for DCIS has a high recurrence rate that is partly reduced with tamoxifen," Dr. Stuart said.

"DCIS treatment will ultimately depend on the individual patient, their general condition, their tumor, and their fears."

"Conservative surgery plus radiation therapy almost halves the ipsilateral recurrence rate, and has a breast cancer death rate that is equivalent to that of the mastectomy population.

"Conservative surgery and radiation therapy plus tamoxifen halves the invasive local recurrence rate, from 8% to 4%, and halves the breast cancer death rate, from 3% to 1.5%."

In a separate study Dr. Julia Wong of the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, both in Boston, presented 8-year follow-up data on wide-area excision alone in 132 patients treated for DCIS. The investigators found that 19 patients had a local recurrence. The cumulative 8-year local recurrence rate was 14.4%. A total of 13 of the recurrences were DCIS, and 6 were invasive disease. All but one of the recurrences was detectable by mammogram, and one was palpable.

A total of 14 of the recurrences were in the same quadrant as the original tumor, and 5 were elsewhere in the same breast. Of the six patients with invasive disease, none had axillary involvement, and no patients developed distant metastases.

Other events seen in the study included 13 contralateral breast cancers (4 DCIS, 9 invasive), 1 other cancer, and 3 deaths from other causes.

"Even in this highly selected group of patients with small grade 1 or 2 DCIS treated with wide excision alone and margins 1 cm or greater, there is a substantial local recurrence rate, especially in the same quadrant," Dr. Wong said.

The meta-analysis was internally funded. Dr. Stuart reported having no relevant financial disclosures. Dr. Wong’s study was funded by participating institutions. Dr. Wong reported no other relevant financial disclosures.

MIAMI BEACH – Adding radiotherapy and tamoxifen to breast-conserving surgery significantly reduces the local recurrence rate and the breast cancer–specific death rate in women with ductal carcinoma in situ, according to a systematic review and meta-analysis.

The review of 22 studies with a minimum of 10-year follow-up data showed that surgery plus radiation therapy nearly halved the rate of ipsilateral local recurrence from 23.5% with surgery alone to 13.5%, and the addition of tamoxifen cut the rate even further, to 9.2%.

The addition of tamoxifen to surgery and radiation also reduced breast cancer death rates from 3.1% without the drug to 1.5% with it, reported Dr. Kirsty Stuart of the Westmead Breast Cancer Institute at Westmead Hospital in Sydney, Australia.

"DCIS [ductal carcinoma in situ] treatment, however, will ultimately depend on the individual patient, their general condition, their tumor, and their fears," she told attendees at the annual meeting of the American Society for Radiation Oncology.

Dr. Stuart and colleagues conducted a meta-analysis of published randomized or nonrandomized trials of long-term outcomes in DCIS to determine the benefits of adjuvant radiotherapy and tamoxifen, a selective estrogen receptor modulator. The subjects all had pure DCIS with a minimum of 10-years’ follow-up, with data on treatment type and local recurrence. All studies were peer reviewed.

The investigators defined local recurrence as subsequent ipsilateral breast or chest wall disease (DCIS or invasive), and calculated the breast cancer death rate as the number of deaths from breast cancer divided by the total number of DCIS cases.

They identified a total of 22 qualifying studies dating from 1974 through 2011 with 6,167 patients. In all, 4.9% of patients had mastectomies, 51.8% had conservative surgery plus radiation, 41.2% had conservative surgery alone, and 2.1% had biopsy alone.

Among all cases, ipsilateral local recurrence was seen in 3.3% of mastectomy patients, 13.5% of patients who had surgery and radiation, 23.5% of surgery only patients, and 35.1% of biopsy only patients. Between-treatment comparisons showed that mastectomy was significantly better than each of the forms of therapy, both at preventing all cases of ipsilateral local recurrences and all cases of invasive local recurrence.

Looking at the addition of tamoxifen to surgery with or without radiation, the authors found that the drug significantly reduced the rate of local recurrence, from 24.1% with surgery alone to 19.8% with surgery and tamoxifen, and from 14.9% for the surgery/radiation combination to 9.2% for the two modalities plus tamoxifen.

Between-treatment comparisons showed that adding tamoxifen to radiation and surgery significantly improved recurrence rates over surgery plus radiation (P = .037), surgery plus tamoxifen (P = .0086), or surgery alone (P less than .000001). Compared with surgery only, the relative risk for invasive local recurrence was 0.71 for surgery plus tamoxifen, 0.63 for surgery plus radiotherapy, and 0.35 for all three treatments.

Invasive breast cancer death rates were also significantly lower when tamoxifen was added to surgery and radiation, decreasing from 8.4% without the drug to 4.3% with it.

"From the pooled data, conservative surgery alone for DCIS has a high recurrence rate that is partly reduced with tamoxifen," Dr. Stuart said.

"DCIS treatment will ultimately depend on the individual patient, their general condition, their tumor, and their fears."

"Conservative surgery plus radiation therapy almost halves the ipsilateral recurrence rate, and has a breast cancer death rate that is equivalent to that of the mastectomy population.

"Conservative surgery and radiation therapy plus tamoxifen halves the invasive local recurrence rate, from 8% to 4%, and halves the breast cancer death rate, from 3% to 1.5%."

In a separate study Dr. Julia Wong of the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, both in Boston, presented 8-year follow-up data on wide-area excision alone in 132 patients treated for DCIS. The investigators found that 19 patients had a local recurrence. The cumulative 8-year local recurrence rate was 14.4%. A total of 13 of the recurrences were DCIS, and 6 were invasive disease. All but one of the recurrences was detectable by mammogram, and one was palpable.

A total of 14 of the recurrences were in the same quadrant as the original tumor, and 5 were elsewhere in the same breast. Of the six patients with invasive disease, none had axillary involvement, and no patients developed distant metastases.

Other events seen in the study included 13 contralateral breast cancers (4 DCIS, 9 invasive), 1 other cancer, and 3 deaths from other causes.

"Even in this highly selected group of patients with small grade 1 or 2 DCIS treated with wide excision alone and margins 1 cm or greater, there is a substantial local recurrence rate, especially in the same quadrant," Dr. Wong said.

The meta-analysis was internally funded. Dr. Stuart reported having no relevant financial disclosures. Dr. Wong’s study was funded by participating institutions. Dr. Wong reported no other relevant financial disclosures.

Blue Shield of California will soon stop covering bevacizumab for the treatment of metastatic breast cancer.

The coverage decision, which goes into effect on Oct. 17, comes a few months after the Food and Drug Administration’s Oncologic Drugs Advisory Committee recommended that the agency withdraw its approval of bevacizumab (Avastin) when used in combination with paclitaxel chemotherapy for first-line HER2-negative metastatic breast cancer, concluding that the treatment was not safe or effective.

The FDA commissioner has not made a final decision about whether to withdraw bevacizumab’s approval for metastatic breast cancer.

Blue Shield of California, which insures about 3.3 million Californians, will consider paying for bevacizumab for the treatment metastatic breast cancer on a "case-by-case basis," the company wrote in its updated coverage policy. They will also continue to cover the drug for women who are already being treated with it. The decision will not affect the insurer’s coverage of other indications of bevacizumab.

Blue Shield of California is not the first health plan to suspend coverage of bevacizumab, but it is the largest. Earlier this year, three regional insurers dropped coverage for bevacizumab for metastatic breast cancer. However, the Centers for Medicare and Medicaid Services continues to offer coverage through Medicare.

Charlotte Arnold, a spokeswoman for bevacizumab’s manufacturer, Genentech, said health plans should continue to cover the drug since it is still FDA approved and recommended for use under guidelines from the National Comprehensive Cancer Network. "We continue to believe that women with this incurable disease should have the ability to choose Avastin as an option if they and their doctor believe it’s the right option for them," she said.

Blue Shield of California will soon stop covering bevacizumab for the treatment of metastatic breast cancer.

The coverage decision, which goes into effect on Oct. 17, comes a few months after the Food and Drug Administration’s Oncologic Drugs Advisory Committee recommended that the agency withdraw its approval of bevacizumab (Avastin) when used in combination with paclitaxel chemotherapy for first-line HER2-negative metastatic breast cancer, concluding that the treatment was not safe or effective.

The FDA commissioner has not made a final decision about whether to withdraw bevacizumab’s approval for metastatic breast cancer.

Blue Shield of California, which insures about 3.3 million Californians, will consider paying for bevacizumab for the treatment metastatic breast cancer on a "case-by-case basis," the company wrote in its updated coverage policy. They will also continue to cover the drug for women who are already being treated with it. The decision will not affect the insurer’s coverage of other indications of bevacizumab.

Blue Shield of California is not the first health plan to suspend coverage of bevacizumab, but it is the largest. Earlier this year, three regional insurers dropped coverage for bevacizumab for metastatic breast cancer. However, the Centers for Medicare and Medicaid Services continues to offer coverage through Medicare.

Charlotte Arnold, a spokeswoman for bevacizumab’s manufacturer, Genentech, said health plans should continue to cover the drug since it is still FDA approved and recommended for use under guidelines from the National Comprehensive Cancer Network. "We continue to believe that women with this incurable disease should have the ability to choose Avastin as an option if they and their doctor believe it’s the right option for them," she said.

Blue Shield of California will soon stop covering bevacizumab for the treatment of metastatic breast cancer.

The coverage decision, which goes into effect on Oct. 17, comes a few months after the Food and Drug Administration’s Oncologic Drugs Advisory Committee recommended that the agency withdraw its approval of bevacizumab (Avastin) when used in combination with paclitaxel chemotherapy for first-line HER2-negative metastatic breast cancer, concluding that the treatment was not safe or effective.

The FDA commissioner has not made a final decision about whether to withdraw bevacizumab’s approval for metastatic breast cancer.

Blue Shield of California, which insures about 3.3 million Californians, will consider paying for bevacizumab for the treatment metastatic breast cancer on a "case-by-case basis," the company wrote in its updated coverage policy. They will also continue to cover the drug for women who are already being treated with it. The decision will not affect the insurer’s coverage of other indications of bevacizumab.

Blue Shield of California is not the first health plan to suspend coverage of bevacizumab, but it is the largest. Earlier this year, three regional insurers dropped coverage for bevacizumab for metastatic breast cancer. However, the Centers for Medicare and Medicaid Services continues to offer coverage through Medicare.

Charlotte Arnold, a spokeswoman for bevacizumab’s manufacturer, Genentech, said health plans should continue to cover the drug since it is still FDA approved and recommended for use under guidelines from the National Comprehensive Cancer Network. "We continue to believe that women with this incurable disease should have the ability to choose Avastin as an option if they and their doctor believe it’s the right option for them," she said.

MIAMI BEACH – Placing breast cancer patients in a prone rather than supine position during whole breast irradiation may significantly reduce their risk for secondary lung cancers, investigators reported at the annual meeting of the American Society for Radiation Oncology.

The total radiation dose that would be delivered to the corresponding (ipsilateral) lung of patients treated while they were lying face down was less than one-tenth of the dose delivered to that of patients treated while lying on their backs, said Dr. John Ng, senior radiation oncology resident at Columbia University Medical Center in New York.

The mean expected lifetime risk for radiation-associated secondary lung cancer is 1.99% in patients given whole breast irradiation with a prone technique, compared with 4.86% for patients treated with a supine technique, he reported. It was 3.87% for patients treated with a 3-D conformal partial breast irradiation technique, and 2.92% for patients treated with balloon brachytherapy (P less than .001 for all comparisons).

By way of comparison, the estimated expected background risk for lung cancer is about 1.5%, Dr. Ng and his colleagues wrote in a poster presentation.

"It’s documented that there is some excess relative risk of lung cancers after breast radiation treatment – I think everybody agrees with that. What people will disagree on is how significant this risk is, and that\'s what motivates us to do this study," Dr. Ng said in an interview.

The prone technique is, however, considerably more time consuming in terms of treatment planning and positioning of the patient, resulting in treatment sessions that are about twice as long as those for patients treated supinely (about 45 vs. 20 minutes, Dr. Ng said).

The investigators used a mathematical model to estimate the risk of both spontaneous and radiation-induced lung cancer risk in 25 women with early-stage breast cancer undergoing treatment planning with CT simulation for post-lumpectomy radiation therapy. Patients scheduled for whole breast irradiation were simulated in both the prone and the supine positions; those scheduled for partial breast irradiation were simulated in the supine position only.

The model encompassed standard dosing (50 Gy, delivered in 25 fractions), hypofractionation (42 Gy in 16 fractions), or standard external-beam accelerated partial breast irradiation (38.5 Gy in 10 fractions).

For each of the 15 patients treated in the prone technique, there would be significantly less radiation (54.2 cGy, on average) delivered to the lung than with the supine technique (646.5 cGy), balloon brachytherapy (291.0 cGy), or partial-breast irradiation (275.2 cGy; P less than .001 for all comparisons).

The relative risks for each technique and dosing schedule, compared with background risk, were 4.04 for supine standard fractionation, 3.98 for supine hypofractionation, 2.54 for balloon brachytherapy, 2.36 for 3D conformal accelerated partial-breast irradiation, and 1.56 for standard fractionation.

"The take-home point is that there is substantial risk of secondary lung malignancy from our standard technique. You can improve it with partial breast irradiation, but our study shows that the best results come from the prone technique," Dr. Ng said.

Dr. Phillip M. Devlin, chief of the division of brachytherapy at Dana-Farber Cancer Institute, Boston, commented that the study was interesting but complex, with the issue of prone vs. supine muddied by the inclusion of brachytherapy into the mix.

"In this small study, the hypothesis is generated that there would be less cancer caused by prone technique than by supine technique, and therefore a prospective analysis of this may be warranted. However, with these findings one might even ask whether it would be ethical to do the prospective study," said Dr. Devlin, who was not involved in the study.

He noted that the prone technique was originally developed to help women with more pendulous breasts tolerate whole breast irradiation better, with fewer side effects and improved cosmesis.

"Given the fact that we chose this technique for other end points, isn’t it interesting that if we also look at reasonable modeling done on a reasonably small data set, in the model the risk is lower with the prone technique, further endorsing what we’ve already found for a bigger and different reason. The cost to achieve this in terms of patient throughput is in play, but it is counterbalanced against the potential extra cost of treating either a local recurrence or a second malignant neoplasm," Dr. Devlin said.

The study was internally funded. Neither Dr. Ng nor Dr. Devlin had conflicts of interest to disclose.

MIAMI BEACH – Placing breast cancer patients in a prone rather than supine position during whole breast irradiation may significantly reduce their risk for secondary lung cancers, investigators reported at the annual meeting of the American Society for Radiation Oncology.

The total radiation dose that would be delivered to the corresponding (ipsilateral) lung of patients treated while they were lying face down was less than one-tenth of the dose delivered to that of patients treated while lying on their backs, said Dr. John Ng, senior radiation oncology resident at Columbia University Medical Center in New York.

The mean expected lifetime risk for radiation-associated secondary lung cancer is 1.99% in patients given whole breast irradiation with a prone technique, compared with 4.86% for patients treated with a supine technique, he reported. It was 3.87% for patients treated with a 3-D conformal partial breast irradiation technique, and 2.92% for patients treated with balloon brachytherapy (P less than .001 for all comparisons).

By way of comparison, the estimated expected background risk for lung cancer is about 1.5%, Dr. Ng and his colleagues wrote in a poster presentation.

"It’s documented that there is some excess relative risk of lung cancers after breast radiation treatment – I think everybody agrees with that. What people will disagree on is how significant this risk is, and that\'s what motivates us to do this study," Dr. Ng said in an interview.

The prone technique is, however, considerably more time consuming in terms of treatment planning and positioning of the patient, resulting in treatment sessions that are about twice as long as those for patients treated supinely (about 45 vs. 20 minutes, Dr. Ng said).

The investigators used a mathematical model to estimate the risk of both spontaneous and radiation-induced lung cancer risk in 25 women with early-stage breast cancer undergoing treatment planning with CT simulation for post-lumpectomy radiation therapy. Patients scheduled for whole breast irradiation were simulated in both the prone and the supine positions; those scheduled for partial breast irradiation were simulated in the supine position only.

The model encompassed standard dosing (50 Gy, delivered in 25 fractions), hypofractionation (42 Gy in 16 fractions), or standard external-beam accelerated partial breast irradiation (38.5 Gy in 10 fractions).

For each of the 15 patients treated in the prone technique, there would be significantly less radiation (54.2 cGy, on average) delivered to the lung than with the supine technique (646.5 cGy), balloon brachytherapy (291.0 cGy), or partial-breast irradiation (275.2 cGy; P less than .001 for all comparisons).

The relative risks for each technique and dosing schedule, compared with background risk, were 4.04 for supine standard fractionation, 3.98 for supine hypofractionation, 2.54 for balloon brachytherapy, 2.36 for 3D conformal accelerated partial-breast irradiation, and 1.56 for standard fractionation.

"The take-home point is that there is substantial risk of secondary lung malignancy from our standard technique. You can improve it with partial breast irradiation, but our study shows that the best results come from the prone technique," Dr. Ng said.

Dr. Phillip M. Devlin, chief of the division of brachytherapy at Dana-Farber Cancer Institute, Boston, commented that the study was interesting but complex, with the issue of prone vs. supine muddied by the inclusion of brachytherapy into the mix.

"In this small study, the hypothesis is generated that there would be less cancer caused by prone technique than by supine technique, and therefore a prospective analysis of this may be warranted. However, with these findings one might even ask whether it would be ethical to do the prospective study," said Dr. Devlin, who was not involved in the study.

He noted that the prone technique was originally developed to help women with more pendulous breasts tolerate whole breast irradiation better, with fewer side effects and improved cosmesis.

"Given the fact that we chose this technique for other end points, isn’t it interesting that if we also look at reasonable modeling done on a reasonably small data set, in the model the risk is lower with the prone technique, further endorsing what we’ve already found for a bigger and different reason. The cost to achieve this in terms of patient throughput is in play, but it is counterbalanced against the potential extra cost of treating either a local recurrence or a second malignant neoplasm," Dr. Devlin said.

The study was internally funded. Neither Dr. Ng nor Dr. Devlin had conflicts of interest to disclose.

MIAMI BEACH – Placing breast cancer patients in a prone rather than supine position during whole breast irradiation may significantly reduce their risk for secondary lung cancers, investigators reported at the annual meeting of the American Society for Radiation Oncology.

The total radiation dose that would be delivered to the corresponding (ipsilateral) lung of patients treated while they were lying face down was less than one-tenth of the dose delivered to that of patients treated while lying on their backs, said Dr. John Ng, senior radiation oncology resident at Columbia University Medical Center in New York.

The mean expected lifetime risk for radiation-associated secondary lung cancer is 1.99% in patients given whole breast irradiation with a prone technique, compared with 4.86% for patients treated with a supine technique, he reported. It was 3.87% for patients treated with a 3-D conformal partial breast irradiation technique, and 2.92% for patients treated with balloon brachytherapy (P less than .001 for all comparisons).

By way of comparison, the estimated expected background risk for lung cancer is about 1.5%, Dr. Ng and his colleagues wrote in a poster presentation.

"It’s documented that there is some excess relative risk of lung cancers after breast radiation treatment – I think everybody agrees with that. What people will disagree on is how significant this risk is, and that\'s what motivates us to do this study," Dr. Ng said in an interview.

The prone technique is, however, considerably more time consuming in terms of treatment planning and positioning of the patient, resulting in treatment sessions that are about twice as long as those for patients treated supinely (about 45 vs. 20 minutes, Dr. Ng said).

The investigators used a mathematical model to estimate the risk of both spontaneous and radiation-induced lung cancer risk in 25 women with early-stage breast cancer undergoing treatment planning with CT simulation for post-lumpectomy radiation therapy. Patients scheduled for whole breast irradiation were simulated in both the prone and the supine positions; those scheduled for partial breast irradiation were simulated in the supine position only.

The model encompassed standard dosing (50 Gy, delivered in 25 fractions), hypofractionation (42 Gy in 16 fractions), or standard external-beam accelerated partial breast irradiation (38.5 Gy in 10 fractions).

For each of the 15 patients treated in the prone technique, there would be significantly less radiation (54.2 cGy, on average) delivered to the lung than with the supine technique (646.5 cGy), balloon brachytherapy (291.0 cGy), or partial-breast irradiation (275.2 cGy; P less than .001 for all comparisons).

The relative risks for each technique and dosing schedule, compared with background risk, were 4.04 for supine standard fractionation, 3.98 for supine hypofractionation, 2.54 for balloon brachytherapy, 2.36 for 3D conformal accelerated partial-breast irradiation, and 1.56 for standard fractionation.

"The take-home point is that there is substantial risk of secondary lung malignancy from our standard technique. You can improve it with partial breast irradiation, but our study shows that the best results come from the prone technique," Dr. Ng said.

Dr. Phillip M. Devlin, chief of the division of brachytherapy at Dana-Farber Cancer Institute, Boston, commented that the study was interesting but complex, with the issue of prone vs. supine muddied by the inclusion of brachytherapy into the mix.

"In this small study, the hypothesis is generated that there would be less cancer caused by prone technique than by supine technique, and therefore a prospective analysis of this may be warranted. However, with these findings one might even ask whether it would be ethical to do the prospective study," said Dr. Devlin, who was not involved in the study.

He noted that the prone technique was originally developed to help women with more pendulous breasts tolerate whole breast irradiation better, with fewer side effects and improved cosmesis.

"Given the fact that we chose this technique for other end points, isn’t it interesting that if we also look at reasonable modeling done on a reasonably small data set, in the model the risk is lower with the prone technique, further endorsing what we’ve already found for a bigger and different reason. The cost to achieve this in terms of patient throughput is in play, but it is counterbalanced against the potential extra cost of treating either a local recurrence or a second malignant neoplasm," Dr. Devlin said.

The study was internally funded. Neither Dr. Ng nor Dr. Devlin had conflicts of interest to disclose.

Daughters of known carriers of BRCA1 or BRCA2 gene mutations are understandably stressed, reported A. Farkas Patenaude, PhD, in a paper, “What do young adult daughters of BRCA mutation carriers know about hereditary risk and how much do they worry,” presented at The Era of Hope Conference in Orlando, Florida, August 2–6.

These 18-to-24-year-olds are at a 50% to 85% risk for breast and related ovarian cancers²—significantly more so than that of the general population (at 30 years, a 0.43% risk).¹ In addition, these types of breast and ovarian cancer often occur at an unusually young age.²

Although ACOG recommends that annual screening mammograms begin at age 40,³ daughters of women who are known gene-mutation carriers should begin screening mammography at age 25.⁴ The ability of these women to make informed health decisions depends on their becoming knowledgeable about the risks, the availability of genetic testing, and options for screening and risk-reducing prophylactic surgery.

Although the daughters expressed worry about hereditary breast cancer, they had limited understanding of screening and risk-reduction options. If they did have the information, Dr. Patenaude’s study found, the young women were often afraid to have the testing.^2,4

“Young, high-risk women have little knowledge about the probabilities and options for managing the cancers for which their risks are remarkably increased. Further, many report intense anxiety related to their potential cancer development,” said Dr. Patenaude of the Dana Farber Cancer Institute. “These data support the need and can provide the foundation for the development of targeted educational materials to reduce that anxiety and ultimately improve participation in effective screening and risk-reducing interventions that can improve survival and quality of life for these young women.”²

The Era of Hope Conference provides a forum for scientists and clinicians from a variety of disciplines to join breast cancer survivors and advocates to discuss the advances made by the Congressionally Directed Breast Cancer Research Programs BCRP awardees, and to identify innovative, high-impact approaches for future research. Recognized as one of the premiere breast cancer research meetings.⁵

We want to hear from you! Tell us what you think.

Daughters of known carriers of BRCA1 or BRCA2 gene mutations are understandably stressed, reported A. Farkas Patenaude, PhD, in a paper, “What do young adult daughters of BRCA mutation carriers know about hereditary risk and how much do they worry,” presented at The Era of Hope Conference in Orlando, Florida, August 2–6.

These 18-to-24-year-olds are at a 50% to 85% risk for breast and related ovarian cancers²—significantly more so than that of the general population (at 30 years, a 0.43% risk).¹ In addition, these types of breast and ovarian cancer often occur at an unusually young age.²

Although ACOG recommends that annual screening mammograms begin at age 40,³ daughters of women who are known gene-mutation carriers should begin screening mammography at age 25.⁴ The ability of these women to make informed health decisions depends on their becoming knowledgeable about the risks, the availability of genetic testing, and options for screening and risk-reducing prophylactic surgery.

Although the daughters expressed worry about hereditary breast cancer, they had limited understanding of screening and risk-reduction options. If they did have the information, Dr. Patenaude’s study found, the young women were often afraid to have the testing.^2,4

“Young, high-risk women have little knowledge about the probabilities and options for managing the cancers for which their risks are remarkably increased. Further, many report intense anxiety related to their potential cancer development,” said Dr. Patenaude of the Dana Farber Cancer Institute. “These data support the need and can provide the foundation for the development of targeted educational materials to reduce that anxiety and ultimately improve participation in effective screening and risk-reducing interventions that can improve survival and quality of life for these young women.”²

The Era of Hope Conference provides a forum for scientists and clinicians from a variety of disciplines to join breast cancer survivors and advocates to discuss the advances made by the Congressionally Directed Breast Cancer Research Programs BCRP awardees, and to identify innovative, high-impact approaches for future research. Recognized as one of the premiere breast cancer research meetings.⁵

We want to hear from you! Tell us what you think.

Daughters of known carriers of BRCA1 or BRCA2 gene mutations are understandably stressed, reported A. Farkas Patenaude, PhD, in a paper, “What do young adult daughters of BRCA mutation carriers know about hereditary risk and how much do they worry,” presented at The Era of Hope Conference in Orlando, Florida, August 2–6.

These 18-to-24-year-olds are at a 50% to 85% risk for breast and related ovarian cancers²—significantly more so than that of the general population (at 30 years, a 0.43% risk).¹ In addition, these types of breast and ovarian cancer often occur at an unusually young age.²

Although ACOG recommends that annual screening mammograms begin at age 40,³ daughters of women who are known gene-mutation carriers should begin screening mammography at age 25.⁴ The ability of these women to make informed health decisions depends on their becoming knowledgeable about the risks, the availability of genetic testing, and options for screening and risk-reducing prophylactic surgery.

Although the daughters expressed worry about hereditary breast cancer, they had limited understanding of screening and risk-reduction options. If they did have the information, Dr. Patenaude’s study found, the young women were often afraid to have the testing.^2,4

“Young, high-risk women have little knowledge about the probabilities and options for managing the cancers for which their risks are remarkably increased. Further, many report intense anxiety related to their potential cancer development,” said Dr. Patenaude of the Dana Farber Cancer Institute. “These data support the need and can provide the foundation for the development of targeted educational materials to reduce that anxiety and ultimately improve participation in effective screening and risk-reducing interventions that can improve survival and quality of life for these young women.”²

The Era of Hope Conference provides a forum for scientists and clinicians from a variety of disciplines to join breast cancer survivors and advocates to discuss the advances made by the Congressionally Directed Breast Cancer Research Programs BCRP awardees, and to identify innovative, high-impact approaches for future research. Recognized as one of the premiere breast cancer research meetings.⁵

We want to hear from you! Tell us what you think.

STOCKHOLM – Coupling everolimus with exemestane has produced such dramatic disease control in women with advanced hormone resistant, estrogen receptor-positive breast cancer that it is expected to transform the management of these patients.

A preplanned interim analysis of the phase III BOLERO-2 trial found that everolimus (Afinitor) increased the primary end point of progression-free survival, by local assessment, from a median of 2.8 months with exemestane (Aromasin) alone to 6.9 months. This corresponds to a 57% risk reduction (hazard ratio 0.43; P less than .0001).

Based on central assessment, everolimus produced a 64% reduction in the risk of progression or death (10.6 months vs. 4.1 months; HR = 0.36; P less than .0001). The trial was stopped early based on the benefit shown in the interim data.

"Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory estrogen receptor (ER)–positive patients," lead author Dr. José Baselga said at the European Multidisciplinary Cancer Congress.

"Our results could represent a paradigm shift in the management of patients with hormone receptor-positive breast cancer," he added

Invited discussant Dr. Fabrice André, from the Institut Gustave Roussy in Villejuif, France, called everolimus the most important advance in breast cancer since trastuzumab (Herceptin).

"The efficacy of everolimus in the BOLERO-2 trial is in the range of the most important advances in medical oncology," he said.

Novartis plans to submit the data for worldwide regulatory approval of everolimus as a treatment for ER-positive advanced breast cancer by year’s end, although the medical oncology community could embrace off-label use in this indication since both drugs are already available.

Everolimus is approved in the United States for progressive neuroendocrine tumors of pancreatic origin, subependymal giant cell astrocytoma associated with inoperable tuberous sclerosis and advanced renal cell carcinoma after sunitinib (Sutent) or sorafenib (Nexavar) treatment failure. Exemestane, an aromatase inhibitor, is approved as neoadjuvant therapy for hormone receptor–positive disease in postmenopausal women.

Everolimus was evaluated because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy, said Dr. Baselga, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston.

BOLERO-2 enrolled 724 women postmenopausal women with advanced ER-positive, HER2-negative breast cancer who were refractory to letrozole (Femara) or anastrozole (Arimidex). Prior treatment also included chemotherapy for metastatic disease in roughly 25%, tamoxifen in 48% and fulvestrant (Faslodex) in about 16%. Patients were randomized to everolimus 10 mg daily or placebo, with both arms receiving exemestane 25 mg daily.

The overall response rate was 9.5% for the everolimus arm and 0.4% for the placebo arm (P less than .0001).

The clinical benefit rate was 33.4% and 18%, respectively (P less than .0001), Dr. Baselga said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

A progression-free survival subgroup analysis showed consistent results across all subgroups.

At the time of the interim analysis, 83 deaths had occurred (10.6% in the everolimus arm and 13% in the placebo arm), but the data are immature, he said.

Adverse events were consistent with previous everolimus experience including stomatitis, fatigue, noninfectious pneumonitis, and hyperglycemia, Dr. Baselga said.

Dr. André said BOLERO-2 provides robust and clinically relevant data, but added that "preclinical data suggest we can do even better." He pointed out that inhibiting mTORC1 alone is not optimal because of the activation of alternative compensatory or parallel pathways, and he suggested moving to combination trials to inhibit alternative pathways and reverse resistance.

"BOLERO-2 is just part of the iceberg coming," Dr. Jean-Charles Soria, cochair of the Congress scientific program and a cancer specialist at Institut Gustave Roussy in Villejuif, France, said in an interview. "The whole question now is about building a triplet combination that is not too toxic and that is feasible."

He referenced the ongoing phase III BOLERO-1 and BOLERO-3 trials assessing everolimus in combination with paclitaxel and trastuzumab in HER2-positive metastatic breast cancer and the triple combination of everolimus, vinorelbine, and trastuzumab in HER2-positive, locally advanced, taxane-pretreated disease resistant to trastuzumab (Herceptin).

"I’m pretty convinced from what I’ve seen in phase I and II, that the phase IIIs in combination with Herceptin might also come out as positive," he said. "So, the way we think about breast cancer is probably going to change with mTOR inhibitors."

Dr. Baselga reports consulting for several pharmaceutical companies including the study sponsor, Novartis. Dr. André has previously reported no conflicts. Dr. Soria has previously reported consulting for Boehringer Ingelheim, Roche, AstraZeneca Pharmaceuticals, and Pfizer.

STOCKHOLM – Coupling everolimus with exemestane has produced such dramatic disease control in women with advanced hormone resistant, estrogen receptor-positive breast cancer that it is expected to transform the management of these patients.

A preplanned interim analysis of the phase III BOLERO-2 trial found that everolimus (Afinitor) increased the primary end point of progression-free survival, by local assessment, from a median of 2.8 months with exemestane (Aromasin) alone to 6.9 months. This corresponds to a 57% risk reduction (hazard ratio 0.43; P less than .0001).

Based on central assessment, everolimus produced a 64% reduction in the risk of progression or death (10.6 months vs. 4.1 months; HR = 0.36; P less than .0001). The trial was stopped early based on the benefit shown in the interim data.

"Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory estrogen receptor (ER)–positive patients," lead author Dr. José Baselga said at the European Multidisciplinary Cancer Congress.

"Our results could represent a paradigm shift in the management of patients with hormone receptor-positive breast cancer," he added

Invited discussant Dr. Fabrice André, from the Institut Gustave Roussy in Villejuif, France, called everolimus the most important advance in breast cancer since trastuzumab (Herceptin).

"The efficacy of everolimus in the BOLERO-2 trial is in the range of the most important advances in medical oncology," he said.

Novartis plans to submit the data for worldwide regulatory approval of everolimus as a treatment for ER-positive advanced breast cancer by year’s end, although the medical oncology community could embrace off-label use in this indication since both drugs are already available.

Everolimus is approved in the United States for progressive neuroendocrine tumors of pancreatic origin, subependymal giant cell astrocytoma associated with inoperable tuberous sclerosis and advanced renal cell carcinoma after sunitinib (Sutent) or sorafenib (Nexavar) treatment failure. Exemestane, an aromatase inhibitor, is approved as neoadjuvant therapy for hormone receptor–positive disease in postmenopausal women.

Everolimus was evaluated because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy, said Dr. Baselga, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston.

BOLERO-2 enrolled 724 women postmenopausal women with advanced ER-positive, HER2-negative breast cancer who were refractory to letrozole (Femara) or anastrozole (Arimidex). Prior treatment also included chemotherapy for metastatic disease in roughly 25%, tamoxifen in 48% and fulvestrant (Faslodex) in about 16%. Patients were randomized to everolimus 10 mg daily or placebo, with both arms receiving exemestane 25 mg daily.

The overall response rate was 9.5% for the everolimus arm and 0.4% for the placebo arm (P less than .0001).

The clinical benefit rate was 33.4% and 18%, respectively (P less than .0001), Dr. Baselga said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

A progression-free survival subgroup analysis showed consistent results across all subgroups.

At the time of the interim analysis, 83 deaths had occurred (10.6% in the everolimus arm and 13% in the placebo arm), but the data are immature, he said.

Adverse events were consistent with previous everolimus experience including stomatitis, fatigue, noninfectious pneumonitis, and hyperglycemia, Dr. Baselga said.

Dr. André said BOLERO-2 provides robust and clinically relevant data, but added that "preclinical data suggest we can do even better." He pointed out that inhibiting mTORC1 alone is not optimal because of the activation of alternative compensatory or parallel pathways, and he suggested moving to combination trials to inhibit alternative pathways and reverse resistance.

"BOLERO-2 is just part of the iceberg coming," Dr. Jean-Charles Soria, cochair of the Congress scientific program and a cancer specialist at Institut Gustave Roussy in Villejuif, France, said in an interview. "The whole question now is about building a triplet combination that is not too toxic and that is feasible."

He referenced the ongoing phase III BOLERO-1 and BOLERO-3 trials assessing everolimus in combination with paclitaxel and trastuzumab in HER2-positive metastatic breast cancer and the triple combination of everolimus, vinorelbine, and trastuzumab in HER2-positive, locally advanced, taxane-pretreated disease resistant to trastuzumab (Herceptin).

"I’m pretty convinced from what I’ve seen in phase I and II, that the phase IIIs in combination with Herceptin might also come out as positive," he said. "So, the way we think about breast cancer is probably going to change with mTOR inhibitors."

Dr. Baselga reports consulting for several pharmaceutical companies including the study sponsor, Novartis. Dr. André has previously reported no conflicts. Dr. Soria has previously reported consulting for Boehringer Ingelheim, Roche, AstraZeneca Pharmaceuticals, and Pfizer.

STOCKHOLM – Coupling everolimus with exemestane has produced such dramatic disease control in women with advanced hormone resistant, estrogen receptor-positive breast cancer that it is expected to transform the management of these patients.

A preplanned interim analysis of the phase III BOLERO-2 trial found that everolimus (Afinitor) increased the primary end point of progression-free survival, by local assessment, from a median of 2.8 months with exemestane (Aromasin) alone to 6.9 months. This corresponds to a 57% risk reduction (hazard ratio 0.43; P less than .0001).

Based on central assessment, everolimus produced a 64% reduction in the risk of progression or death (10.6 months vs. 4.1 months; HR = 0.36; P less than .0001). The trial was stopped early based on the benefit shown in the interim data.

"Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory estrogen receptor (ER)–positive patients," lead author Dr. José Baselga said at the European Multidisciplinary Cancer Congress.

"Our results could represent a paradigm shift in the management of patients with hormone receptor-positive breast cancer," he added

Invited discussant Dr. Fabrice André, from the Institut Gustave Roussy in Villejuif, France, called everolimus the most important advance in breast cancer since trastuzumab (Herceptin).

"The efficacy of everolimus in the BOLERO-2 trial is in the range of the most important advances in medical oncology," he said.

Novartis plans to submit the data for worldwide regulatory approval of everolimus as a treatment for ER-positive advanced breast cancer by year’s end, although the medical oncology community could embrace off-label use in this indication since both drugs are already available.

Everolimus is approved in the United States for progressive neuroendocrine tumors of pancreatic origin, subependymal giant cell astrocytoma associated with inoperable tuberous sclerosis and advanced renal cell carcinoma after sunitinib (Sutent) or sorafenib (Nexavar) treatment failure. Exemestane, an aromatase inhibitor, is approved as neoadjuvant therapy for hormone receptor–positive disease in postmenopausal women.

Everolimus was evaluated because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy, said Dr. Baselga, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston.

BOLERO-2 enrolled 724 women postmenopausal women with advanced ER-positive, HER2-negative breast cancer who were refractory to letrozole (Femara) or anastrozole (Arimidex). Prior treatment also included chemotherapy for metastatic disease in roughly 25%, tamoxifen in 48% and fulvestrant (Faslodex) in about 16%. Patients were randomized to everolimus 10 mg daily or placebo, with both arms receiving exemestane 25 mg daily.

The overall response rate was 9.5% for the everolimus arm and 0.4% for the placebo arm (P less than .0001).

The clinical benefit rate was 33.4% and 18%, respectively (P less than .0001), Dr. Baselga said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

A progression-free survival subgroup analysis showed consistent results across all subgroups.

At the time of the interim analysis, 83 deaths had occurred (10.6% in the everolimus arm and 13% in the placebo arm), but the data are immature, he said.

Adverse events were consistent with previous everolimus experience including stomatitis, fatigue, noninfectious pneumonitis, and hyperglycemia, Dr. Baselga said.

Dr. André said BOLERO-2 provides robust and clinically relevant data, but added that "preclinical data suggest we can do even better." He pointed out that inhibiting mTORC1 alone is not optimal because of the activation of alternative compensatory or parallel pathways, and he suggested moving to combination trials to inhibit alternative pathways and reverse resistance.

"BOLERO-2 is just part of the iceberg coming," Dr. Jean-Charles Soria, cochair of the Congress scientific program and a cancer specialist at Institut Gustave Roussy in Villejuif, France, said in an interview. "The whole question now is about building a triplet combination that is not too toxic and that is feasible."

He referenced the ongoing phase III BOLERO-1 and BOLERO-3 trials assessing everolimus in combination with paclitaxel and trastuzumab in HER2-positive metastatic breast cancer and the triple combination of everolimus, vinorelbine, and trastuzumab in HER2-positive, locally advanced, taxane-pretreated disease resistant to trastuzumab (Herceptin).

"I’m pretty convinced from what I’ve seen in phase I and II, that the phase IIIs in combination with Herceptin might also come out as positive," he said. "So, the way we think about breast cancer is probably going to change with mTOR inhibitors."

Dr. Baselga reports consulting for several pharmaceutical companies including the study sponsor, Novartis. Dr. André has previously reported no conflicts. Dr. Soria has previously reported consulting for Boehringer Ingelheim, Roche, AstraZeneca Pharmaceuticals, and Pfizer.

STOCKHOLM – Novel antibody-guided trastuzumab emtansine therapy not only improved progression-free survival by 5 months in women with HER2-positive metastatic breast cancer, but it also had an impressively tame side effect profile, according to Dr. Sara Hurvitz.*

Treatment with trastuzumab emtansine (T-DM1) resulted in a median progression-free survival of 14 months vs. 9 months with trastuzumab (Herceptin) and docetaxel (Taxotere) in a phase II open-label study with 137 women. T-DM1 reduced the relative risk of disease progression by 41% with a hazard ratio of 0.59 (P = .0353), she reported at the European Multidisciplinary Cancer Congress.

"These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index," said Dr. Hurvitz of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

An antibody drug conjugate, T-DM1 retains the targeting properties of monoclonal antibody trastuzumab in HER2-positive breast cancer while transporting a potent cytotoxic agent (DM1) that inhibits tubulin polymerization and microtubule dynamics into cancer cells.

Invited discussant Dr. Martine J. Piccart-Gebhart talked excitedly about the results, but also urged caution.

"You have to remember that this is an open-label study. I am saying that because I believe that T-DM1 is the magic drug for medical oncologists – the drug that we have been waiting for, for so many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell," said Dr. Piccart-Gebhart of the Jules Bordet Institute at the Université Libre de Bruxelles in Belgium.

However, "in an open-label study, you have to worry a little bit because we want to give this T-DM1 drug to our patients," so it may be tempting to interpret the results too favorably, she told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The researchers recruited 137 women with HER2-positive, recurrent locally advanced breast cancer or metastatic breast cancer. The patients were randomized to receive either trastuzumab and docetaxel or T-DM1 alone.

Trastuzumab was given as an 8-mg/kg loading dose and then as 6 mg/kg every 3 weeks. Docetaxel was given in a dose of 75 mg/m² or 100 mg/m² for 3 weeks. T-DM1 was given intravenously at a dose of 3.6 mg/kg every 3 weeks. In all, 70 women received trastuzumab and docetaxel and 67 received T-DM1.

The primary end points were progression-free survival by investigator assessment and safety. Data analyses were based on clinical data as of Nov. 15, 2010, and prior to any T-DM1 crossover. Overall survival data are expected in 2012. Quality of life data will be presented as a poster at the San Antonio Breast Cancer Symposium this December.

Most of the patients in each group (85%) had centrally confirmed HER2-positive breast cancer. "Relatively few patients had received neoadjuvant or adjuvant trastuzumab. This was likely owing to the international nature of the study and the lack of availability at some centers for trastuzumab in the adjuvant setting," said Dr. Hurvitz.

Dr. Piccart-Gebhart observed that one-third of patients in this study were stage IV at diagnosis and only 20%-25% were exposed to adjuvant trastuzumab. These numbers are likely to change with time, as more patients are exposed to trastuzumab.

At the time of data cutoff, 21% of patients on trastuzumab and docetaxel were still on the treatment, compared with 43% of those in the T-DM1 arm. "The majority of patients came off of treatment for disease progression," she said.

The objective response rate was similar – 58% for the T-DM1 arm vs. 64% for the control arm. Patients in the trastuzumab/docetaxel arm had a median duration of response of 9.5 months. The duration of response in the T-DM1 arm has not yet been reached.

"In terms of safety and tolerability, it is very clear that the safety profile of T-DM1 is far better than the one for docetaxel and trastuzumab," said Dr. Piccart-Gebhart. Patients who received T-DM1 had many fewer adverse events of grade 3 or greater – 32 vs. 59.

Among hematologic adverse events, neutropenia of any grade was more common in the control arm – 63.6% compared with 17.4% – but any grade thrombocytopenia was more common in the T-DM1 arm (30% vs. 6%).

Among nonhematologic events, any grade alopecia was less than 4% for the T-DM1 arm compared with 67% for the control arm. Likewise, the incidence of any grade diarrhea was much lower in the T-DM1 arm – 16% for those on T-DM1 compared with 46% for those on the trastuzumab/docetaxel. Peripheral edema of any grade was also much lower in the T-DM1 arm (10% vs. 44%).

"Cardiac safety is important to look at whenever you’re talking about HER-2 targeting agent," said Dr. Hurvitz.

Adjuvant anthracyclines were given to 45% and 49% of patients in the T-DM1 arm and control arm. On local assessment two patients in the control arm, compared with none in the T-DM1 arm, had a postbaseline left ventricular ejection fraction of 40% or less.

"There were no clinically significant cardiac events reported," she noted.

Dr. Hurvitz and Dr. Piccart-Gebhart agreed that large phase III trials are needed to confirm these findings. The drug is being evaluated in three large phase III clinical trials for HER2-postive metastatic breast cancer.

The study was funded by F. Hoffmann-La Roche. Dr. Hurvitz reported that she has no relevant financial disclosures. Dr. Piccart-Gebhart has previously reported that she is a consultant for and has received research support from several pharmaceutical companies, including Roche.

* Clarification, 9/29/2011: The original version of this article stated that trastuzumab emtansine improved disease-free progression. However, it is more accurate to say that it improved progression-free survival. This version has been updated.

STOCKHOLM – Novel antibody-guided trastuzumab emtansine therapy not only improved progression-free survival by 5 months in women with HER2-positive metastatic breast cancer, but it also had an impressively tame side effect profile, according to Dr. Sara Hurvitz.*

Treatment with trastuzumab emtansine (T-DM1) resulted in a median progression-free survival of 14 months vs. 9 months with trastuzumab (Herceptin) and docetaxel (Taxotere) in a phase II open-label study with 137 women. T-DM1 reduced the relative risk of disease progression by 41% with a hazard ratio of 0.59 (P = .0353), she reported at the European Multidisciplinary Cancer Congress.

"These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index," said Dr. Hurvitz of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

An antibody drug conjugate, T-DM1 retains the targeting properties of monoclonal antibody trastuzumab in HER2-positive breast cancer while transporting a potent cytotoxic agent (DM1) that inhibits tubulin polymerization and microtubule dynamics into cancer cells.

Invited discussant Dr. Martine J. Piccart-Gebhart talked excitedly about the results, but also urged caution.

"You have to remember that this is an open-label study. I am saying that because I believe that T-DM1 is the magic drug for medical oncologists – the drug that we have been waiting for, for so many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell," said Dr. Piccart-Gebhart of the Jules Bordet Institute at the Université Libre de Bruxelles in Belgium.

However, "in an open-label study, you have to worry a little bit because we want to give this T-DM1 drug to our patients," so it may be tempting to interpret the results too favorably, she told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The researchers recruited 137 women with HER2-positive, recurrent locally advanced breast cancer or metastatic breast cancer. The patients were randomized to receive either trastuzumab and docetaxel or T-DM1 alone.

Trastuzumab was given as an 8-mg/kg loading dose and then as 6 mg/kg every 3 weeks. Docetaxel was given in a dose of 75 mg/m² or 100 mg/m² for 3 weeks. T-DM1 was given intravenously at a dose of 3.6 mg/kg every 3 weeks. In all, 70 women received trastuzumab and docetaxel and 67 received T-DM1.

The primary end points were progression-free survival by investigator assessment and safety. Data analyses were based on clinical data as of Nov. 15, 2010, and prior to any T-DM1 crossover. Overall survival data are expected in 2012. Quality of life data will be presented as a poster at the San Antonio Breast Cancer Symposium this December.

Most of the patients in each group (85%) had centrally confirmed HER2-positive breast cancer. "Relatively few patients had received neoadjuvant or adjuvant trastuzumab. This was likely owing to the international nature of the study and the lack of availability at some centers for trastuzumab in the adjuvant setting," said Dr. Hurvitz.

Dr. Piccart-Gebhart observed that one-third of patients in this study were stage IV at diagnosis and only 20%-25% were exposed to adjuvant trastuzumab. These numbers are likely to change with time, as more patients are exposed to trastuzumab.

At the time of data cutoff, 21% of patients on trastuzumab and docetaxel were still on the treatment, compared with 43% of those in the T-DM1 arm. "The majority of patients came off of treatment for disease progression," she said.

The objective response rate was similar – 58% for the T-DM1 arm vs. 64% for the control arm. Patients in the trastuzumab/docetaxel arm had a median duration of response of 9.5 months. The duration of response in the T-DM1 arm has not yet been reached.

"In terms of safety and tolerability, it is very clear that the safety profile of T-DM1 is far better than the one for docetaxel and trastuzumab," said Dr. Piccart-Gebhart. Patients who received T-DM1 had many fewer adverse events of grade 3 or greater – 32 vs. 59.

Among hematologic adverse events, neutropenia of any grade was more common in the control arm – 63.6% compared with 17.4% – but any grade thrombocytopenia was more common in the T-DM1 arm (30% vs. 6%).

Among nonhematologic events, any grade alopecia was less than 4% for the T-DM1 arm compared with 67% for the control arm. Likewise, the incidence of any grade diarrhea was much lower in the T-DM1 arm – 16% for those on T-DM1 compared with 46% for those on the trastuzumab/docetaxel. Peripheral edema of any grade was also much lower in the T-DM1 arm (10% vs. 44%).

"Cardiac safety is important to look at whenever you’re talking about HER-2 targeting agent," said Dr. Hurvitz.

Adjuvant anthracyclines were given to 45% and 49% of patients in the T-DM1 arm and control arm. On local assessment two patients in the control arm, compared with none in the T-DM1 arm, had a postbaseline left ventricular ejection fraction of 40% or less.

"There were no clinically significant cardiac events reported," she noted.

Dr. Hurvitz and Dr. Piccart-Gebhart agreed that large phase III trials are needed to confirm these findings. The drug is being evaluated in three large phase III clinical trials for HER2-postive metastatic breast cancer.

The study was funded by F. Hoffmann-La Roche. Dr. Hurvitz reported that she has no relevant financial disclosures. Dr. Piccart-Gebhart has previously reported that she is a consultant for and has received research support from several pharmaceutical companies, including Roche.

* Clarification, 9/29/2011: The original version of this article stated that trastuzumab emtansine improved disease-free progression. However, it is more accurate to say that it improved progression-free survival. This version has been updated.

STOCKHOLM – Novel antibody-guided trastuzumab emtansine therapy not only improved progression-free survival by 5 months in women with HER2-positive metastatic breast cancer, but it also had an impressively tame side effect profile, according to Dr. Sara Hurvitz.*

Treatment with trastuzumab emtansine (T-DM1) resulted in a median progression-free survival of 14 months vs. 9 months with trastuzumab (Herceptin) and docetaxel (Taxotere) in a phase II open-label study with 137 women. T-DM1 reduced the relative risk of disease progression by 41% with a hazard ratio of 0.59 (P = .0353), she reported at the European Multidisciplinary Cancer Congress.

"These results validate the hypothesis that the unique properties of T-DM1 may lead to an improved therapeutic index," said Dr. Hurvitz of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

An antibody drug conjugate, T-DM1 retains the targeting properties of monoclonal antibody trastuzumab in HER2-positive breast cancer while transporting a potent cytotoxic agent (DM1) that inhibits tubulin polymerization and microtubule dynamics into cancer cells.

Invited discussant Dr. Martine J. Piccart-Gebhart talked excitedly about the results, but also urged caution.

"You have to remember that this is an open-label study. I am saying that because I believe that T-DM1 is the magic drug for medical oncologists – the drug that we have been waiting for, for so many years. It is a clever drug. It brings the cytotoxic agent inside the cancer cell," said Dr. Piccart-Gebhart of the Jules Bordet Institute at the Université Libre de Bruxelles in Belgium.

However, "in an open-label study, you have to worry a little bit because we want to give this T-DM1 drug to our patients," so it may be tempting to interpret the results too favorably, she told attendees at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The researchers recruited 137 women with HER2-positive, recurrent locally advanced breast cancer or metastatic breast cancer. The patients were randomized to receive either trastuzumab and docetaxel or T-DM1 alone.

Trastuzumab was given as an 8-mg/kg loading dose and then as 6 mg/kg every 3 weeks. Docetaxel was given in a dose of 75 mg/m² or 100 mg/m² for 3 weeks. T-DM1 was given intravenously at a dose of 3.6 mg/kg every 3 weeks. In all, 70 women received trastuzumab and docetaxel and 67 received T-DM1.

The primary end points were progression-free survival by investigator assessment and safety. Data analyses were based on clinical data as of Nov. 15, 2010, and prior to any T-DM1 crossover. Overall survival data are expected in 2012. Quality of life data will be presented as a poster at the San Antonio Breast Cancer Symposium this December.

Most of the patients in each group (85%) had centrally confirmed HER2-positive breast cancer. "Relatively few patients had received neoadjuvant or adjuvant trastuzumab. This was likely owing to the international nature of the study and the lack of availability at some centers for trastuzumab in the adjuvant setting," said Dr. Hurvitz.

Dr. Piccart-Gebhart observed that one-third of patients in this study were stage IV at diagnosis and only 20%-25% were exposed to adjuvant trastuzumab. These numbers are likely to change with time, as more patients are exposed to trastuzumab.

At the time of data cutoff, 21% of patients on trastuzumab and docetaxel were still on the treatment, compared with 43% of those in the T-DM1 arm. "The majority of patients came off of treatment for disease progression," she said.

The objective response rate was similar – 58% for the T-DM1 arm vs. 64% for the control arm. Patients in the trastuzumab/docetaxel arm had a median duration of response of 9.5 months. The duration of response in the T-DM1 arm has not yet been reached.

"In terms of safety and tolerability, it is very clear that the safety profile of T-DM1 is far better than the one for docetaxel and trastuzumab," said Dr. Piccart-Gebhart. Patients who received T-DM1 had many fewer adverse events of grade 3 or greater – 32 vs. 59.

Among hematologic adverse events, neutropenia of any grade was more common in the control arm – 63.6% compared with 17.4% – but any grade thrombocytopenia was more common in the T-DM1 arm (30% vs. 6%).

Among nonhematologic events, any grade alopecia was less than 4% for the T-DM1 arm compared with 67% for the control arm. Likewise, the incidence of any grade diarrhea was much lower in the T-DM1 arm – 16% for those on T-DM1 compared with 46% for those on the trastuzumab/docetaxel. Peripheral edema of any grade was also much lower in the T-DM1 arm (10% vs. 44%).

"Cardiac safety is important to look at whenever you’re talking about HER-2 targeting agent," said Dr. Hurvitz.

Adjuvant anthracyclines were given to 45% and 49% of patients in the T-DM1 arm and control arm. On local assessment two patients in the control arm, compared with none in the T-DM1 arm, had a postbaseline left ventricular ejection fraction of 40% or less.

"There were no clinically significant cardiac events reported," she noted.

Dr. Hurvitz and Dr. Piccart-Gebhart agreed that large phase III trials are needed to confirm these findings. The drug is being evaluated in three large phase III clinical trials for HER2-postive metastatic breast cancer.

The study was funded by F. Hoffmann-La Roche. Dr. Hurvitz reported that she has no relevant financial disclosures. Dr. Piccart-Gebhart has previously reported that she is a consultant for and has received research support from several pharmaceutical companies, including Roche.

* Clarification, 9/29/2011: The original version of this article stated that trastuzumab emtansine improved disease-free progression. However, it is more accurate to say that it improved progression-free survival. This version has been updated.

SAN FRANCISCO – Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987-2005.

Results showed that with a median follow-up of 7-8 years, the rate of freedom from locoregional recurrence was high (90% or greater at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

"For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy," Dr. Mittendorf, a surgical oncologist, commented, adding, "It is important to obtain a negative margin at the time of surgery."

"It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy," she said.

However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of "oversimplification of [a] complex issue ... especially in the era of personalized therapy."

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

"The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important," commented Dr. Fowble. "Initial stage, molecular subtype, and response to therapy will impact on outcome."

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor–negative disease, and to have multifocal disease. Median durations of follow-up were 7.2 and 7.9 years.

In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%) (P less than .001).

"Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy," Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P less than .001). For example, the 10-year rate was 90% with the former and 94% with the latter.

"Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors," she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence.

Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (hazard ratio, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor–negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor–positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence–free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

SAN FRANCISCO – Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987-2005.

Results showed that with a median follow-up of 7-8 years, the rate of freedom from locoregional recurrence was high (90% or greater at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

"For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy," Dr. Mittendorf, a surgical oncologist, commented, adding, "It is important to obtain a negative margin at the time of surgery."

"It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy," she said.

However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of "oversimplification of [a] complex issue ... especially in the era of personalized therapy."

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

"The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important," commented Dr. Fowble. "Initial stage, molecular subtype, and response to therapy will impact on outcome."

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor–negative disease, and to have multifocal disease. Median durations of follow-up were 7.2 and 7.9 years.

In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%) (P less than .001).

"Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy," Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P less than .001). For example, the 10-year rate was 90% with the former and 94% with the latter.

"Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors," she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence.

Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (hazard ratio, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor–negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor–positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence–free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

SAN FRANCISCO – Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987-2005.

Results showed that with a median follow-up of 7-8 years, the rate of freedom from locoregional recurrence was high (90% or greater at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

"For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy," Dr. Mittendorf, a surgical oncologist, commented, adding, "It is important to obtain a negative margin at the time of surgery."

"It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy," she said.

However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of "oversimplification of [a] complex issue ... especially in the era of personalized therapy."

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

"The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important," commented Dr. Fowble. "Initial stage, molecular subtype, and response to therapy will impact on outcome."

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor–negative disease, and to have multifocal disease. Median durations of follow-up were 7.2 and 7.9 years.

In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%) (P less than .001).

"Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy," Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P less than .001). For example, the 10-year rate was 90% with the former and 94% with the latter.

"Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors," she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence.

Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (hazard ratio, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor–negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor–positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence–free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

SAN FRANCISCO – A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor–positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor–positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole (Femara) or placebo.

Study results, reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled.

The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor–positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

"If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component," he explained.

"If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy," he continued. "For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials."

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase–polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

"We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually," he noted. "In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence."

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = .014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = .019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported. In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = .037).

"Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = .02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I," he said. "These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy."

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

SAN FRANCISCO – A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor–positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor–positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole (Femara) or placebo.

Study results, reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled.

The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor–positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

"If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component," he explained.

"If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy," he continued. "For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials."

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase–polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

"We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually," he noted. "In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence."

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = .014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = .019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported. In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = .037).

"Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = .02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I," he said. "These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy."

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

SAN FRANCISCO – A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor–positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor–positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole (Femara) or placebo.

Study results, reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled.

The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor–positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

"If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component," he explained.

"If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy," he continued. "For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials."

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase–polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

"We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually," he noted. "In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence."

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = .014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = .019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported. In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = .037).

"Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = .02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I," he said. "These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy."

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

WASHINGTON – Magnetic resonance imaging screening for breast cancer is feasible and cost effective for high-risk underserved women, according to a study conducted by Duke University Medical Center researchers.

The investigators, led by Dr. Anne C. Ford, assistant professor of obstetrics and gynecology at the center, wanted to determine whether targeting MRI screening, which has the potential to increase the number of benign biopsies, would increase costs.

The researchers included 299 women who participate in a high-risk clinic at Duke, who were given a digital mammogram followed by an MRI, as well as 299 average-risk women recruited through an outreach program to serve as controls. High risk was defined as a greater than 20% lifetime risk of breast cancer, the investigators reported at a conference sponsored by the American Association for Cancer Research.

The women were racially diverse. The mammography group was 40% African American, 25% white, 25% Hispanic, and 10% other. The MRI group was 62% white, 33% African American, 3% Hispanic, and 2% other.

Women found to have an abnormal mammogram were evaluated by ultrasound, ultrasound-guided biopsy, and/or stereotactic biopsy. Women with an abnormal breast MRI were evaluated with ultrasound, ultrasound-guided biopsy, and/or MRI-guided biopsy. Patient navigators accompanied all women to all appointments, including follow-up care.

Overall, there were seven benign biopsies conducted in the mammography group. One cancer was found, for a detection rate of 12%. Thirty-one benign biopsies were done in the combination group; seven cancers were discovered, for a detection rate of 18%.

Of the cancers that were staged, the MRI had detected one stage 0 tumor, four that were stage I, and one each that were stage II and III. The mammogram detected one tumor that was stage II. So the MRI detected some cancers in an early stage.

For screening alone, the cost per diagnosis was $37,375 for mammography, compared with $27,722 for MRI.

These figures, however, were calculated using a lower MRI rate than many institutions might pay. For the study, the cost of the MRI was negotiated to a reduced rate of $649. Dr. Ford said in an interview that the calculation might change if the MRI rate were more or less.

There also was a very good compliance rate with follow-up studies. Most likely, that is because those services were offered free of charge to participants and because they were constantly interacting with patient navigators, said Dr. Ford.

Six of seven women in the mammography group who were referred for follow-up complied. Twenty-eight of the 31 MRI screening patients returned for follow-up.

The study was supported by the Susan G. Komen for the Cure, the Avon Foundation Breast Care Fund, the Kate B. Reynolds Charitable Trust, and the Breast Cancer Relief Foundation.

WASHINGTON – Magnetic resonance imaging screening for breast cancer is feasible and cost effective for high-risk underserved women, according to a study conducted by Duke University Medical Center researchers.

The investigators, led by Dr. Anne C. Ford, assistant professor of obstetrics and gynecology at the center, wanted to determine whether targeting MRI screening, which has the potential to increase the number of benign biopsies, would increase costs.

The researchers included 299 women who participate in a high-risk clinic at Duke, who were given a digital mammogram followed by an MRI, as well as 299 average-risk women recruited through an outreach program to serve as controls. High risk was defined as a greater than 20% lifetime risk of breast cancer, the investigators reported at a conference sponsored by the American Association for Cancer Research.

The women were racially diverse. The mammography group was 40% African American, 25% white, 25% Hispanic, and 10% other. The MRI group was 62% white, 33% African American, 3% Hispanic, and 2% other.

Women found to have an abnormal mammogram were evaluated by ultrasound, ultrasound-guided biopsy, and/or stereotactic biopsy. Women with an abnormal breast MRI were evaluated with ultrasound, ultrasound-guided biopsy, and/or MRI-guided biopsy. Patient navigators accompanied all women to all appointments, including follow-up care.

Overall, there were seven benign biopsies conducted in the mammography group. One cancer was found, for a detection rate of 12%. Thirty-one benign biopsies were done in the combination group; seven cancers were discovered, for a detection rate of 18%.

Of the cancers that were staged, the MRI had detected one stage 0 tumor, four that were stage I, and one each that were stage II and III. The mammogram detected one tumor that was stage II. So the MRI detected some cancers in an early stage.

For screening alone, the cost per diagnosis was $37,375 for mammography, compared with $27,722 for MRI.

These figures, however, were calculated using a lower MRI rate than many institutions might pay. For the study, the cost of the MRI was negotiated to a reduced rate of $649. Dr. Ford said in an interview that the calculation might change if the MRI rate were more or less.

There also was a very good compliance rate with follow-up studies. Most likely, that is because those services were offered free of charge to participants and because they were constantly interacting with patient navigators, said Dr. Ford.

Six of seven women in the mammography group who were referred for follow-up complied. Twenty-eight of the 31 MRI screening patients returned for follow-up.

The study was supported by the Susan G. Komen for the Cure, the Avon Foundation Breast Care Fund, the Kate B. Reynolds Charitable Trust, and the Breast Cancer Relief Foundation.

WASHINGTON – Magnetic resonance imaging screening for breast cancer is feasible and cost effective for high-risk underserved women, according to a study conducted by Duke University Medical Center researchers.

The investigators, led by Dr. Anne C. Ford, assistant professor of obstetrics and gynecology at the center, wanted to determine whether targeting MRI screening, which has the potential to increase the number of benign biopsies, would increase costs.

The researchers included 299 women who participate in a high-risk clinic at Duke, who were given a digital mammogram followed by an MRI, as well as 299 average-risk women recruited through an outreach program to serve as controls. High risk was defined as a greater than 20% lifetime risk of breast cancer, the investigators reported at a conference sponsored by the American Association for Cancer Research.

The women were racially diverse. The mammography group was 40% African American, 25% white, 25% Hispanic, and 10% other. The MRI group was 62% white, 33% African American, 3% Hispanic, and 2% other.

Women found to have an abnormal mammogram were evaluated by ultrasound, ultrasound-guided biopsy, and/or stereotactic biopsy. Women with an abnormal breast MRI were evaluated with ultrasound, ultrasound-guided biopsy, and/or MRI-guided biopsy. Patient navigators accompanied all women to all appointments, including follow-up care.

Overall, there were seven benign biopsies conducted in the mammography group. One cancer was found, for a detection rate of 12%. Thirty-one benign biopsies were done in the combination group; seven cancers were discovered, for a detection rate of 18%.

Of the cancers that were staged, the MRI had detected one stage 0 tumor, four that were stage I, and one each that were stage II and III. The mammogram detected one tumor that was stage II. So the MRI detected some cancers in an early stage.

For screening alone, the cost per diagnosis was $37,375 for mammography, compared with $27,722 for MRI.

These figures, however, were calculated using a lower MRI rate than many institutions might pay. For the study, the cost of the MRI was negotiated to a reduced rate of $649. Dr. Ford said in an interview that the calculation might change if the MRI rate were more or less.

There also was a very good compliance rate with follow-up studies. Most likely, that is because those services were offered free of charge to participants and because they were constantly interacting with patient navigators, said Dr. Ford.

Six of seven women in the mammography group who were referred for follow-up complied. Twenty-eight of the 31 MRI screening patients returned for follow-up.

The study was supported by the Susan G. Komen for the Cure, the Avon Foundation Breast Care Fund, the Kate B. Reynolds Charitable Trust, and the Breast Cancer Relief Foundation.