Breast Cancer

Bevacizumab improves survival in HER2-positive metastatic disease

Bevacizumab (Avastin) improved progression-free survival (PFS) when added to standard treatment in a study of more than 400 women with human epidermal growth factor receptor 2 (HER2)–positive locally recurrent or metastatic breast cancer.

That finding, which emerged from the AVEREL trial, adds another wrinkle in the ongoing controversy regarding use of bevacizumab in breast cancer treatment.

For the primary endpoint of investigator- assessed PFS, conducted at a median follow-up of 26 months, the addition of bevacizumab resulted in a hazard ratio (HR) of 0.82 (P = 0.0775), compared with treatment with trastuzumab (Herceptin) and docetaxel alone. This difference was not statistically significant. Median investigator-assessed PFS was 16.5 months with bevacizumab versus 13.7 months without it.

In an assessment by an independent review committee (IRC), however, a significant improvement in PFS was seen with the addition of bevacizumab (hazard ratio, 0.72; P = 0.0162). Median IRC-assessed PFS was 16.8 months with bevacizumab, compared with 13.9 months without the drug.

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

Bevacizumab improves survival in HER2-positive metastatic disease

Bevacizumab (Avastin) improved progression-free survival (PFS) when added to standard treatment in a study of more than 400 women with human epidermal growth factor receptor 2 (HER2)–positive locally recurrent or metastatic breast cancer.

That finding, which emerged from the AVEREL trial, adds another wrinkle in the ongoing controversy regarding use of bevacizumab in breast cancer treatment.

For the primary endpoint of investigator- assessed PFS, conducted at a median follow-up of 26 months, the addition of bevacizumab resulted in a hazard ratio (HR) of 0.82 (P = 0.0775), compared with treatment with trastuzumab (Herceptin) and docetaxel alone. This difference was not statistically significant. Median investigator-assessed PFS was 16.5 months with bevacizumab versus 13.7 months without it.

In an assessment by an independent review committee (IRC), however, a significant improvement in PFS was seen with the addition of bevacizumab (hazard ratio, 0.72; P = 0.0162). Median IRC-assessed PFS was 16.8 months with bevacizumab, compared with 13.9 months without the drug.

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

Bevacizumab improves survival in HER2-positive metastatic disease

Bevacizumab (Avastin) improved progression-free survival (PFS) when added to standard treatment in a study of more than 400 women with human epidermal growth factor receptor 2 (HER2)–positive locally recurrent or metastatic breast cancer.

That finding, which emerged from the AVEREL trial, adds another wrinkle in the ongoing controversy regarding use of bevacizumab in breast cancer treatment.

For the primary endpoint of investigator- assessed PFS, conducted at a median follow-up of 26 months, the addition of bevacizumab resulted in a hazard ratio (HR) of 0.82 (P = 0.0775), compared with treatment with trastuzumab (Herceptin) and docetaxel alone. This difference was not statistically significant. Median investigator-assessed PFS was 16.5 months with bevacizumab versus 13.7 months without it.

In an assessment by an independent review committee (IRC), however, a significant improvement in PFS was seen with the addition of bevacizumab (hazard ratio, 0.72; P = 0.0162). Median IRC-assessed PFS was 16.8 months with bevacizumab, compared with 13.9 months without the drug.

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

Whole-breast irradiation (WBI) plus regional nodal irradiation (RNI) significantly improved disease-free survival, but not overall survival, in a randomized, multicenter phase III trial of women with node-positive or high-risk node-negative disease who were treated with breast-conserving surgery and adjuvant therapy. An interim analysis of 1,832 women with breast cancer found that after a median follow-up of 62 months (between March 2000 and March 2007), WBI plus RNI significantly reduced the risk of locoregional recurrence from 5.5% to 3.2% (hazard ratio [HR], 0.58; P = 0.02) and distant recurrence from 13.0% to 7.6% (HR, 0.64; P = 0.002), according to the lead investigator, Dr. Timothy Whelan, head of radiation oncology at McMaster University and the Juravinski Cancer Centre, Hamilton, Ontario, Canada.

As a result, disease-free survival rate improved from 84.0% for WBI to 89.7% for WBI plus RNI (HR, 0.67; P = 0.003). Overall survival in the intergroup trial was 90.7% with WBI, compared with 92.3% with the combined radiation regimen, but the difference did not reach statistical significance (HR, 0.76; P = 0.07). In view of the positive findings from the National Cancer Institute of Canada Clinical Trials Group MA.20 study, the data safety monitoring committee recommended that the results be released. The data were presented by Dr. Whelan at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO).¹

Report prepared by Matt Stenger, MS

* For a PDF of the complete article, click on the link to the left of this introduction.

Whole-breast irradiation (WBI) plus regional nodal irradiation (RNI) significantly improved disease-free survival, but not overall survival, in a randomized, multicenter phase III trial of women with node-positive or high-risk node-negative disease who were treated with breast-conserving surgery and adjuvant therapy. An interim analysis of 1,832 women with breast cancer found that after a median follow-up of 62 months (between March 2000 and March 2007), WBI plus RNI significantly reduced the risk of locoregional recurrence from 5.5% to 3.2% (hazard ratio [HR], 0.58; P = 0.02) and distant recurrence from 13.0% to 7.6% (HR, 0.64; P = 0.002), according to the lead investigator, Dr. Timothy Whelan, head of radiation oncology at McMaster University and the Juravinski Cancer Centre, Hamilton, Ontario, Canada.

As a result, disease-free survival rate improved from 84.0% for WBI to 89.7% for WBI plus RNI (HR, 0.67; P = 0.003). Overall survival in the intergroup trial was 90.7% with WBI, compared with 92.3% with the combined radiation regimen, but the difference did not reach statistical significance (HR, 0.76; P = 0.07). In view of the positive findings from the National Cancer Institute of Canada Clinical Trials Group MA.20 study, the data safety monitoring committee recommended that the results be released. The data were presented by Dr. Whelan at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO).¹

Report prepared by Matt Stenger, MS

* For a PDF of the complete article, click on the link to the left of this introduction.

Whole-breast irradiation (WBI) plus regional nodal irradiation (RNI) significantly improved disease-free survival, but not overall survival, in a randomized, multicenter phase III trial of women with node-positive or high-risk node-negative disease who were treated with breast-conserving surgery and adjuvant therapy. An interim analysis of 1,832 women with breast cancer found that after a median follow-up of 62 months (between March 2000 and March 2007), WBI plus RNI significantly reduced the risk of locoregional recurrence from 5.5% to 3.2% (hazard ratio [HR], 0.58; P = 0.02) and distant recurrence from 13.0% to 7.6% (HR, 0.64; P = 0.002), according to the lead investigator, Dr. Timothy Whelan, head of radiation oncology at McMaster University and the Juravinski Cancer Centre, Hamilton, Ontario, Canada.

As a result, disease-free survival rate improved from 84.0% for WBI to 89.7% for WBI plus RNI (HR, 0.67; P = 0.003). Overall survival in the intergroup trial was 90.7% with WBI, compared with 92.3% with the combined radiation regimen, but the difference did not reach statistical significance (HR, 0.76; P = 0.07). In view of the positive findings from the National Cancer Institute of Canada Clinical Trials Group MA.20 study, the data safety monitoring committee recommended that the results be released. The data were presented by Dr. Whelan at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO).¹

Report prepared by Matt Stenger, MS

* For a PDF of the complete article, click on the link to the left of this introduction.

Dr. David Henry is your audio tour guide to the November 2011 issue of Community Oncology. Issue highlights include Community Translations, which addresses the role of everolimus in treating hormone-resistant ER-positive breast cancer; a review of guidelines for screening cancer patients for distress by Amy E. Lowery and Jimmie C. Holland; and original research on the impact of bone metastases and skeletal-related events on healthcare costs in prostate cancer patients on hormonal therapy by May Hagiwara, et.al. Also, reports from recent oncology meetings and regulatory news from Congress and the FDA.

Dr. David Henry is your audio tour guide to the November 2011 issue of Community Oncology. Issue highlights include Community Translations, which addresses the role of everolimus in treating hormone-resistant ER-positive breast cancer; a review of guidelines for screening cancer patients for distress by Amy E. Lowery and Jimmie C. Holland; and original research on the impact of bone metastases and skeletal-related events on healthcare costs in prostate cancer patients on hormonal therapy by May Hagiwara, et.al. Also, reports from recent oncology meetings and regulatory news from Congress and the FDA.

Dr. David Henry is your audio tour guide to the November 2011 issue of Community Oncology. Issue highlights include Community Translations, which addresses the role of everolimus in treating hormone-resistant ER-positive breast cancer; a review of guidelines for screening cancer patients for distress by Amy E. Lowery and Jimmie C. Holland; and original research on the impact of bone metastases and skeletal-related events on healthcare costs in prostate cancer patients on hormonal therapy by May Hagiwara, et.al. Also, reports from recent oncology meetings and regulatory news from Congress and the FDA.

CHICAGO – Women aged 40-49 years with and without a family history of breast cancer had virtually the same rates of invasive disease in a retrospective analysis of data on more than 1,000 patients diagnosed over a 10-year period at a single site.

The finding adds weight to the American Cancer Society’s recommendation in favor of annual screening mammograms for women beginning at age 40, said principal author Dr. Stamatia V. Destounis of Elizabeth Wende Breast Care LLC in Rochester, N.Y. Dr. Destounis presented the results of her study in a press briefing at the annual meeting of the Radiological Society of North America.

A study presented at last year’s meeting by researchers at the London Breast Institute of the Princess Grace Hospital indicated that annual mammograms could reduce by half the risk of mastectomy in women who were diagnosed with breast cancer between the ages of 40 and 50 years.

Both studies challenge the recommendation against routine annual mammography for women under the age of 50 made in 2009 by the United States Preventive Services Task Force.

"These conflicting recommendations have led to confusion among patients and physicians," Dr. Destounis said.

In the present study, Dr. Destounis and her colleagues analyzed data on women between the ages of 40 and 49 years who underwent screening mammography at the center between 2000 and 2010.

In all, 1,116 cancers were found in 1,071 patients aged 40-49 years. Of these patients, 373 were diagnosed by screening mammography. Of these 373 women, 144 (39%) had a family history of breast cancer, 228 (61%) did not, and 1 patient did not know her family history. (A total of 7 patients with and 16 patients without a family history of breast cancer also had a personal history of breast cancer.)

Among women with a family history, 32% (46) had a first-degree relative with a premenopausal history, 38% (54) had a first-degree relative with a postmenopausal history, and 31% (44) had a second- or third-degree relative with a pre- or postmenopausal history of the disease.

The incidence of invasive breast cancer was virtually the same – 63% (91) and 64% (146), respectively – in women with and without a family history. The incidence of noninvasive disease in the two groups was also similar, at 37% and 36%, respectively. Those with and without a family history shared similar rates of lymph node metastatic disease (31% and 29%) as well.

"Family history does not seem to [affect] the rate of invasive disease in our patient cohort," Dr. Destounis said.

The following types of lesions were found in women with and without a family history, respectively: mass (42, 86), microcalcification (69, 97), mass with calcification (21, 18), architectural distortion (11, 18), and asymmetry (1, 9).

All 144 patients with a family history and 227 of 228 patients in the no family history group proceeded to surgery. One patient had metastatic disease and opted for no surgery or treatment.

Among women with and without a family history, 63% and 68%, respectively, underwent a lumpectomy. Some of these patients did not have clear margins after surgery and went on to mastectomy. In all, 38% (54) of women with a family history and 31% (71) women without a family history went on to mastectomy.

Since no difference in the rate of invasive breast cancer between women with and without a family history was found in this population, "the recommendation should be that women in their 40s have a screening mammogram yearly," she said.

Dr. Destounis and her colleagues are currently collecting additional data on breast density, demographics, and survival rates for this patient group.

Dr. Destounis disclosed that she has been an investigator for Siemens AG, Fujifilm Holdings, Hologic Inc., and Koning Corp. She has also served as an advisory board member for Philips Electronics and Matakina International Ltd.

CHICAGO – Women aged 40-49 years with and without a family history of breast cancer had virtually the same rates of invasive disease in a retrospective analysis of data on more than 1,000 patients diagnosed over a 10-year period at a single site.

The finding adds weight to the American Cancer Society’s recommendation in favor of annual screening mammograms for women beginning at age 40, said principal author Dr. Stamatia V. Destounis of Elizabeth Wende Breast Care LLC in Rochester, N.Y. Dr. Destounis presented the results of her study in a press briefing at the annual meeting of the Radiological Society of North America.

A study presented at last year’s meeting by researchers at the London Breast Institute of the Princess Grace Hospital indicated that annual mammograms could reduce by half the risk of mastectomy in women who were diagnosed with breast cancer between the ages of 40 and 50 years.

Both studies challenge the recommendation against routine annual mammography for women under the age of 50 made in 2009 by the United States Preventive Services Task Force.

"These conflicting recommendations have led to confusion among patients and physicians," Dr. Destounis said.

In the present study, Dr. Destounis and her colleagues analyzed data on women between the ages of 40 and 49 years who underwent screening mammography at the center between 2000 and 2010.

In all, 1,116 cancers were found in 1,071 patients aged 40-49 years. Of these patients, 373 were diagnosed by screening mammography. Of these 373 women, 144 (39%) had a family history of breast cancer, 228 (61%) did not, and 1 patient did not know her family history. (A total of 7 patients with and 16 patients without a family history of breast cancer also had a personal history of breast cancer.)

Among women with a family history, 32% (46) had a first-degree relative with a premenopausal history, 38% (54) had a first-degree relative with a postmenopausal history, and 31% (44) had a second- or third-degree relative with a pre- or postmenopausal history of the disease.

The incidence of invasive breast cancer was virtually the same – 63% (91) and 64% (146), respectively – in women with and without a family history. The incidence of noninvasive disease in the two groups was also similar, at 37% and 36%, respectively. Those with and without a family history shared similar rates of lymph node metastatic disease (31% and 29%) as well.

"Family history does not seem to [affect] the rate of invasive disease in our patient cohort," Dr. Destounis said.

The following types of lesions were found in women with and without a family history, respectively: mass (42, 86), microcalcification (69, 97), mass with calcification (21, 18), architectural distortion (11, 18), and asymmetry (1, 9).

All 144 patients with a family history and 227 of 228 patients in the no family history group proceeded to surgery. One patient had metastatic disease and opted for no surgery or treatment.

Among women with and without a family history, 63% and 68%, respectively, underwent a lumpectomy. Some of these patients did not have clear margins after surgery and went on to mastectomy. In all, 38% (54) of women with a family history and 31% (71) women without a family history went on to mastectomy.

Since no difference in the rate of invasive breast cancer between women with and without a family history was found in this population, "the recommendation should be that women in their 40s have a screening mammogram yearly," she said.

Dr. Destounis and her colleagues are currently collecting additional data on breast density, demographics, and survival rates for this patient group.

Dr. Destounis disclosed that she has been an investigator for Siemens AG, Fujifilm Holdings, Hologic Inc., and Koning Corp. She has also served as an advisory board member for Philips Electronics and Matakina International Ltd.

CHICAGO – Women aged 40-49 years with and without a family history of breast cancer had virtually the same rates of invasive disease in a retrospective analysis of data on more than 1,000 patients diagnosed over a 10-year period at a single site.

The finding adds weight to the American Cancer Society’s recommendation in favor of annual screening mammograms for women beginning at age 40, said principal author Dr. Stamatia V. Destounis of Elizabeth Wende Breast Care LLC in Rochester, N.Y. Dr. Destounis presented the results of her study in a press briefing at the annual meeting of the Radiological Society of North America.

A study presented at last year’s meeting by researchers at the London Breast Institute of the Princess Grace Hospital indicated that annual mammograms could reduce by half the risk of mastectomy in women who were diagnosed with breast cancer between the ages of 40 and 50 years.

Both studies challenge the recommendation against routine annual mammography for women under the age of 50 made in 2009 by the United States Preventive Services Task Force.

"These conflicting recommendations have led to confusion among patients and physicians," Dr. Destounis said.

In the present study, Dr. Destounis and her colleagues analyzed data on women between the ages of 40 and 49 years who underwent screening mammography at the center between 2000 and 2010.

In all, 1,116 cancers were found in 1,071 patients aged 40-49 years. Of these patients, 373 were diagnosed by screening mammography. Of these 373 women, 144 (39%) had a family history of breast cancer, 228 (61%) did not, and 1 patient did not know her family history. (A total of 7 patients with and 16 patients without a family history of breast cancer also had a personal history of breast cancer.)

Among women with a family history, 32% (46) had a first-degree relative with a premenopausal history, 38% (54) had a first-degree relative with a postmenopausal history, and 31% (44) had a second- or third-degree relative with a pre- or postmenopausal history of the disease.

The incidence of invasive breast cancer was virtually the same – 63% (91) and 64% (146), respectively – in women with and without a family history. The incidence of noninvasive disease in the two groups was also similar, at 37% and 36%, respectively. Those with and without a family history shared similar rates of lymph node metastatic disease (31% and 29%) as well.

"Family history does not seem to [affect] the rate of invasive disease in our patient cohort," Dr. Destounis said.

The following types of lesions were found in women with and without a family history, respectively: mass (42, 86), microcalcification (69, 97), mass with calcification (21, 18), architectural distortion (11, 18), and asymmetry (1, 9).

All 144 patients with a family history and 227 of 228 patients in the no family history group proceeded to surgery. One patient had metastatic disease and opted for no surgery or treatment.

Among women with and without a family history, 63% and 68%, respectively, underwent a lumpectomy. Some of these patients did not have clear margins after surgery and went on to mastectomy. In all, 38% (54) of women with a family history and 31% (71) women without a family history went on to mastectomy.

Since no difference in the rate of invasive breast cancer between women with and without a family history was found in this population, "the recommendation should be that women in their 40s have a screening mammogram yearly," she said.

Dr. Destounis and her colleagues are currently collecting additional data on breast density, demographics, and survival rates for this patient group.

Dr. Destounis disclosed that she has been an investigator for Siemens AG, Fujifilm Holdings, Hologic Inc., and Koning Corp. She has also served as an advisory board member for Philips Electronics and Matakina International Ltd.

The Centers for Medicare and Medicaid Services will keep the status quo for now regarding Medicare Part B coverage for Roche/Genentech’s Avastin (bevacizumab) in metastatic breast cancer despite the Food and Drug Administration’s decision to formally withdraw approval for the indication, according to a CMS spokesman.

"Medicare will continue to cover Avastin. CMS will monitor the issue and evaluate coverage options as a result of action by the FDA but has no immediate plans to change coverage policies," the spokesman said in an e-mail. The FDA announced its final conclusion Nov. 18, maintaining that the safety risks associated with Avastin are not outweighed by any benefit in metastatic breast cancer (MBC).

But it also means there is a chance that local Medicare contractors may decide to deny coverage for the patients whose claims they manage now that the indication is officially off label. Administrative claims contractors are allowed to use their discretion in coverage decisions when CMS has no formal national reimbursement policy in place.

Last January, one of the largest contractors, Palmetto GBA, moved to drop coverage for Avastin in MBC but then quickly reversed itself, stating it would await a final decision by FDA before acting. At the time, Palmetto said it would continue to review relevant clinical trials and literature on the effectiveness of the drug in breast cancer and, if it determines a coverage policy change is warranted, would initiate a formal notice-and-comment process before any final decision is made.

Medicare contractors, like other payers, typically rely on medical policy guidelines in cases where a treatment is off label. One of the more influential sets of guidelines, the National Comprehensive Cancer Network Clinical Practice Guidelines for Oncology, recently reaffirmed its support for the treatment of Avastin in MBC.

The guidelines recommend that "bevacizumab in combination with paclitaxel is an appropriate therapeutic option for metastatic breast cancer with the evidence designation 2A," which means that "based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate."

In the private sector, a small but growing number of regional plans previously announced plans to drop coverage for Avastin in MBC, including Blue Shield of California.

[Poll: Tell us what you think of the Avastin decision.]

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Centers for Medicare and Medicaid Services will keep the status quo for now regarding Medicare Part B coverage for Roche/Genentech’s Avastin (bevacizumab) in metastatic breast cancer despite the Food and Drug Administration’s decision to formally withdraw approval for the indication, according to a CMS spokesman.

"Medicare will continue to cover Avastin. CMS will monitor the issue and evaluate coverage options as a result of action by the FDA but has no immediate plans to change coverage policies," the spokesman said in an e-mail. The FDA announced its final conclusion Nov. 18, maintaining that the safety risks associated with Avastin are not outweighed by any benefit in metastatic breast cancer (MBC).

But it also means there is a chance that local Medicare contractors may decide to deny coverage for the patients whose claims they manage now that the indication is officially off label. Administrative claims contractors are allowed to use their discretion in coverage decisions when CMS has no formal national reimbursement policy in place.

Last January, one of the largest contractors, Palmetto GBA, moved to drop coverage for Avastin in MBC but then quickly reversed itself, stating it would await a final decision by FDA before acting. At the time, Palmetto said it would continue to review relevant clinical trials and literature on the effectiveness of the drug in breast cancer and, if it determines a coverage policy change is warranted, would initiate a formal notice-and-comment process before any final decision is made.

Medicare contractors, like other payers, typically rely on medical policy guidelines in cases where a treatment is off label. One of the more influential sets of guidelines, the National Comprehensive Cancer Network Clinical Practice Guidelines for Oncology, recently reaffirmed its support for the treatment of Avastin in MBC.

The guidelines recommend that "bevacizumab in combination with paclitaxel is an appropriate therapeutic option for metastatic breast cancer with the evidence designation 2A," which means that "based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate."

In the private sector, a small but growing number of regional plans previously announced plans to drop coverage for Avastin in MBC, including Blue Shield of California.

[Poll: Tell us what you think of the Avastin decision.]

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Centers for Medicare and Medicaid Services will keep the status quo for now regarding Medicare Part B coverage for Roche/Genentech’s Avastin (bevacizumab) in metastatic breast cancer despite the Food and Drug Administration’s decision to formally withdraw approval for the indication, according to a CMS spokesman.

"Medicare will continue to cover Avastin. CMS will monitor the issue and evaluate coverage options as a result of action by the FDA but has no immediate plans to change coverage policies," the spokesman said in an e-mail. The FDA announced its final conclusion Nov. 18, maintaining that the safety risks associated with Avastin are not outweighed by any benefit in metastatic breast cancer (MBC).

But it also means there is a chance that local Medicare contractors may decide to deny coverage for the patients whose claims they manage now that the indication is officially off label. Administrative claims contractors are allowed to use their discretion in coverage decisions when CMS has no formal national reimbursement policy in place.

Last January, one of the largest contractors, Palmetto GBA, moved to drop coverage for Avastin in MBC but then quickly reversed itself, stating it would await a final decision by FDA before acting. At the time, Palmetto said it would continue to review relevant clinical trials and literature on the effectiveness of the drug in breast cancer and, if it determines a coverage policy change is warranted, would initiate a formal notice-and-comment process before any final decision is made.

Medicare contractors, like other payers, typically rely on medical policy guidelines in cases where a treatment is off label. One of the more influential sets of guidelines, the National Comprehensive Cancer Network Clinical Practice Guidelines for Oncology, recently reaffirmed its support for the treatment of Avastin in MBC.

The guidelines recommend that "bevacizumab in combination with paclitaxel is an appropriate therapeutic option for metastatic breast cancer with the evidence designation 2A," which means that "based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate."

In the private sector, a small but growing number of regional plans previously announced plans to drop coverage for Avastin in MBC, including Blue Shield of California.

[Poll: Tell us what you think of the Avastin decision.]

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Tell us what you think of the Avastin decision; cast your vote in our polls and see whether your colleagues agree.

Tell us what you think of the Avastin decision; cast your vote in our polls and see whether your colleagues agree.

Tell us what you think of the Avastin decision; cast your vote in our polls and see whether your colleagues agree.

The approval of bevacizumab, the angiogenesis inhibitor marketed as Avastin, as a treatment for metastatic breast cancer is being withdrawn by the Food and Drug Administration, the agency announced Nov. 18.

In the statement announcing the decision, FDA commissioner Dr. Margaret Hamburg said she is revoking the approval, because the use of Avastin as a first-line treatment for metastatic breast cancer has not been shown to be safe and effective. Avastin is approved for several other types of cancers, so it will remain on the U.S. market.

The FDA granted an accelerated approval to bevacizumab in combination with paclitaxel as a first-line treatment for metastatic breast cancer in February 2008, based on an open-label study that found a survival advantage for the combined treatment, compared with treatment with paclitaxel alone. Studies confirming the beneficial effects are a condition of accelerated approvals. In this case, though, follow-up studies failed to confirm the benefit, and the FDA decided to withdraw its approval of the breast cancer indication

In an unusual move, the manufacturer, Genentech, requested a hearing on the decision, which was held in July 2011. At that meeting, the Oncologic Drugs Advisory Committee unanimously voted that approval for the breast cancer indication should be withdrawn because clinical trials did not show an improvement in overall survival or any clinically meaningful improvements in progression-free survival. The final decision was left to Dr. Hamburg.

"This was a difficult decision. FDA recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use," Dr. Hamburg said in the statement. "After reviewing the available studies, it is clear that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, in terms of delay in tumor growth, that would justify those risks. Nor is there evidence that use of Avastin will either help them live longer or improve their quality of life." Her decision is explained in a 69-page opinion.

A statement issued by Genentech immediately after the FDA statement was released said that the company was disappointed with the outcome, remained committed to women with the disease, and would "continue to provide help through our patient support programs to those who may be facing obstacles to receiving their treatment." Despite the FDA’s decision, the company said it planned to start a new phase III study of Avastin in combination with paclitaxel in women with previously untreated metastatic breast cancer, which would "evaluate a potential biomarker that may help identify which people might derive a more substantial benefit from Avastin."

In the FDA statement, Dr. Hamburg said that she encouraged Genentech to consider other studies "to identify if there are select subgroups of women suffering from breast cancer who might benefit from this drug."

At least for now, Medicare coverage of bevacizumab will continue for women with breast cancer. A statement issued by the Centers for Medicare & Medicaid Services said that the agency would “monitor the issue and evaluate coverage options as a result of action by the FDA but has no immediate plans to change coverage policies.”

Avastin is still approved for treating metastatic breast cancer in more than 80 countries.

This story was updated November 18, 2011.

The approval of bevacizumab, the angiogenesis inhibitor marketed as Avastin, as a treatment for metastatic breast cancer is being withdrawn by the Food and Drug Administration, the agency announced Nov. 18.

In the statement announcing the decision, FDA commissioner Dr. Margaret Hamburg said she is revoking the approval, because the use of Avastin as a first-line treatment for metastatic breast cancer has not been shown to be safe and effective. Avastin is approved for several other types of cancers, so it will remain on the U.S. market.

The FDA granted an accelerated approval to bevacizumab in combination with paclitaxel as a first-line treatment for metastatic breast cancer in February 2008, based on an open-label study that found a survival advantage for the combined treatment, compared with treatment with paclitaxel alone. Studies confirming the beneficial effects are a condition of accelerated approvals. In this case, though, follow-up studies failed to confirm the benefit, and the FDA decided to withdraw its approval of the breast cancer indication

In an unusual move, the manufacturer, Genentech, requested a hearing on the decision, which was held in July 2011. At that meeting, the Oncologic Drugs Advisory Committee unanimously voted that approval for the breast cancer indication should be withdrawn because clinical trials did not show an improvement in overall survival or any clinically meaningful improvements in progression-free survival. The final decision was left to Dr. Hamburg.

"This was a difficult decision. FDA recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use," Dr. Hamburg said in the statement. "After reviewing the available studies, it is clear that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, in terms of delay in tumor growth, that would justify those risks. Nor is there evidence that use of Avastin will either help them live longer or improve their quality of life." Her decision is explained in a 69-page opinion.

A statement issued by Genentech immediately after the FDA statement was released said that the company was disappointed with the outcome, remained committed to women with the disease, and would "continue to provide help through our patient support programs to those who may be facing obstacles to receiving their treatment." Despite the FDA’s decision, the company said it planned to start a new phase III study of Avastin in combination with paclitaxel in women with previously untreated metastatic breast cancer, which would "evaluate a potential biomarker that may help identify which people might derive a more substantial benefit from Avastin."

In the FDA statement, Dr. Hamburg said that she encouraged Genentech to consider other studies "to identify if there are select subgroups of women suffering from breast cancer who might benefit from this drug."

At least for now, Medicare coverage of bevacizumab will continue for women with breast cancer. A statement issued by the Centers for Medicare & Medicaid Services said that the agency would “monitor the issue and evaluate coverage options as a result of action by the FDA but has no immediate plans to change coverage policies.”

Avastin is still approved for treating metastatic breast cancer in more than 80 countries.

This story was updated November 18, 2011.

The approval of bevacizumab, the angiogenesis inhibitor marketed as Avastin, as a treatment for metastatic breast cancer is being withdrawn by the Food and Drug Administration, the agency announced Nov. 18.

In the statement announcing the decision, FDA commissioner Dr. Margaret Hamburg said she is revoking the approval, because the use of Avastin as a first-line treatment for metastatic breast cancer has not been shown to be safe and effective. Avastin is approved for several other types of cancers, so it will remain on the U.S. market.

The FDA granted an accelerated approval to bevacizumab in combination with paclitaxel as a first-line treatment for metastatic breast cancer in February 2008, based on an open-label study that found a survival advantage for the combined treatment, compared with treatment with paclitaxel alone. Studies confirming the beneficial effects are a condition of accelerated approvals. In this case, though, follow-up studies failed to confirm the benefit, and the FDA decided to withdraw its approval of the breast cancer indication

In an unusual move, the manufacturer, Genentech, requested a hearing on the decision, which was held in July 2011. At that meeting, the Oncologic Drugs Advisory Committee unanimously voted that approval for the breast cancer indication should be withdrawn because clinical trials did not show an improvement in overall survival or any clinically meaningful improvements in progression-free survival. The final decision was left to Dr. Hamburg.

"This was a difficult decision. FDA recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use," Dr. Hamburg said in the statement. "After reviewing the available studies, it is clear that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, in terms of delay in tumor growth, that would justify those risks. Nor is there evidence that use of Avastin will either help them live longer or improve their quality of life." Her decision is explained in a 69-page opinion.

A statement issued by Genentech immediately after the FDA statement was released said that the company was disappointed with the outcome, remained committed to women with the disease, and would "continue to provide help through our patient support programs to those who may be facing obstacles to receiving their treatment." Despite the FDA’s decision, the company said it planned to start a new phase III study of Avastin in combination with paclitaxel in women with previously untreated metastatic breast cancer, which would "evaluate a potential biomarker that may help identify which people might derive a more substantial benefit from Avastin."

In the FDA statement, Dr. Hamburg said that she encouraged Genentech to consider other studies "to identify if there are select subgroups of women suffering from breast cancer who might benefit from this drug."

At least for now, Medicare coverage of bevacizumab will continue for women with breast cancer. A statement issued by the Centers for Medicare & Medicaid Services said that the agency would “monitor the issue and evaluate coverage options as a result of action by the FDA but has no immediate plans to change coverage policies.”

Avastin is still approved for treating metastatic breast cancer in more than 80 countries.

This story was updated November 18, 2011.

PARIS – Women older than 65 years of age with early-stage breast cancer have worse long-term survival if they report poor overall health and have significant limitations in how far they can walk, according to the results of a prospective trial.

At 10 years, 80% of women with a low self-rated health status and a walking limitation had died, compared with 50% of those with a high self-rated health status and no walking limitation (P less than .0001). The probability of survival in women with low self-rated health but no walking limitation was 47%, and in those with high self-rated health and a walking limitation it was 44%.

©Els van der Gun/iStockphoto.com

"Approximately 192,000 new cases of invasive breast cancer were diagnosed in the United States in 2009," and more than half of those cases were in women older than age 60, said study investigator Dr. Jessica A. Eng of Boston University.

"There are many challenges in managing cancer in older adults," and one of the major ones is determining what the optimal treatment benefits are, compared with the risks, Dr. Eng added. Having a simple tool that could, early on, help identify those patients who are likely to do worse could be of great practical benefit, she suggested at the annual meeting of the International Society of Geriatric Oncology.

Dr. Eng and colleagues have previously shown that three or more deficits on a cancer-specific geriatric assessment are predictive of 5- and 10-year mortality in older women with breast cancer (Eur. J. Cancer 2011 July 7 [doi:10.1016/j.ejca.2011.06.016]).

In the current study, the researchers looked at whether self-rated health status and mobility could also be linked to mortality in the same population of 660 women who were aged 65 years or older and had stage I-IIIA breast cancer.

All women in the study were asked two questions at baseline: first, to rate their overall health as excellent, very good, good, or poor; and second, whether they could walk a couple of street blocks with no, a little, or a lot of limitation.

The women were followed for 10 years via annual telephone interviews, and the U.S. National Death Index was used to determine mortality rates.

At baseline, the majority of women were aged 65-79 years, with 18% aged 80 years or older. Most (94%) of the women were white, and 84% had 12 years or more of education. At least one comorbidity was present in 59% of participants, 51% had stage I breast cancer, and 76% were estrogen receptor positive.

Dr. Eng reported that 39% of women rated their health status as low, and 28% said that their ability to walk several street blocks was limited a little or a lot.

There was an absolute difference of 27% in the survival of women with a walking limitation plus high vs. low self-rated health, and a 24% absolute difference in the survival of women with low self-rated health plus no vs. some walking limitation.

Adjusted analysis showed that the risk of dying from any cause was doubled by being older than 80 years, with a hazard ratio of 2.11. The presence of at least one comorbidity also increased the risk of death significantly (HR, 1.37), compared with no comorbidity.

The hazard ratio for low self-rated health plus a walking limitation was 1.58. Separately, low self-rated health and a walking limitation did not increase the mortality risk.

"The combination of low self-rated health and limitation in walking several blocks at diagnosis is an important predictor of all-cause mortality at 10 years," concluded Dr. Eng, adding that the effect was independent of age, comorbidity, tumor characteristics, and treatment.

"Using these two easily assessed questions in clinical practice may represent an effective strategy to improve treatment decision making in older adults with cancer," Dr. Eng said.

The study was supported by the U.S. National Cancer Institute. Dr. Eng had no conflicts of interest.

PARIS – Women older than 65 years of age with early-stage breast cancer have worse long-term survival if they report poor overall health and have significant limitations in how far they can walk, according to the results of a prospective trial.

At 10 years, 80% of women with a low self-rated health status and a walking limitation had died, compared with 50% of those with a high self-rated health status and no walking limitation (P less than .0001). The probability of survival in women with low self-rated health but no walking limitation was 47%, and in those with high self-rated health and a walking limitation it was 44%.

©Els van der Gun/iStockphoto.com

"Approximately 192,000 new cases of invasive breast cancer were diagnosed in the United States in 2009," and more than half of those cases were in women older than age 60, said study investigator Dr. Jessica A. Eng of Boston University.

"There are many challenges in managing cancer in older adults," and one of the major ones is determining what the optimal treatment benefits are, compared with the risks, Dr. Eng added. Having a simple tool that could, early on, help identify those patients who are likely to do worse could be of great practical benefit, she suggested at the annual meeting of the International Society of Geriatric Oncology.

Dr. Eng and colleagues have previously shown that three or more deficits on a cancer-specific geriatric assessment are predictive of 5- and 10-year mortality in older women with breast cancer (Eur. J. Cancer 2011 July 7 [doi:10.1016/j.ejca.2011.06.016]).

In the current study, the researchers looked at whether self-rated health status and mobility could also be linked to mortality in the same population of 660 women who were aged 65 years or older and had stage I-IIIA breast cancer.

All women in the study were asked two questions at baseline: first, to rate their overall health as excellent, very good, good, or poor; and second, whether they could walk a couple of street blocks with no, a little, or a lot of limitation.

The women were followed for 10 years via annual telephone interviews, and the U.S. National Death Index was used to determine mortality rates.

At baseline, the majority of women were aged 65-79 years, with 18% aged 80 years or older. Most (94%) of the women were white, and 84% had 12 years or more of education. At least one comorbidity was present in 59% of participants, 51% had stage I breast cancer, and 76% were estrogen receptor positive.

Dr. Eng reported that 39% of women rated their health status as low, and 28% said that their ability to walk several street blocks was limited a little or a lot.

There was an absolute difference of 27% in the survival of women with a walking limitation plus high vs. low self-rated health, and a 24% absolute difference in the survival of women with low self-rated health plus no vs. some walking limitation.

Adjusted analysis showed that the risk of dying from any cause was doubled by being older than 80 years, with a hazard ratio of 2.11. The presence of at least one comorbidity also increased the risk of death significantly (HR, 1.37), compared with no comorbidity.

The hazard ratio for low self-rated health plus a walking limitation was 1.58. Separately, low self-rated health and a walking limitation did not increase the mortality risk.

"The combination of low self-rated health and limitation in walking several blocks at diagnosis is an important predictor of all-cause mortality at 10 years," concluded Dr. Eng, adding that the effect was independent of age, comorbidity, tumor characteristics, and treatment.

"Using these two easily assessed questions in clinical practice may represent an effective strategy to improve treatment decision making in older adults with cancer," Dr. Eng said.

The study was supported by the U.S. National Cancer Institute. Dr. Eng had no conflicts of interest.

PARIS – Women older than 65 years of age with early-stage breast cancer have worse long-term survival if they report poor overall health and have significant limitations in how far they can walk, according to the results of a prospective trial.

At 10 years, 80% of women with a low self-rated health status and a walking limitation had died, compared with 50% of those with a high self-rated health status and no walking limitation (P less than .0001). The probability of survival in women with low self-rated health but no walking limitation was 47%, and in those with high self-rated health and a walking limitation it was 44%.

©Els van der Gun/iStockphoto.com

"Approximately 192,000 new cases of invasive breast cancer were diagnosed in the United States in 2009," and more than half of those cases were in women older than age 60, said study investigator Dr. Jessica A. Eng of Boston University.

"There are many challenges in managing cancer in older adults," and one of the major ones is determining what the optimal treatment benefits are, compared with the risks, Dr. Eng added. Having a simple tool that could, early on, help identify those patients who are likely to do worse could be of great practical benefit, she suggested at the annual meeting of the International Society of Geriatric Oncology.

Dr. Eng and colleagues have previously shown that three or more deficits on a cancer-specific geriatric assessment are predictive of 5- and 10-year mortality in older women with breast cancer (Eur. J. Cancer 2011 July 7 [doi:10.1016/j.ejca.2011.06.016]).

In the current study, the researchers looked at whether self-rated health status and mobility could also be linked to mortality in the same population of 660 women who were aged 65 years or older and had stage I-IIIA breast cancer.

All women in the study were asked two questions at baseline: first, to rate their overall health as excellent, very good, good, or poor; and second, whether they could walk a couple of street blocks with no, a little, or a lot of limitation.

The women were followed for 10 years via annual telephone interviews, and the U.S. National Death Index was used to determine mortality rates.

At baseline, the majority of women were aged 65-79 years, with 18% aged 80 years or older. Most (94%) of the women were white, and 84% had 12 years or more of education. At least one comorbidity was present in 59% of participants, 51% had stage I breast cancer, and 76% were estrogen receptor positive.

Dr. Eng reported that 39% of women rated their health status as low, and 28% said that their ability to walk several street blocks was limited a little or a lot.

There was an absolute difference of 27% in the survival of women with a walking limitation plus high vs. low self-rated health, and a 24% absolute difference in the survival of women with low self-rated health plus no vs. some walking limitation.

Adjusted analysis showed that the risk of dying from any cause was doubled by being older than 80 years, with a hazard ratio of 2.11. The presence of at least one comorbidity also increased the risk of death significantly (HR, 1.37), compared with no comorbidity.

The hazard ratio for low self-rated health plus a walking limitation was 1.58. Separately, low self-rated health and a walking limitation did not increase the mortality risk.

"The combination of low self-rated health and limitation in walking several blocks at diagnosis is an important predictor of all-cause mortality at 10 years," concluded Dr. Eng, adding that the effect was independent of age, comorbidity, tumor characteristics, and treatment.

"Using these two easily assessed questions in clinical practice may represent an effective strategy to improve treatment decision making in older adults with cancer," Dr. Eng said.

The study was supported by the U.S. National Cancer Institute. Dr. Eng had no conflicts of interest.

Treatment of triple-negative breast cancer, so named because it lacks estrogen receptors, progesterone receptors, and HER2 overexpression, is one of the most challenging areas of breast oncology. Not only do patients with this aggressive cancer have some of the shortest absolute survival times, but they also are the only group for whom we still have no targeted therap

It is becoming increasingly clear that effectively treating triple-negative disease will require recognition of its diversity. Viewing it as a single entity is inherently flawed, an oversimplified way of referring to a disease that’s incredibly heterogeneous and complicated. And that’s probably been our biggest challenge in the design of clinical trials for this cancer.

Gene expression profiling is helping to tease apart molecular subtypes of triple-negative breast cancers (Mol. Oncol. 2011;5:5-23). These subtypes often have distinctly different behavior and treatment responses.

We are also learning more about the overlap between triple negativity and mutation of the BRCA1 tumor suppressor gene. About 90% of BRCA1-mutated breast cancers have a triple-negative phenotype. But interestingly, most triple-negative tumors have normal BRCA1 function. Recent data suggest that a subset of these tumors may have posttranslational modifications that affect BRCA1 function, so if you look for the DNA mutation, you won’t find it. Sporadic basal-like tumors and hereditary BRCA1 tumors have a similar phenotype, so a defect in BRCA1 may have a role in these sporadic basal-like tumors.

Recent clinical trials are adding to our arsenal several new drugs – and a few old ones – from different classes that target vulnerabilities of triple-negative breast cancer and offer promise for improving outcomes in this hard-to-treat disease.

Cytotoxic Chemotherapeutic Agents

We know that triple-negative tumors are sensitive to cytotoxic chemotherapy, especially in the neoadjuvant and adjuvant settings.

Recognition that there is a defect in DNA repair in BRCA1 tumors and at least some triple-negative tumors has generated interest in the use of DNA-damaging agents such as platinums. The pathologic complete response rate to neoadjuvant cisplatin has been around 75% in BRCA1 tumors, but just 15% to 16% in sporadic triple-negative tumors, suggesting selective sensitivity to platinum-based agents in the former. An ongoing randomized phase II neoadjuvant trial is looking at this issue more closely, using carboplatin and bevacizumab (NCT00861705), and we hope that the results of this study will help us to better understand the responsiveness to platinums in sporadic triple-negative breast cancer.

Ixabepilone (Ixempra), an approved agent for the treatment of metastatic and locally advanced breast cancer, also appears promising. A pooled analysis of data from women with pretreated advanced triple-negative disease treated in a pair of phase III trials testing addition of ixabepilone to capecitabine showed a doubling of response rate and progression-free survival (San Antonio Breast Cancer Symposium 2008. Abstract 3057). But the combination also had substantial toxicity, so there is now more interest in using ixabepilone alone and farther out, in patients having multidrug-resistant disease.

EGFR Inhibitors

The epidermal growth factor receptor (EGFR) is upregulated in many triple-negative breast cancers, making this an attractive treatment target. Unfortunately, trials combining cetuximab (Erbitux) with carboplatin or with carboplatin-irinotecan have found small or no improvement in outcomes, along with added toxicity.

But the BALI-1 trial in patients with triple-negative metastatic breast cancer found a doubling of the overall response rate and progression-free survival with addition of cetuximab to cisplatin (SABCS 2010 meeting, Abstract PD01-01), although this trial did not meet its primary end point). We are waiting anxiously to see data from correlative markers obtained from these patients’ primary and metastatic tumors.

The bottom line here is that patient selection will be critical if we are going to pursue EGFR blockade in triple-negative disease.

PARP Inhibitors

There has been tremendous interest in using inhibitors of poly(ADP-ribose polymerase) or PARP, which interfere with the repair of DNA damage, in triple-negative disease. Trials to date have had mixed results and provided some valuable lessons.

A randomized phase II trial among patients with triple-negative metastatic breast cancer found that adding iniparib, an investigational PARP inhibitor, to gemcitabine-carboplatin dramatically improved progression-free and overall survival (N. Engl. J. Med. 2011;364:205-14). But the subsequent, far larger randomized phase III trial using the same regimens did not meet either of these end points (ASCO 2011 meeting. Abstract 1007).

This was very surprising and made us realize that patient selection of disease may have a significant impact on evaluation of outcome parameters. Triple-negative breast cancer is a heterogeneous disease, and we didn’t understand it well enough. In addition, we did not have enough data to understand the clinical activity of backbone in triple-negative breast cancer; in fact, patients treated with gemcitabine-carboplatin alone had a better response and PFS than expected.

Another issue was that, at least to date, tumor molecular profiles differed between the two trials. For example, only 25% of patients in the phase III trial had basal-like disease, compared with more than 40% in the phase II trial. Both trials had some patients with luminal A type, which usually corresponds to estrogen receptor–positive disease. This suggests that triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition and that we need trials with tissue analysis.

Finally, it turns out we weren’t really giving a PARP inhibitor in these trials. Iniparib at the doses that were delivered does not inhibit PARP. Efforts are now underway to study escalation. And the actual mechanism of action of this drug remains to be determined.

Antiangiogenic Agents

Agents that interfere with angiogenesis, such as bevacizumab (Avastin), are of interest in triple-negative breast cancer to target the hypoxia signature that is characteristic of this and other rapidly proliferating tumors.

We know that bevacizumab adds to clinical efficacy of chemotherapy in breast cancer. But it’s been hard to show specific subsets that benefit, and that’s our current quandary. A meta-analysis of the first-line trials in triple-negative disease suggested patients with triple-negative disease had similar improvements in outcomes from the addition of bevacizumab as did other subsets of patients (SABCS 2010 meeting. Abstract P6-12-03).

In the second-line RIBBON 2 trial, adding bevacizumab to chemotherapy appeared to have greater benefit in the triple-negative subset of patients compared with the whole group, but numbers were too small to draw definitive conclusions (ASCO 2011 Breast Cancer Symposium. Abstract 290).

Other Targeted Agents

A variety of other targeted agents are being evaluated for activity in triple-negative breast cancer. Tigatuzumab, an antibody to TRAIL receptor 2, one of the so-called death receptors, had impressive results in preclinical testing. It is now being evaluated in a randomized phase II trial in which patients with metastatic triple-negative breast cancer are treated with nanoparticle albumin–bound (nab)-paclitaxel (Abraxane) with or without tigatuzumab (NCT01307891).

An interesting finding has been that approximately 5% of patients with triple-negative disease have upregulation of the androgen receptor. Thus, another phase II trial is testing bicalutamide (Casodex) in patients whose tumors have these receptors but neither estrogen nor progesterone receptors (NCT00468715). This is a fascinating approach and could be of great benefit for this small subset of patients, as some patients have had stable disease for a year on bicalutamide therapy, which has minimal toxicity.

Treatment of triple-negative breast cancer, so named because it lacks estrogen receptors, progesterone receptors, and HER2 overexpression, is one of the most challenging areas of breast oncology. Not only do patients with this aggressive cancer have some of the shortest absolute survival times, but they also are the only group for whom we still have no targeted therap

It is becoming increasingly clear that effectively treating triple-negative disease will require recognition of its diversity. Viewing it as a single entity is inherently flawed, an oversimplified way of referring to a disease that’s incredibly heterogeneous and complicated. And that’s probably been our biggest challenge in the design of clinical trials for this cancer.

Gene expression profiling is helping to tease apart molecular subtypes of triple-negative breast cancers (Mol. Oncol. 2011;5:5-23). These subtypes often have distinctly different behavior and treatment responses.

We are also learning more about the overlap between triple negativity and mutation of the BRCA1 tumor suppressor gene. About 90% of BRCA1-mutated breast cancers have a triple-negative phenotype. But interestingly, most triple-negative tumors have normal BRCA1 function. Recent data suggest that a subset of these tumors may have posttranslational modifications that affect BRCA1 function, so if you look for the DNA mutation, you won’t find it. Sporadic basal-like tumors and hereditary BRCA1 tumors have a similar phenotype, so a defect in BRCA1 may have a role in these sporadic basal-like tumors.

Recent clinical trials are adding to our arsenal several new drugs – and a few old ones – from different classes that target vulnerabilities of triple-negative breast cancer and offer promise for improving outcomes in this hard-to-treat disease.

Cytotoxic Chemotherapeutic Agents

We know that triple-negative tumors are sensitive to cytotoxic chemotherapy, especially in the neoadjuvant and adjuvant settings.

Recognition that there is a defect in DNA repair in BRCA1 tumors and at least some triple-negative tumors has generated interest in the use of DNA-damaging agents such as platinums. The pathologic complete response rate to neoadjuvant cisplatin has been around 75% in BRCA1 tumors, but just 15% to 16% in sporadic triple-negative tumors, suggesting selective sensitivity to platinum-based agents in the former. An ongoing randomized phase II neoadjuvant trial is looking at this issue more closely, using carboplatin and bevacizumab (NCT00861705), and we hope that the results of this study will help us to better understand the responsiveness to platinums in sporadic triple-negative breast cancer.

Ixabepilone (Ixempra), an approved agent for the treatment of metastatic and locally advanced breast cancer, also appears promising. A pooled analysis of data from women with pretreated advanced triple-negative disease treated in a pair of phase III trials testing addition of ixabepilone to capecitabine showed a doubling of response rate and progression-free survival (San Antonio Breast Cancer Symposium 2008. Abstract 3057). But the combination also had substantial toxicity, so there is now more interest in using ixabepilone alone and farther out, in patients having multidrug-resistant disease.

EGFR Inhibitors

The epidermal growth factor receptor (EGFR) is upregulated in many triple-negative breast cancers, making this an attractive treatment target. Unfortunately, trials combining cetuximab (Erbitux) with carboplatin or with carboplatin-irinotecan have found small or no improvement in outcomes, along with added toxicity.

But the BALI-1 trial in patients with triple-negative metastatic breast cancer found a doubling of the overall response rate and progression-free survival with addition of cetuximab to cisplatin (SABCS 2010 meeting, Abstract PD01-01), although this trial did not meet its primary end point). We are waiting anxiously to see data from correlative markers obtained from these patients’ primary and metastatic tumors.

The bottom line here is that patient selection will be critical if we are going to pursue EGFR blockade in triple-negative disease.

PARP Inhibitors

There has been tremendous interest in using inhibitors of poly(ADP-ribose polymerase) or PARP, which interfere with the repair of DNA damage, in triple-negative disease. Trials to date have had mixed results and provided some valuable lessons.

A randomized phase II trial among patients with triple-negative metastatic breast cancer found that adding iniparib, an investigational PARP inhibitor, to gemcitabine-carboplatin dramatically improved progression-free and overall survival (N. Engl. J. Med. 2011;364:205-14). But the subsequent, far larger randomized phase III trial using the same regimens did not meet either of these end points (ASCO 2011 meeting. Abstract 1007).

This was very surprising and made us realize that patient selection of disease may have a significant impact on evaluation of outcome parameters. Triple-negative breast cancer is a heterogeneous disease, and we didn’t understand it well enough. In addition, we did not have enough data to understand the clinical activity of backbone in triple-negative breast cancer; in fact, patients treated with gemcitabine-carboplatin alone had a better response and PFS than expected.

Another issue was that, at least to date, tumor molecular profiles differed between the two trials. For example, only 25% of patients in the phase III trial had basal-like disease, compared with more than 40% in the phase II trial. Both trials had some patients with luminal A type, which usually corresponds to estrogen receptor–positive disease. This suggests that triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition and that we need trials with tissue analysis.

Finally, it turns out we weren’t really giving a PARP inhibitor in these trials. Iniparib at the doses that were delivered does not inhibit PARP. Efforts are now underway to study escalation. And the actual mechanism of action of this drug remains to be determined.

Antiangiogenic Agents

Agents that interfere with angiogenesis, such as bevacizumab (Avastin), are of interest in triple-negative breast cancer to target the hypoxia signature that is characteristic of this and other rapidly proliferating tumors.

We know that bevacizumab adds to clinical efficacy of chemotherapy in breast cancer. But it’s been hard to show specific subsets that benefit, and that’s our current quandary. A meta-analysis of the first-line trials in triple-negative disease suggested patients with triple-negative disease had similar improvements in outcomes from the addition of bevacizumab as did other subsets of patients (SABCS 2010 meeting. Abstract P6-12-03).

In the second-line RIBBON 2 trial, adding bevacizumab to chemotherapy appeared to have greater benefit in the triple-negative subset of patients compared with the whole group, but numbers were too small to draw definitive conclusions (ASCO 2011 Breast Cancer Symposium. Abstract 290).

Other Targeted Agents

A variety of other targeted agents are being evaluated for activity in triple-negative breast cancer. Tigatuzumab, an antibody to TRAIL receptor 2, one of the so-called death receptors, had impressive results in preclinical testing. It is now being evaluated in a randomized phase II trial in which patients with metastatic triple-negative breast cancer are treated with nanoparticle albumin–bound (nab)-paclitaxel (Abraxane) with or without tigatuzumab (NCT01307891).

An interesting finding has been that approximately 5% of patients with triple-negative disease have upregulation of the androgen receptor. Thus, another phase II trial is testing bicalutamide (Casodex) in patients whose tumors have these receptors but neither estrogen nor progesterone receptors (NCT00468715). This is a fascinating approach and could be of great benefit for this small subset of patients, as some patients have had stable disease for a year on bicalutamide therapy, which has minimal toxicity.

Treatment of triple-negative breast cancer, so named because it lacks estrogen receptors, progesterone receptors, and HER2 overexpression, is one of the most challenging areas of breast oncology. Not only do patients with this aggressive cancer have some of the shortest absolute survival times, but they also are the only group for whom we still have no targeted therap

It is becoming increasingly clear that effectively treating triple-negative disease will require recognition of its diversity. Viewing it as a single entity is inherently flawed, an oversimplified way of referring to a disease that’s incredibly heterogeneous and complicated. And that’s probably been our biggest challenge in the design of clinical trials for this cancer.

Gene expression profiling is helping to tease apart molecular subtypes of triple-negative breast cancers (Mol. Oncol. 2011;5:5-23). These subtypes often have distinctly different behavior and treatment responses.

We are also learning more about the overlap between triple negativity and mutation of the BRCA1 tumor suppressor gene. About 90% of BRCA1-mutated breast cancers have a triple-negative phenotype. But interestingly, most triple-negative tumors have normal BRCA1 function. Recent data suggest that a subset of these tumors may have posttranslational modifications that affect BRCA1 function, so if you look for the DNA mutation, you won’t find it. Sporadic basal-like tumors and hereditary BRCA1 tumors have a similar phenotype, so a defect in BRCA1 may have a role in these sporadic basal-like tumors.

Recent clinical trials are adding to our arsenal several new drugs – and a few old ones – from different classes that target vulnerabilities of triple-negative breast cancer and offer promise for improving outcomes in this hard-to-treat disease.

Cytotoxic Chemotherapeutic Agents

We know that triple-negative tumors are sensitive to cytotoxic chemotherapy, especially in the neoadjuvant and adjuvant settings.

Recognition that there is a defect in DNA repair in BRCA1 tumors and at least some triple-negative tumors has generated interest in the use of DNA-damaging agents such as platinums. The pathologic complete response rate to neoadjuvant cisplatin has been around 75% in BRCA1 tumors, but just 15% to 16% in sporadic triple-negative tumors, suggesting selective sensitivity to platinum-based agents in the former. An ongoing randomized phase II neoadjuvant trial is looking at this issue more closely, using carboplatin and bevacizumab (NCT00861705), and we hope that the results of this study will help us to better understand the responsiveness to platinums in sporadic triple-negative breast cancer.

Ixabepilone (Ixempra), an approved agent for the treatment of metastatic and locally advanced breast cancer, also appears promising. A pooled analysis of data from women with pretreated advanced triple-negative disease treated in a pair of phase III trials testing addition of ixabepilone to capecitabine showed a doubling of response rate and progression-free survival (San Antonio Breast Cancer Symposium 2008. Abstract 3057). But the combination also had substantial toxicity, so there is now more interest in using ixabepilone alone and farther out, in patients having multidrug-resistant disease.

EGFR Inhibitors

The epidermal growth factor receptor (EGFR) is upregulated in many triple-negative breast cancers, making this an attractive treatment target. Unfortunately, trials combining cetuximab (Erbitux) with carboplatin or with carboplatin-irinotecan have found small or no improvement in outcomes, along with added toxicity.

But the BALI-1 trial in patients with triple-negative metastatic breast cancer found a doubling of the overall response rate and progression-free survival with addition of cetuximab to cisplatin (SABCS 2010 meeting, Abstract PD01-01), although this trial did not meet its primary end point). We are waiting anxiously to see data from correlative markers obtained from these patients’ primary and metastatic tumors.

The bottom line here is that patient selection will be critical if we are going to pursue EGFR blockade in triple-negative disease.

PARP Inhibitors

There has been tremendous interest in using inhibitors of poly(ADP-ribose polymerase) or PARP, which interfere with the repair of DNA damage, in triple-negative disease. Trials to date have had mixed results and provided some valuable lessons.

A randomized phase II trial among patients with triple-negative metastatic breast cancer found that adding iniparib, an investigational PARP inhibitor, to gemcitabine-carboplatin dramatically improved progression-free and overall survival (N. Engl. J. Med. 2011;364:205-14). But the subsequent, far larger randomized phase III trial using the same regimens did not meet either of these end points (ASCO 2011 meeting. Abstract 1007).

This was very surprising and made us realize that patient selection of disease may have a significant impact on evaluation of outcome parameters. Triple-negative breast cancer is a heterogeneous disease, and we didn’t understand it well enough. In addition, we did not have enough data to understand the clinical activity of backbone in triple-negative breast cancer; in fact, patients treated with gemcitabine-carboplatin alone had a better response and PFS than expected.

Another issue was that, at least to date, tumor molecular profiles differed between the two trials. For example, only 25% of patients in the phase III trial had basal-like disease, compared with more than 40% in the phase II trial. Both trials had some patients with luminal A type, which usually corresponds to estrogen receptor–positive disease. This suggests that triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition and that we need trials with tissue analysis.

Finally, it turns out we weren’t really giving a PARP inhibitor in these trials. Iniparib at the doses that were delivered does not inhibit PARP. Efforts are now underway to study escalation. And the actual mechanism of action of this drug remains to be determined.

Antiangiogenic Agents

Agents that interfere with angiogenesis, such as bevacizumab (Avastin), are of interest in triple-negative breast cancer to target the hypoxia signature that is characteristic of this and other rapidly proliferating tumors.

We know that bevacizumab adds to clinical efficacy of chemotherapy in breast cancer. But it’s been hard to show specific subsets that benefit, and that’s our current quandary. A meta-analysis of the first-line trials in triple-negative disease suggested patients with triple-negative disease had similar improvements in outcomes from the addition of bevacizumab as did other subsets of patients (SABCS 2010 meeting. Abstract P6-12-03).

In the second-line RIBBON 2 trial, adding bevacizumab to chemotherapy appeared to have greater benefit in the triple-negative subset of patients compared with the whole group, but numbers were too small to draw definitive conclusions (ASCO 2011 Breast Cancer Symposium. Abstract 290).

Other Targeted Agents

A variety of other targeted agents are being evaluated for activity in triple-negative breast cancer. Tigatuzumab, an antibody to TRAIL receptor 2, one of the so-called death receptors, had impressive results in preclinical testing. It is now being evaluated in a randomized phase II trial in which patients with metastatic triple-negative breast cancer are treated with nanoparticle albumin–bound (nab)-paclitaxel (Abraxane) with or without tigatuzumab (NCT01307891).

An interesting finding has been that approximately 5% of patients with triple-negative disease have upregulation of the androgen receptor. Thus, another phase II trial is testing bicalutamide (Casodex) in patients whose tumors have these receptors but neither estrogen nor progesterone receptors (NCT00468715). This is a fascinating approach and could be of great benefit for this small subset of patients, as some patients have had stable disease for a year on bicalutamide therapy, which has minimal toxicity.

Breast cancer outcomes have improved over time, but more so in younger women than in those aged 75 years and older, according to findings from a review of data spanning nearly three decades.

The findings are concerning, because women aged 75 and older represent the fastest growing group of women affected by the disease, Dr. Benjamin D. Smith of the University of Texas M.D. Anderson Cancer Center, Houston, and his colleagues reported online in the Journal of Clinical Oncology.

According to data from National Vital Statistics Reports, breast cancer death rates began to decrease in 1990. Between that year and 2007, the breast cancer death rate in the general population declined by 2.5% per year among women aged 20-49 years, by 2.1% per year among those aged 50-64 years, and by 2.0% per year for those aged 65-74 years – but only by 1.1% per year for those aged 75 years and older.

Underlying factors that may account for the discrepancy include lower use of screening mammography in older women, lack of understanding regarding the optimal treatment for older women due to lack of representation of the older age group in clinical trials, conflicting evidence regarding the magnitude of benefit from adjuvant chemotherapy in different age groups, and a tendency to reduce chemotherapy dose intensity in older patients because of concern about increased risk of toxicity.

The "evolving disparity by age in breast cancer outcome" demonstrated by this study suggests research is needed "to understand preferences of older adults for screening and treatment and to identify optimal adjuvant therapy regimens that are both effective and tolerable in the setting of the functional status, comorbid illnesses, and social support of older women," the authors stated.

Based on data from 219,024 women diagnosed with breast cancer between 1980 and 1997 who were part of the Surveillance, Epidemiology, and End Results nine-registry cohort (SEER-9), the investigators reported that the risk of breast cancer death within 10 years decreased from 29.6% for those diagnosed in 1980-1984 to 20.1% for those diagnosed between 1995 and 1997, (J. Clin. Oncol. 2011 [doi:10.1200/JCO.2011.35.8408]).

"In multivariate analysis, the risk of breast cancer death decreased by a relative amount of 4.5% per diagnosis year after adjusting for age, race, and SEER registry," they said, adding that the 10-year absolute risk of breast cancer death from 1980 to 1997 decreased by 10.1% for women aged 20-49 years at diagnosis, by 15.3% for those aged 50-64 years at diagnosis, and by 12.5% for those aged 65-74 years at diagnosis – but only by 7.5% for those aged 75 years and older at diagnosis.

From 1980-1994, the older women experienced the lowest risk of 10-year breast cancer death at 24.8%, compared with rates ranging from 28.0% to 31.9% for the other age groups, but by 1995-1997 the older women experienced a higher risk of breast cancer death than other postmenopausal women (17.3% vs. 15.4%-16.6%), they said.

The findings demonstrate that both the rate of breast cancer death in the general population and the risk of breast cancer death in newly diagnosed patients decreased two to three times more rapidly for younger women, compared with women aged 75 and older, the investigators said, noting that it appears older women "may have missed out on advances in breast cancer diagnosis and treatment."

"Notably, approximately 40,000 women [aged 75 years or older] are diagnosed with breast cancer each year in the United States ... older women are the most rapidly growing cohort of patients with breast cancer, with 57% growth expected over the next 20 years as the US population ages," they wrote, adding: "Although our data provided reassurance that younger women have experienced substantial gains in breast cancer outcomes as a result of improvements in screening and treatment, these gains do not appear to have fully extended to the oldest 20% of patients with breast cancer."

Of note, the investigators also found race-based disparities in breast cancer outcomes. The findings indicate that, "black women are another sociodemographic group that has not fully reaped the benefits of improved breast cancer outcomes," they said, noting that the race-based gap emerged in the 1980s and continues to increase.

Dr. Smith reported receiving research funding from Varian Medical Systems. Another study author, Dr. Arti Huria, reported receiving research funding from Celgene, GlaxoSmithKline, and Abraxis BioScience, as well as serving as a consultant or in an advisory role for Genentech, Amgen, and GTx. The study was supported in part by a philanthropic gift from Ann Cazalot and Clarence Cazalot.

Breast cancer outcomes have improved over time, but more so in younger women than in those aged 75 years and older, according to findings from a review of data spanning nearly three decades.

The findings are concerning, because women aged 75 and older represent the fastest growing group of women affected by the disease, Dr. Benjamin D. Smith of the University of Texas M.D. Anderson Cancer Center, Houston, and his colleagues reported online in the Journal of Clinical Oncology.

According to data from National Vital Statistics Reports, breast cancer death rates began to decrease in 1990. Between that year and 2007, the breast cancer death rate in the general population declined by 2.5% per year among women aged 20-49 years, by 2.1% per year among those aged 50-64 years, and by 2.0% per year for those aged 65-74 years – but only by 1.1% per year for those aged 75 years and older.

Underlying factors that may account for the discrepancy include lower use of screening mammography in older women, lack of understanding regarding the optimal treatment for older women due to lack of representation of the older age group in clinical trials, conflicting evidence regarding the magnitude of benefit from adjuvant chemotherapy in different age groups, and a tendency to reduce chemotherapy dose intensity in older patients because of concern about increased risk of toxicity.

The "evolving disparity by age in breast cancer outcome" demonstrated by this study suggests research is needed "to understand preferences of older adults for screening and treatment and to identify optimal adjuvant therapy regimens that are both effective and tolerable in the setting of the functional status, comorbid illnesses, and social support of older women," the authors stated.

Based on data from 219,024 women diagnosed with breast cancer between 1980 and 1997 who were part of the Surveillance, Epidemiology, and End Results nine-registry cohort (SEER-9), the investigators reported that the risk of breast cancer death within 10 years decreased from 29.6% for those diagnosed in 1980-1984 to 20.1% for those diagnosed between 1995 and 1997, (J. Clin. Oncol. 2011 [doi:10.1200/JCO.2011.35.8408]).

"In multivariate analysis, the risk of breast cancer death decreased by a relative amount of 4.5% per diagnosis year after adjusting for age, race, and SEER registry," they said, adding that the 10-year absolute risk of breast cancer death from 1980 to 1997 decreased by 10.1% for women aged 20-49 years at diagnosis, by 15.3% for those aged 50-64 years at diagnosis, and by 12.5% for those aged 65-74 years at diagnosis – but only by 7.5% for those aged 75 years and older at diagnosis.

From 1980-1994, the older women experienced the lowest risk of 10-year breast cancer death at 24.8%, compared with rates ranging from 28.0% to 31.9% for the other age groups, but by 1995-1997 the older women experienced a higher risk of breast cancer death than other postmenopausal women (17.3% vs. 15.4%-16.6%), they said.

The findings demonstrate that both the rate of breast cancer death in the general population and the risk of breast cancer death in newly diagnosed patients decreased two to three times more rapidly for younger women, compared with women aged 75 and older, the investigators said, noting that it appears older women "may have missed out on advances in breast cancer diagnosis and treatment."

"Notably, approximately 40,000 women [aged 75 years or older] are diagnosed with breast cancer each year in the United States ... older women are the most rapidly growing cohort of patients with breast cancer, with 57% growth expected over the next 20 years as the US population ages," they wrote, adding: "Although our data provided reassurance that younger women have experienced substantial gains in breast cancer outcomes as a result of improvements in screening and treatment, these gains do not appear to have fully extended to the oldest 20% of patients with breast cancer."

Of note, the investigators also found race-based disparities in breast cancer outcomes. The findings indicate that, "black women are another sociodemographic group that has not fully reaped the benefits of improved breast cancer outcomes," they said, noting that the race-based gap emerged in the 1980s and continues to increase.

Dr. Smith reported receiving research funding from Varian Medical Systems. Another study author, Dr. Arti Huria, reported receiving research funding from Celgene, GlaxoSmithKline, and Abraxis BioScience, as well as serving as a consultant or in an advisory role for Genentech, Amgen, and GTx. The study was supported in part by a philanthropic gift from Ann Cazalot and Clarence Cazalot.

Breast cancer outcomes have improved over time, but more so in younger women than in those aged 75 years and older, according to findings from a review of data spanning nearly three decades.

The findings are concerning, because women aged 75 and older represent the fastest growing group of women affected by the disease, Dr. Benjamin D. Smith of the University of Texas M.D. Anderson Cancer Center, Houston, and his colleagues reported online in the Journal of Clinical Oncology.

According to data from National Vital Statistics Reports, breast cancer death rates began to decrease in 1990. Between that year and 2007, the breast cancer death rate in the general population declined by 2.5% per year among women aged 20-49 years, by 2.1% per year among those aged 50-64 years, and by 2.0% per year for those aged 65-74 years – but only by 1.1% per year for those aged 75 years and older.

Underlying factors that may account for the discrepancy include lower use of screening mammography in older women, lack of understanding regarding the optimal treatment for older women due to lack of representation of the older age group in clinical trials, conflicting evidence regarding the magnitude of benefit from adjuvant chemotherapy in different age groups, and a tendency to reduce chemotherapy dose intensity in older patients because of concern about increased risk of toxicity.

The "evolving disparity by age in breast cancer outcome" demonstrated by this study suggests research is needed "to understand preferences of older adults for screening and treatment and to identify optimal adjuvant therapy regimens that are both effective and tolerable in the setting of the functional status, comorbid illnesses, and social support of older women," the authors stated.

Based on data from 219,024 women diagnosed with breast cancer between 1980 and 1997 who were part of the Surveillance, Epidemiology, and End Results nine-registry cohort (SEER-9), the investigators reported that the risk of breast cancer death within 10 years decreased from 29.6% for those diagnosed in 1980-1984 to 20.1% for those diagnosed between 1995 and 1997, (J. Clin. Oncol. 2011 [doi:10.1200/JCO.2011.35.8408]).

"In multivariate analysis, the risk of breast cancer death decreased by a relative amount of 4.5% per diagnosis year after adjusting for age, race, and SEER registry," they said, adding that the 10-year absolute risk of breast cancer death from 1980 to 1997 decreased by 10.1% for women aged 20-49 years at diagnosis, by 15.3% for those aged 50-64 years at diagnosis, and by 12.5% for those aged 65-74 years at diagnosis – but only by 7.5% for those aged 75 years and older at diagnosis.

From 1980-1994, the older women experienced the lowest risk of 10-year breast cancer death at 24.8%, compared with rates ranging from 28.0% to 31.9% for the other age groups, but by 1995-1997 the older women experienced a higher risk of breast cancer death than other postmenopausal women (17.3% vs. 15.4%-16.6%), they said.

The findings demonstrate that both the rate of breast cancer death in the general population and the risk of breast cancer death in newly diagnosed patients decreased two to three times more rapidly for younger women, compared with women aged 75 and older, the investigators said, noting that it appears older women "may have missed out on advances in breast cancer diagnosis and treatment."

"Notably, approximately 40,000 women [aged 75 years or older] are diagnosed with breast cancer each year in the United States ... older women are the most rapidly growing cohort of patients with breast cancer, with 57% growth expected over the next 20 years as the US population ages," they wrote, adding: "Although our data provided reassurance that younger women have experienced substantial gains in breast cancer outcomes as a result of improvements in screening and treatment, these gains do not appear to have fully extended to the oldest 20% of patients with breast cancer."

Of note, the investigators also found race-based disparities in breast cancer outcomes. The findings indicate that, "black women are another sociodemographic group that has not fully reaped the benefits of improved breast cancer outcomes," they said, noting that the race-based gap emerged in the 1980s and continues to increase.

Dr. Smith reported receiving research funding from Varian Medical Systems. Another study author, Dr. Arti Huria, reported receiving research funding from Celgene, GlaxoSmithKline, and Abraxis BioScience, as well as serving as a consultant or in an advisory role for Genentech, Amgen, and GTx. The study was supported in part by a philanthropic gift from Ann Cazalot and Clarence Cazalot.