Breast Cancer

Women who undergo radiotherapy to the conserved breast after breast-conserving cancer surgery can expect a reduction in the rate of recurrence (locoregional or distant) of approximately 50% and a reduction in the rate of death from breast cancer of about one sixth. Those are the latest findings from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), published online in The Lancet.¹

The EBCTCG report updates earlier analyses of individual patient data from randomized trials of radiotherapy after breast-conserving therapy. It adds follow-up data from nine of 10 trials analyzed earlier. It also includes information from seven new trials (six of them in low-risk women). Overall, it boosts the total number of women analyzed by almost 50%.¹

The EBCTCG performed a meta-analysis using individual patient data from 10,801 women in 17 randomized trials of radiotherapy versus no radiotherapy after breast-conserving surgery. Of these women, 8,337 had pathologically confirmed lymph node status (7,287 with negative nodes and 1,050 with positive nodes).

Among the findings:

• Women randomized to radiotherapy had an average annual rate of any first recurrence 50% lower than the women who underwent surgery alone (rate ratio, 0.52; 95% confidence interval [CI], 0.48–0.56), with the greatest reduction seen in the first year after treatment (rate ratio, 0.31; 95% CI, 0.26–0.37). The reduction in the rate of recurrence persisted during years 5–9 (rate ratio, 0.59; 95% CI, 0.50–0.70).
• Women allocated to radiotherapy had a reduction in the risk of death from breast cancer of about 17% (rate ratio, 0.82; 95% CI, 0.75–0.90).
• Women who had negative nodes experienced a reduction in the average annual recurrence rate of about 50% during the first decade (rate ratio, 0.46; 95% CI, 0.41–0.51), lowering the 10-year-risk of any first recurrence from 31.0% to 15.6%, an absolute reduction of 15.4% (95% CI, 13.2–17.6; 2p<.00001).
• For women who had positive nodes, randomization to radiotherapy reduced the 1-year risk of recurrence from 26.0% to 5.1%, a fivefold reduction (rate ratio, 0.20; 95% CI, 0.14–0.29)
• Overall, one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10.

“The overall findings from these trials show that radiotherapy after breast-conserving surgery not only substantially reduces the risk of recurrence but also moderately reduces the risk of death from breast cancer,” the investigators write. “These results suggest that killing microscopic tumor foci in the conserved breast with radiotherapy reduces the potential for both local recurrence and distant metastasis.”

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

Women who undergo radiotherapy to the conserved breast after breast-conserving cancer surgery can expect a reduction in the rate of recurrence (locoregional or distant) of approximately 50% and a reduction in the rate of death from breast cancer of about one sixth. Those are the latest findings from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), published online in The Lancet.¹

The EBCTCG report updates earlier analyses of individual patient data from randomized trials of radiotherapy after breast-conserving therapy. It adds follow-up data from nine of 10 trials analyzed earlier. It also includes information from seven new trials (six of them in low-risk women). Overall, it boosts the total number of women analyzed by almost 50%.¹

The EBCTCG performed a meta-analysis using individual patient data from 10,801 women in 17 randomized trials of radiotherapy versus no radiotherapy after breast-conserving surgery. Of these women, 8,337 had pathologically confirmed lymph node status (7,287 with negative nodes and 1,050 with positive nodes).

Among the findings:

• Women randomized to radiotherapy had an average annual rate of any first recurrence 50% lower than the women who underwent surgery alone (rate ratio, 0.52; 95% confidence interval [CI], 0.48–0.56), with the greatest reduction seen in the first year after treatment (rate ratio, 0.31; 95% CI, 0.26–0.37). The reduction in the rate of recurrence persisted during years 5–9 (rate ratio, 0.59; 95% CI, 0.50–0.70).
• Women allocated to radiotherapy had a reduction in the risk of death from breast cancer of about 17% (rate ratio, 0.82; 95% CI, 0.75–0.90).
• Women who had negative nodes experienced a reduction in the average annual recurrence rate of about 50% during the first decade (rate ratio, 0.46; 95% CI, 0.41–0.51), lowering the 10-year-risk of any first recurrence from 31.0% to 15.6%, an absolute reduction of 15.4% (95% CI, 13.2–17.6; 2p<.00001).
• For women who had positive nodes, randomization to radiotherapy reduced the 1-year risk of recurrence from 26.0% to 5.1%, a fivefold reduction (rate ratio, 0.20; 95% CI, 0.14–0.29)
• Overall, one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10.

“The overall findings from these trials show that radiotherapy after breast-conserving surgery not only substantially reduces the risk of recurrence but also moderately reduces the risk of death from breast cancer,” the investigators write. “These results suggest that killing microscopic tumor foci in the conserved breast with radiotherapy reduces the potential for both local recurrence and distant metastasis.”

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

Women who undergo radiotherapy to the conserved breast after breast-conserving cancer surgery can expect a reduction in the rate of recurrence (locoregional or distant) of approximately 50% and a reduction in the rate of death from breast cancer of about one sixth. Those are the latest findings from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), published online in The Lancet.¹

The EBCTCG report updates earlier analyses of individual patient data from randomized trials of radiotherapy after breast-conserving therapy. It adds follow-up data from nine of 10 trials analyzed earlier. It also includes information from seven new trials (six of them in low-risk women). Overall, it boosts the total number of women analyzed by almost 50%.¹

The EBCTCG performed a meta-analysis using individual patient data from 10,801 women in 17 randomized trials of radiotherapy versus no radiotherapy after breast-conserving surgery. Of these women, 8,337 had pathologically confirmed lymph node status (7,287 with negative nodes and 1,050 with positive nodes).

Among the findings:

• Women randomized to radiotherapy had an average annual rate of any first recurrence 50% lower than the women who underwent surgery alone (rate ratio, 0.52; 95% confidence interval [CI], 0.48–0.56), with the greatest reduction seen in the first year after treatment (rate ratio, 0.31; 95% CI, 0.26–0.37). The reduction in the rate of recurrence persisted during years 5–9 (rate ratio, 0.59; 95% CI, 0.50–0.70).
• Women allocated to radiotherapy had a reduction in the risk of death from breast cancer of about 17% (rate ratio, 0.82; 95% CI, 0.75–0.90).
• Women who had negative nodes experienced a reduction in the average annual recurrence rate of about 50% during the first decade (rate ratio, 0.46; 95% CI, 0.41–0.51), lowering the 10-year-risk of any first recurrence from 31.0% to 15.6%, an absolute reduction of 15.4% (95% CI, 13.2–17.6; 2p<.00001).
• For women who had positive nodes, randomization to radiotherapy reduced the 1-year risk of recurrence from 26.0% to 5.1%, a fivefold reduction (rate ratio, 0.20; 95% CI, 0.14–0.29)
• Overall, one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10.

“The overall findings from these trials show that radiotherapy after breast-conserving surgery not only substantially reduces the risk of recurrence but also moderately reduces the risk of death from breast cancer,” the investigators write. “These results suggest that killing microscopic tumor foci in the conserved breast with radiotherapy reduces the potential for both local recurrence and distant metastasis.”

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

A preplanned interim analysis of the phase III BOLERO- 2 trial in women with advanced hormone-resistant, estrogen receptor– positive (ER+) breast cancer showed that everolimus (Afinitor) combined with the aromatase inhibitor exemestane increased progression-free survival (PFS), by local assessment, from a median of 2.8 months with exemestane alone to 6.9 months—a 57% risk reduction (hazard ratio [HR], 0.43; P = 1.4 × 10–15). The results were presented at the recent 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.¹

Based on central assessment, the everolimus-exemestane combination produced a 64% reduction in the risk of progression or death (10.6 months vs 4.1 months; HR = 0.36; P = 3.3 × 10–15), according to lead investigator José Baselga, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

The researchers evaluated everolimus because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials have suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy.2

The group enrolled 724 postmenopausal women (median age, 62 years) with advanced ER+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer who were refractory to letrozole or anastrozole. Previous treatment also included chemotherapy for metastatic disease in roughly 68% of the patients, tamoxifen in 48%, and fulvestrant (Faslodex) in about 16%. The patients were randomized to treatment with everolimus 10 mg/d or placebo, with both arms receiving exemestane 25 mg/d. Treatment was continued until disease progression or unacceptable toxicity occurred. The primary endpoint was PFS, as assessed by the investigators; secondary endpoints included survival, response rate, and safety. The preplanned interim analysis was performed and reviewed by an independent data monitoring committee after observing 359 PFS events.

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

A preplanned interim analysis of the phase III BOLERO- 2 trial in women with advanced hormone-resistant, estrogen receptor– positive (ER+) breast cancer showed that everolimus (Afinitor) combined with the aromatase inhibitor exemestane increased progression-free survival (PFS), by local assessment, from a median of 2.8 months with exemestane alone to 6.9 months—a 57% risk reduction (hazard ratio [HR], 0.43; P = 1.4 × 10–15). The results were presented at the recent 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.¹

Based on central assessment, the everolimus-exemestane combination produced a 64% reduction in the risk of progression or death (10.6 months vs 4.1 months; HR = 0.36; P = 3.3 × 10–15), according to lead investigator José Baselga, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

The researchers evaluated everolimus because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials have suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy.2

The group enrolled 724 postmenopausal women (median age, 62 years) with advanced ER+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer who were refractory to letrozole or anastrozole. Previous treatment also included chemotherapy for metastatic disease in roughly 68% of the patients, tamoxifen in 48%, and fulvestrant (Faslodex) in about 16%. The patients were randomized to treatment with everolimus 10 mg/d or placebo, with both arms receiving exemestane 25 mg/d. Treatment was continued until disease progression or unacceptable toxicity occurred. The primary endpoint was PFS, as assessed by the investigators; secondary endpoints included survival, response rate, and safety. The preplanned interim analysis was performed and reviewed by an independent data monitoring committee after observing 359 PFS events.

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

A preplanned interim analysis of the phase III BOLERO- 2 trial in women with advanced hormone-resistant, estrogen receptor– positive (ER+) breast cancer showed that everolimus (Afinitor) combined with the aromatase inhibitor exemestane increased progression-free survival (PFS), by local assessment, from a median of 2.8 months with exemestane alone to 6.9 months—a 57% risk reduction (hazard ratio [HR], 0.43; P = 1.4 × 10–15). The results were presented at the recent 2011 European Multidisciplinary Cancer Congress in Stockholm, Sweden.¹

Based on central assessment, the everolimus-exemestane combination produced a 64% reduction in the risk of progression or death (10.6 months vs 4.1 months; HR = 0.36; P = 3.3 × 10–15), according to lead investigator José Baselga, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston.

The researchers evaluated everolimus because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials have suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy.2

The group enrolled 724 postmenopausal women (median age, 62 years) with advanced ER+, human epidermal growth factor receptor 2–negative (HER2–) breast cancer who were refractory to letrozole or anastrozole. Previous treatment also included chemotherapy for metastatic disease in roughly 68% of the patients, tamoxifen in 48%, and fulvestrant (Faslodex) in about 16%. The patients were randomized to treatment with everolimus 10 mg/d or placebo, with both arms receiving exemestane 25 mg/d. Treatment was continued until disease progression or unacceptable toxicity occurred. The primary endpoint was PFS, as assessed by the investigators; secondary endpoints included survival, response rate, and safety. The preplanned interim analysis was performed and reviewed by an independent data monitoring committee after observing 359 PFS events.

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

Women who don’t carry their family’s BRCA1 or BRCA2 mutation showed no increase in breast cancer risk in a study of 3,047 population-based families reported online Oct. 31 in the Journal of Clinical Oncology.

"These results support the standard clinical practice of advising noncarriers that they do not have any increase in breast cancer risk attributable to the family-specific BRCA mutation and, in the absence of other strong risk factors, should follow general population guidelines for breast cancer screening," said Dr. Allison W. Kurian of Stanford (Calif.) University and her associates.

Some recent studies have suggested that noncarriers of a family-specific mutation may have a two- to fivefold increase in risk of developing breast cancer, compared with the general population. While lower than the 5- to 20-fold increase in risk for carriers of the mutation, this rate would still be high enough to warrant breast cancer surveillance. Other studies have found no increase in risk among noncarriers.

To clarify the issue, Dr. Kurian and her colleagues assessed breast cancer risk using population-based cancer registries in the United States, Australia, and Canada. They identified 3,047 families in which one woman (the proband) was diagnosed as having breast cancer at a relatively young age, in most cases during 1996-2000, and she and her female first-degree relatives underwent genetic testing for BRCA1 and BRCA2 mutations.

Women in all three countries showed a similar prevalence of the mutations, similar rates of breast and ovarian cancer, and similar ages of onset for the malignancies. Overall, 160 families had BRCA1 mutations and 132 had BRCA2 mutations, the investigators reported (J. Clin. Oncol. 2011 Oct. 31 [doi:10.1200.JCO.2010.34.4440]).

Among noncarriers of family-specific mutations, the risk of developing breast cancer was not significantly higher than the risk among women in families without any BRCA1 or BRCA2 mutations. This relative risk was 0.39.

It is possible that previous studies reporting an increased risk in noncarriers have overestimated this risk, because they compared study subjects with women in the general population rather than women whose relatives have breast cancer. The latter group undergoes more frequent screening and consequently has more frequent diagnoses of breast cancer than women in the general population, Dr. Kurian and her associates noted.

Their study, in which 292 families with BRCA1 or BRCA2 mutations were compared with 2,755 families without such mutations from the same populations, "represents the largest analysis to date of breast cancer risk to noncarriers of family-specific mutations," they added.

The study was supported by the National Cancer Institute, the National Institutes of Health, Cancer Care Ontario, Cancer Prevention Institute of California, and the University of Melbourne. No financial conflicts of interest were reported.

Women who don’t carry their family’s BRCA1 or BRCA2 mutation showed no increase in breast cancer risk in a study of 3,047 population-based families reported online Oct. 31 in the Journal of Clinical Oncology.

"These results support the standard clinical practice of advising noncarriers that they do not have any increase in breast cancer risk attributable to the family-specific BRCA mutation and, in the absence of other strong risk factors, should follow general population guidelines for breast cancer screening," said Dr. Allison W. Kurian of Stanford (Calif.) University and her associates.

Some recent studies have suggested that noncarriers of a family-specific mutation may have a two- to fivefold increase in risk of developing breast cancer, compared with the general population. While lower than the 5- to 20-fold increase in risk for carriers of the mutation, this rate would still be high enough to warrant breast cancer surveillance. Other studies have found no increase in risk among noncarriers.

To clarify the issue, Dr. Kurian and her colleagues assessed breast cancer risk using population-based cancer registries in the United States, Australia, and Canada. They identified 3,047 families in which one woman (the proband) was diagnosed as having breast cancer at a relatively young age, in most cases during 1996-2000, and she and her female first-degree relatives underwent genetic testing for BRCA1 and BRCA2 mutations.

Women in all three countries showed a similar prevalence of the mutations, similar rates of breast and ovarian cancer, and similar ages of onset for the malignancies. Overall, 160 families had BRCA1 mutations and 132 had BRCA2 mutations, the investigators reported (J. Clin. Oncol. 2011 Oct. 31 [doi:10.1200.JCO.2010.34.4440]).

Among noncarriers of family-specific mutations, the risk of developing breast cancer was not significantly higher than the risk among women in families without any BRCA1 or BRCA2 mutations. This relative risk was 0.39.

It is possible that previous studies reporting an increased risk in noncarriers have overestimated this risk, because they compared study subjects with women in the general population rather than women whose relatives have breast cancer. The latter group undergoes more frequent screening and consequently has more frequent diagnoses of breast cancer than women in the general population, Dr. Kurian and her associates noted.

Their study, in which 292 families with BRCA1 or BRCA2 mutations were compared with 2,755 families without such mutations from the same populations, "represents the largest analysis to date of breast cancer risk to noncarriers of family-specific mutations," they added.

The study was supported by the National Cancer Institute, the National Institutes of Health, Cancer Care Ontario, Cancer Prevention Institute of California, and the University of Melbourne. No financial conflicts of interest were reported.

Women who don’t carry their family’s BRCA1 or BRCA2 mutation showed no increase in breast cancer risk in a study of 3,047 population-based families reported online Oct. 31 in the Journal of Clinical Oncology.

"These results support the standard clinical practice of advising noncarriers that they do not have any increase in breast cancer risk attributable to the family-specific BRCA mutation and, in the absence of other strong risk factors, should follow general population guidelines for breast cancer screening," said Dr. Allison W. Kurian of Stanford (Calif.) University and her associates.

Some recent studies have suggested that noncarriers of a family-specific mutation may have a two- to fivefold increase in risk of developing breast cancer, compared with the general population. While lower than the 5- to 20-fold increase in risk for carriers of the mutation, this rate would still be high enough to warrant breast cancer surveillance. Other studies have found no increase in risk among noncarriers.

To clarify the issue, Dr. Kurian and her colleagues assessed breast cancer risk using population-based cancer registries in the United States, Australia, and Canada. They identified 3,047 families in which one woman (the proband) was diagnosed as having breast cancer at a relatively young age, in most cases during 1996-2000, and she and her female first-degree relatives underwent genetic testing for BRCA1 and BRCA2 mutations.

Women in all three countries showed a similar prevalence of the mutations, similar rates of breast and ovarian cancer, and similar ages of onset for the malignancies. Overall, 160 families had BRCA1 mutations and 132 had BRCA2 mutations, the investigators reported (J. Clin. Oncol. 2011 Oct. 31 [doi:10.1200.JCO.2010.34.4440]).

Among noncarriers of family-specific mutations, the risk of developing breast cancer was not significantly higher than the risk among women in families without any BRCA1 or BRCA2 mutations. This relative risk was 0.39.

It is possible that previous studies reporting an increased risk in noncarriers have overestimated this risk, because they compared study subjects with women in the general population rather than women whose relatives have breast cancer. The latter group undergoes more frequent screening and consequently has more frequent diagnoses of breast cancer than women in the general population, Dr. Kurian and her associates noted.

Their study, in which 292 families with BRCA1 or BRCA2 mutations were compared with 2,755 families without such mutations from the same populations, "represents the largest analysis to date of breast cancer risk to noncarriers of family-specific mutations," they added.

The study was supported by the National Cancer Institute, the National Institutes of Health, Cancer Care Ontario, Cancer Prevention Institute of California, and the University of Melbourne. No financial conflicts of interest were reported.

Is there a future for antiangiogenic therapy with hormone therapy in hormone receptor-positive breast cancer? Dr. Hope Rugo discusses a failed sorafenib trial in the last of 3 video commentaries from the European Multidisciplinary Cancer Congress in Stockholm.

Is there a future for antiangiogenic therapy with hormone therapy in hormone receptor-positive breast cancer? Dr. Hope Rugo discusses a failed sorafenib trial in the last of 3 video commentaries from the European Multidisciplinary Cancer Congress in Stockholm.

Is there a future for antiangiogenic therapy with hormone therapy in hormone receptor-positive breast cancer? Dr. Hope Rugo discusses a failed sorafenib trial in the last of 3 video commentaries from the European Multidisciplinary Cancer Congress in Stockholm.

The probability that a breast cancer patient’s life was saved by mammography screening is always less than 25%, according to various "plausible estimates" of the risk of developing and dying from breast cancer published online Oct. 24 in the Archives of Internal Medicine.

In fact, given that the most recent data "confirm that the current benefit of screening mammography is disappointingly small," the probability that a typical woman whose breast cancer was detected by screening mammography owes her life to that procedure "is now likely to be well below 10%," said Dr. H. Gilbert Welch and Ms. Brittney A. Frankel of the Dartmouth Institute for Health Policy and Clinical Practice, Hanover, N.H.

Courtesy Rhoda Baer/National Cancer Institute (NCI)

More people are likely to personally know a cancer survivor than ever before, as the proportion of survivors in the general U.S. population has more than doubled in recent years and now stands at 4%. "Breast cancer survivors are particularly common: they now represent approximately 2.5 million, or one-fifth of the current survivor population."

And "survivor stories" feed the public’s presumption that every survivor whose cancer was detected by mammography has had her life saved by that screening. Most people don’t realize that in many cases, the cancer would have been equally treatable if it hadn’t been detected until it presented clinically. And in many other cases, the malignancy was "overdiagnosed" – it would never have caused symptoms or death if it had been left undetected and untreated.

"It is important to acknowledge that these alternatives exist," they wrote.

They calculated the probabilities that a screening mammography saved a patient’s life using the National Cancer Institute’s DevCan 6.5.0, a tool that helps compute the risks of developing and of dying from cancer at specific ages, based on detailed national epidemiologic data. "The risk of having screen-detected cancer was estimated simply as the product of the risk of developing breast cancer and the proportion of breast cancers found by mammography," they said.

"The absolute risk reduction in mortality due to mammography, or mortality benefit, was calculated as the difference between the estimated 20-year risk of death without mammography and the 20-year risk of death observed currently. The probability that a woman with screen-detected breast cancer has avoided breast cancer death because of screening was the ratio of the mortality benefit and the probability of having screen-detected breast cancer," they noted.

Their results show the estimated relative risk reduction in breast cancer mortality at ages 40, 50, 60, and 70 years, under a variety of conditions.

For example, assuming that screening mammography reduces the risk of breast cancer death by 20% for a 50-year-old woman, the probability that such a 50-year-old woman with a mammography-detected breast cancer has avoided a death from breast cancer is 13%.

The probability that a typical woman whose breast cancer was detected by screening mammography owes her life to that procedure "is now likely to be well below 10%."

If one of the underlying assumptions is changed – for example, assuming that screening mammography reduces the risk of breast cancer by 25% rather than 20% – this probability rises to 17%. If one assumes that screening mammography instead reduces the risk of breast cancer by only 5%, this probability falls to 3%.

The researchers discovered that "the most dramatic" effect of screening mammography on survival occurs in the 70-year-old age group, "because the proportion of screen-detected cancers in this age group is relatively low (52%)." Nevertheless, even in this group the probability that screening mammography saves a woman from breast cancer death remained under 25%.

"All analyses yielded probability estimates below 25%," Dr. Welch and Ms. Frankel noted (Arch. Intern. Med. 2011 Oct. 24 [doi:10.1001/archinternmed.2011.476]).

The benefit of screening mammography has declined over time, in part because women present earlier when they find a breast lump on their own and in part because treatment of such cancers has improved. "Consequently, we believe that readers should focus on the values toward the low end (5%-10%) and recognize that the probability that a woman with screen-detected breast cancer has, in fact, avoided a breast cancer death because of screening mammography is now likely to be well below 10%," they added.

It is important to use this information "to put cancer survivor stories in their proper context," the investigators said.

No financial conflicts of interest were reported.

The probability that a breast cancer patient’s life was saved by mammography screening is always less than 25%, according to various "plausible estimates" of the risk of developing and dying from breast cancer published online Oct. 24 in the Archives of Internal Medicine.

In fact, given that the most recent data "confirm that the current benefit of screening mammography is disappointingly small," the probability that a typical woman whose breast cancer was detected by screening mammography owes her life to that procedure "is now likely to be well below 10%," said Dr. H. Gilbert Welch and Ms. Brittney A. Frankel of the Dartmouth Institute for Health Policy and Clinical Practice, Hanover, N.H.

Courtesy Rhoda Baer/National Cancer Institute (NCI)

More people are likely to personally know a cancer survivor than ever before, as the proportion of survivors in the general U.S. population has more than doubled in recent years and now stands at 4%. "Breast cancer survivors are particularly common: they now represent approximately 2.5 million, or one-fifth of the current survivor population."

And "survivor stories" feed the public’s presumption that every survivor whose cancer was detected by mammography has had her life saved by that screening. Most people don’t realize that in many cases, the cancer would have been equally treatable if it hadn’t been detected until it presented clinically. And in many other cases, the malignancy was "overdiagnosed" – it would never have caused symptoms or death if it had been left undetected and untreated.

"It is important to acknowledge that these alternatives exist," they wrote.

They calculated the probabilities that a screening mammography saved a patient’s life using the National Cancer Institute’s DevCan 6.5.0, a tool that helps compute the risks of developing and of dying from cancer at specific ages, based on detailed national epidemiologic data. "The risk of having screen-detected cancer was estimated simply as the product of the risk of developing breast cancer and the proportion of breast cancers found by mammography," they said.

"The absolute risk reduction in mortality due to mammography, or mortality benefit, was calculated as the difference between the estimated 20-year risk of death without mammography and the 20-year risk of death observed currently. The probability that a woman with screen-detected breast cancer has avoided breast cancer death because of screening was the ratio of the mortality benefit and the probability of having screen-detected breast cancer," they noted.

Their results show the estimated relative risk reduction in breast cancer mortality at ages 40, 50, 60, and 70 years, under a variety of conditions.

For example, assuming that screening mammography reduces the risk of breast cancer death by 20% for a 50-year-old woman, the probability that such a 50-year-old woman with a mammography-detected breast cancer has avoided a death from breast cancer is 13%.

The probability that a typical woman whose breast cancer was detected by screening mammography owes her life to that procedure "is now likely to be well below 10%."

If one of the underlying assumptions is changed – for example, assuming that screening mammography reduces the risk of breast cancer by 25% rather than 20% – this probability rises to 17%. If one assumes that screening mammography instead reduces the risk of breast cancer by only 5%, this probability falls to 3%.

The researchers discovered that "the most dramatic" effect of screening mammography on survival occurs in the 70-year-old age group, "because the proportion of screen-detected cancers in this age group is relatively low (52%)." Nevertheless, even in this group the probability that screening mammography saves a woman from breast cancer death remained under 25%.

"All analyses yielded probability estimates below 25%," Dr. Welch and Ms. Frankel noted (Arch. Intern. Med. 2011 Oct. 24 [doi:10.1001/archinternmed.2011.476]).

The benefit of screening mammography has declined over time, in part because women present earlier when they find a breast lump on their own and in part because treatment of such cancers has improved. "Consequently, we believe that readers should focus on the values toward the low end (5%-10%) and recognize that the probability that a woman with screen-detected breast cancer has, in fact, avoided a breast cancer death because of screening mammography is now likely to be well below 10%," they added.

It is important to use this information "to put cancer survivor stories in their proper context," the investigators said.

No financial conflicts of interest were reported.

The probability that a breast cancer patient’s life was saved by mammography screening is always less than 25%, according to various "plausible estimates" of the risk of developing and dying from breast cancer published online Oct. 24 in the Archives of Internal Medicine.

In fact, given that the most recent data "confirm that the current benefit of screening mammography is disappointingly small," the probability that a typical woman whose breast cancer was detected by screening mammography owes her life to that procedure "is now likely to be well below 10%," said Dr. H. Gilbert Welch and Ms. Brittney A. Frankel of the Dartmouth Institute for Health Policy and Clinical Practice, Hanover, N.H.

Courtesy Rhoda Baer/National Cancer Institute (NCI)

More people are likely to personally know a cancer survivor than ever before, as the proportion of survivors in the general U.S. population has more than doubled in recent years and now stands at 4%. "Breast cancer survivors are particularly common: they now represent approximately 2.5 million, or one-fifth of the current survivor population."

And "survivor stories" feed the public’s presumption that every survivor whose cancer was detected by mammography has had her life saved by that screening. Most people don’t realize that in many cases, the cancer would have been equally treatable if it hadn’t been detected until it presented clinically. And in many other cases, the malignancy was "overdiagnosed" – it would never have caused symptoms or death if it had been left undetected and untreated.

"It is important to acknowledge that these alternatives exist," they wrote.

They calculated the probabilities that a screening mammography saved a patient’s life using the National Cancer Institute’s DevCan 6.5.0, a tool that helps compute the risks of developing and of dying from cancer at specific ages, based on detailed national epidemiologic data. "The risk of having screen-detected cancer was estimated simply as the product of the risk of developing breast cancer and the proportion of breast cancers found by mammography," they said.

"The absolute risk reduction in mortality due to mammography, or mortality benefit, was calculated as the difference between the estimated 20-year risk of death without mammography and the 20-year risk of death observed currently. The probability that a woman with screen-detected breast cancer has avoided breast cancer death because of screening was the ratio of the mortality benefit and the probability of having screen-detected breast cancer," they noted.

Their results show the estimated relative risk reduction in breast cancer mortality at ages 40, 50, 60, and 70 years, under a variety of conditions.

For example, assuming that screening mammography reduces the risk of breast cancer death by 20% for a 50-year-old woman, the probability that such a 50-year-old woman with a mammography-detected breast cancer has avoided a death from breast cancer is 13%.

The probability that a typical woman whose breast cancer was detected by screening mammography owes her life to that procedure "is now likely to be well below 10%."

If one of the underlying assumptions is changed – for example, assuming that screening mammography reduces the risk of breast cancer by 25% rather than 20% – this probability rises to 17%. If one assumes that screening mammography instead reduces the risk of breast cancer by only 5%, this probability falls to 3%.

The researchers discovered that "the most dramatic" effect of screening mammography on survival occurs in the 70-year-old age group, "because the proportion of screen-detected cancers in this age group is relatively low (52%)." Nevertheless, even in this group the probability that screening mammography saves a woman from breast cancer death remained under 25%.

"All analyses yielded probability estimates below 25%," Dr. Welch and Ms. Frankel noted (Arch. Intern. Med. 2011 Oct. 24 [doi:10.1001/archinternmed.2011.476]).

The benefit of screening mammography has declined over time, in part because women present earlier when they find a breast lump on their own and in part because treatment of such cancers has improved. "Consequently, we believe that readers should focus on the values toward the low end (5%-10%) and recognize that the probability that a woman with screen-detected breast cancer has, in fact, avoided a breast cancer death because of screening mammography is now likely to be well below 10%," they added.

It is important to use this information "to put cancer survivor stories in their proper context," the investigators said.

No financial conflicts of interest were reported.

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.