Exemestane Prevents Breast Cancers in Postmenopausal Women

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.

CHICAGO - A daily dose of the aromatase inhibitor exemestane reduced invasive breast cancers by 65% in a placebo-controlled chemoprevention trial that enrolled 4,560 postmenopausal women considered at increased risk of the disease.

Pre-invasive breast cancers and precancerous lesions also were much less common at a median follow-up of 3 years in the study, which is expected to reopen a stalled conversation between women and their physicians regarding the risks and benefits of chemoprevention.

Two selective estrogen receptor modulator (SERM) drugs – tamoxifen and raloxifene (Evista) – are approved for breast cancer prevention, but they are little used for that purpose. Estimated tamoxifen use runs as low as 4% in high-risk women, who are thought to be deterred by rare but potentially serious side effects.

Exemestane (Aromasin) could become a third option for breast cancer prevention in postmenopausal women, Paul E. Goss, M.D., Ph.D., the lead author, said, announcing the results on behalf of the MAP.3 (Mammary Prevention.3 trial) investigators at the annual meeting of the American Society of Clinical Oncology.

"Because of the significant reduction of breast cancer and the excellent safety profile, exemestane has the potential for wider-scale implementation than the selective estrogen modulators in our view," declared Dr. Goss, a professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston.

Women had to be age 35 or older and postmenopausal with at least one specified risk factor to enter the trial, he noted. Age greater than or equal to 60 years by itself was considered a risk factor, as were a five-year Gail risk score greater than 1.66%, prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or prior ductal carcinoma in situ with prior mastectomy.

Dr. Goss stressed that the results should not be extrapolated to premenopausal women or others who do not meet the trial’s eligibility criteria.

The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) led the study, which enrolled women in Canada, the United States, Spain, and France. The findings at a median follow-up of 35 months were published online by the New England Journal of Medicine (2011 June 4;doi:10.1056/NEJMoa1103507) simultaneously with a press briefing at ASCO. These included:

• A 65% relative reduction in annual incidence of invasive breast cancer, based on 11 breast cancers among 2,285 women in the exemestane arm vs. 32 among 2,275 in the placebo arm. The annual incidence was 0.19% vs. 0.55%, respectively (hazard ratio 0.35, P = .002).

• Annual incidence of invasive plus noninvasive (DCIS) breast cancers of 0.35% with exemestane vs. 0.77% with placebo (HR 0.35, P =.004).

Most cancers in both arms of the trial were estrogen receptor-positive, HER2/neu–negative, and node-negative. The investigators said exemestane was superior in all subgroup studies. They said that the number needed to prevent one case of breast cancer would be 94 at 3 years but projected that it would drop to 26 at 5 years.

Physicians – for the most part, those in primary care, as oncologists are not likely to see women who do not have cancer – need to discuss risks and benefits of the three chemoprevention drugs with their patients, stressed Dr. Goss and Dr. Andrew Seidman, moderator of the press briefing. The three agents have different side effect profiles, they noted.

Dr. Seidman, a breast specialist at Memorial Sloan-Kettering Cancer Center and a professor of medicine at Weill Cornell Medical College in New York, credited "heightened fear of endometrial cancers and thrombotic clotting risks" for the sparse use of SERMs as chemoprevention.

Although 88% of women on exemestane and 85% of those on placebo experienced adverse events in the MAP.3 study, none were life-threatening, and the investigators reported that serious events such as skeletal fractures, cardiovascular events, other cancers, and treatment-related deaths were not significantly different between the two groups. Hot flashes and arthritis were more common with exemestane.

Quality of life differences were minimal, they said, characterizing the dropout rates and noncompliance rates as unexceptional for chemoprevention trials. Indeed, the benefits of exemestane were probably higher in women who stuck with the protocol, Dr. Goss said; the intent-to-treat analysis included women who dropped out early in the trial.

"One of the elephants in the kitchen is prophylactic bilateral mastectomy," added Dr. Seidman. He described himself as "always chagrined" at how some women are more willing to undergo "body-altering surgery" than to try chemoprevention.

The Map.3 study randomized women to 25 mg of exemestane or placebo daily. Initially, the study had a third arm in which celecoxib was added to exemestane, but it was dropped because of concerns for "cardiovascular safety" with celecoxib.

Dr. Goss said the investigators plan to look for clearer data on how to define which women are high-risk and would benefit from exemestane. They also will be looking for biomarkers that can show how well a woman does while on chemoprevention: something comparable to measures used when patients take anti-hypertensives or cholesterol-lowering drugs.

Another unknown is whether Pfizer, Inc. will seek a chemoprevention indication for exemestane. Aromasin lost patent protection in the United States in Apri, and will lose it in Europe in July, according to company spokesman Christopher Loder. "We cannot comment on our regulatory plans at this time," he said in a hallway interview at the convention center where ASCO is being held.

Loss of exclusivity is likely to mean lower prices for Aromasin, which could make Pfizer less inclined to invest in applications for the indication. Whether insurance companies would pay for chemoprevention use without an indication is also a question – but price might not be a barrier.

Pfizer helped pay for the trial. Dr. Goss and several of his coauthors received honoraria and research funding from Pfizer, as well as other companies.