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Report prepared by Matt Stenger
The selective estrogen-receptor modulators tamoxifen and raloxifene (Evista) are available for chemoprevention of breast cancer in women at increased risk of disease but are rarely used due to fears of serious adverse effects; there is an increased risk of endometrial cancer with tamoxifen and an increased risk of thromboembolism with both agents. The aromatase inhibitor exemestane (Aromasin) was recently shown to reduce the risk of invasive cancer in women at moderate risk, with no serious toxic effects and minimal changes in quality of life (QOL).1
In a double-blind trial, 4,560 postmenopausal women aged 35 years or older who were at moderate risk of breast cancer were randomized to receive exemestane (25 mg/day; n = 2,285) or placebo (n = 2,275).1 Patients had to have at least one of the following risk factors: age ≥ 60 years, Gail 5-year risk score (chance in 100 of developing invasive breast cancer) > 1.66%, prior atypical ductal hyperplasia (ADH) or lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS), or ductal carcinoma in situ (DCIS) treated with mastectomy. The primary endpoint of the trial was incidence of invasive breast cancer, with the trial being designed to detect a 65% relative reduction in risk with exemestane. The trial was event-driven, with patients continuing to receive study treatment for a planned maximum duration of 5 years or until occurrence of a breast event, neoplastic disease, cardiovascular event, or unacceptable toxicity.
The two study groups were well matched for baseline characteristics and risk factors. The median age was 62.5 years in the exemestane group vs 62.4 years in the placebo group, with 67.6% vs 69.1% being ≥ 60 years of age. The median body mass index values were 27.9 vs 28.1 kg/m2. The Gail model score was > 1.66% in 40.7% vs 39.8%; 48.8% vs 49.5% were aged ≥ 60 years (as a risk factor); 8.1% vs 8.3% had ADH, ALH, or LCIS on biopsy; and 2.5% vs 2.5% had DCIS treated with mastectomy. The median Gail score was 2.3% in both groups, with 57.8% vs 57.1% having a score > 2.0%. Prior use of menopausal hormone therapy; bone mineral density; history of clinical fracture; cardiovascular risk factors; and use of bisphosphonates, lipid-lowering drugs, and cardiovascular drugs were similar in the two groups. At the time of the clinical data cutoff, 33% of women randomized to receive exemestane and 29% of those randomized to receive placebo were no longer taking the study medication. About 5% in each group had completed treatment. The primary reason for discontinuation of treatment was toxicity, which resulted in discontinuation in 15.4% of exemestane recipients and 10.8% of placebo recipients (P < 0.0001). Patient refusal of treatment resulted in discontinuation in 6.9% vs 6.0% (P = not significant).
At a median follow-up of 35 months, invasive breast cancer had occurred in 11 exemestane recipients and 32 placebo recipients, representing a significant 65% reduction in annual incidence with exemestane(0.19% vs 0.55%; hazard ratio [HR], 0.35; P = 0.002; Figure 1). Exemestane was also associated with a lower incidence in the combined endpoint of invasive breast cancer or DCIS (20 vs 44 cases), with a significant 53% reduction in annual incidence (0.35% vs 0.77%; HR, 0.47; P = 0.004). Fewer cases of DCIS (9 vs 14) and the combined endpoint of ADH, ALH, or LCIS (4 vs 11 cases) occurred in the exemestane group, although the reduction in annual incidence of these outcomes did not reach statistical significance (0.16% vs 0.24%; HR, 0.65; P = 0.31 for DCIS; 0.07% vs 0.20%; HR, 0.36; P = 0.08 for ADH, ALH, or LCIS). Exemestane appeared to demonstrate consistent superiority over placebo in the subgroups included in the planned subgroup analysis (Figure 1). The number needed to treat to prevent 1 case of invasive breast cancer with exemestane was 94 over 3 years and 26 over 5 years (although few women had completed 5 years of therapy at data cutoff).
Adverse events of any grade were slightly more common with exemestane (88% vs 85%; P = 0.003). By grade, 21% vs 25% were grade 1; 42% vs 39% were grade 2; 24% vs 19% were grade 3; and 1% vs 1% were grade 4. Table 1 shows the incidence of adverse events that occurred in 5% or more of women, with a difference between groups of 1% or more, and the incidence of toxicities specified as secondary endpoints. Although there were statistically significant differences between groups for some adverse events, the absolute percentage differences were usually small. Menopausal symptoms were frequent and somewhat more common with exemestane. The most frequent adverse events were hot flashes (40% vs 32%; P < 0.001) and joint pain (30% vs 27%; P = 0.04); arthritis was also more common with exemestane (11% vs 9%; P = 0.01). There were no differences between groups in clinical fracture rates, new diagnoses of osteoporosis, new prescriptions for bisphosphonates, cardiovascular events, or rates of other cancers or time to detection of other cancers. There were 19 deaths in each group, with causes consisting of breast cancer in 1 exemestane recipient vs 0 placebo recipients, other cancers in 10 patients vs 12 patients, cardiovascular causes in 5 vs 4, and other causes in 3 vs 3. None of the deaths was considered treatment-related.
Health-related and menopausespecific QOL were assessed by the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and the Menopause-Specific QOL questionnaire. When distributions of worsened, stable, and improved scores were compared, no differences in health-related QOL between groups were found. Women taking exemestane had an overall 7% worsened menopause-related QOL compared with those taking placebo.
Reference
1. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.
COMMENTARY
An aromatase inhibitor for breast cancer prevention: a promising option with barriers to resolve
D. Lawrence Wickerham, MD, Drexel University College of Medicine, Philadelphia, PA
The first results of the National Cancer Institute of Canada Clinical Trials Group (NCIC–CTG) MAP-3 trial, a randomized doubleblind placebo-controlled study of the aromatase inhibitor (AI) exemestane, was presented at the June 2011 meeting of the American Society of Oncology1 and was published in the New England Journal of Medicine.2 They represent good news for postmenopausal women at increased risk for developing breast cancer.
With a median follow-up of 35 months, the exemestane-treated women had a 65% (0.19% vs 0.55%; hazard ratio, 0.35; 95% confidence interval, 0.18 to 0.70; P = 0.002) reduction in the incidence of invasive breast cancer. A total of 4,560 postmenopausal women from the United States, Canada, Spain, and France entered this study between 2004 and 2010. All the women were at increased risk, which was determined based on age 60 years or older, prior breast biopsy showing atypical hyperplasia or lobular carcinoma in situ (LCIS), prior ductal carcinoma in situ (DCIS) treated by mastectomy, or a Gail model risk score of greater than 1.66% of developing breast cancer over the next 5 years.
Concerns and barriers amid the good news
Although I have heard my colleagues express some concerns about the trial results, I find most of their issues to be relatively minor. The median follow-up is only about 3 years, and relatively few of the trial participants have completed 5 years of therapy. However, the results are highly statistically significant and are in keeping with the data in adjuvant therapy trials, where the AIs appear to have a durable benefit in reducing new primary cancers of the opposite breast. At the time of analysis, only 43 invasive breast cancers had been diagnosed— 11 in the exemestane-treated group and 32 in the placebo group.
With the estimated reduction in invasive breast cancer of 65%, again estimated from treatment trials and compared with an untreated control, it takes relatively few events to confirm the reduction in invasive breast cancer, which was the primary endpoint. The women were carefully followed and had annual mammograms. The cancers that did occur in both groups were small, early-stage tumors, making a survival benefit almost impossible to document; however, the study was not designed to demonstrate such a finding.
In addition, the treatment assignments were unblinded, the women were informed of their current treatment, and the placebo group was offered the opportunity to cross over to exemestane. These actions make follow-up analyses less meaningful, but the study officials should be applauded for this approach. Although individuals enter trials such as MAP- 3 with the hope that it will benefit them, they understand that if new information concerning their care options becomes available, they will be informed.
There will be barriers to the routine use of exemestane for risk reduction. First, it has not yet been approved for this use by the US Food and Drug Administration, so insurance coverage may not apply. The drug is scheduled to become available generically in the near future, but it currently costs $300-plus per month.
Second, AIs reduce estrogen levels in postmenopausal women to almost zero; that is an effective way to treat and now prevent breast cancer. However, AIs are associated with potential side effects and toxicities, which can be a barrier to their use. Use of AIs can reduce bone density and may result in bone fractures. In MAP-3, bone density measures were obtained at study entry but not routinely during the trial. During treatment, reports of a diagnosis of osteoporosis were balanced in both groups, and fracture rates were similar. Here, the short follow-up and patient selection may have been factors. With prolonged use of AIs, the bone loss can be cumulative. The development of osteoporosis in women who start with normal bone density is low, but for women who already have lowbone mass, other prevention options may be a better first choice. Following AI-treated women with periodic bone density studies and the use of bisphosphonates to blunt the bone impact is an additional approach but further adds to the cost of treatment.
Third, the biggest problem with exemestane may be that to obtain the 65% risk reduction, the drug must be taken on a daily basis. Among the most common side effects of the AIs are troubling arthralgias and myalgias; these problems are the most common reason for women discontinuing AIs during the treatment of breast cancer, and in MAP-3, almost one-third of the exemestane-treated women had stopped taking their medication. That fact does not impact the trial results, which achieved the risk reduction despite the drop-offs, but for those women who stop their medication early, it is unlikely they will achieve substantial risk reduction. In addition, medication adherence within trials is often better than in the real world, due to patients volunteering and being committed to the trial plus the trial investigators monitoring and encouraging adherence. Similar adherence rates can be achieved outside research studies, but they require effort and reinforcement at each follow-up visit.
Patients with DCIS
Participants with a history of DCIS treated by mastectomy were eligible for MAP-3 and appear to have a risk reduction benefit similar in magnitude to other trial participants. However, it would be premature to begin to use exemestane in the adjuvant treatment of patients with receptor-positive DCIS. That step should await the results of two adjuvant AI trials in DCIS that have completed accrual—IBIS II (International Breast Cancer Intervention Study) and NSABP (National Surgical Adjuvant Breast and Bowel Project) B-35—both of which compare anastrozole with tamoxifen in patients with receptor-positive DCIS treated by lumpectomy. Exemestane did reduce the number of cases of DCIS that were diagnosed, although that reduction did not reach statistical significance. However, given the overall sample size and the median follow-up, the lack of significance is not surprising and is unlikely to be clinically important.
Overall, the MAP-3 results are impressive and demonstrate that exemestane should be included with tamoxifen and raloxifene as an effective option for breast cancer prevention.
References
1. Goss PE, Ingle JN, Ales-Martinez J, et al. Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—a randomized, placebo-controlled clinical trial. J Clin Oncol 2011;29:LBA504.
2. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.
WHAT'S NEW, WHAT'S IMPORTANT
Jame Abraham, MD, Editor
Breast cancer is the most common cancer in women. The National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 studies both showed that selective inhibition of estrogen receptors with such drugs as tamoxifen or raloxifene (Evista) can decrease the incidence of breast cancer by about 50% in women who are at high risk of developing breast cancer based on the Gail risk model. Several studies in postmenopausal patients have shown that aromatase inhibitors are effective agents for the treatment of breast cancer when used in the metastatic, neoadjuvant, or adjuvant setting. The study by Paul Goss and colleagues described here has shown, for the first time, that exemestane, a steroidal aromatize inhibitor, can decrease the incidence of breast cancer by 65% in high-risk, postmenopausal patients.
So what do we tell our patients? In postmenopausal women who are at high risk of developing breast cancer, per the Gail risk criteria, we now have three drugs available: tamoxifen, raloxifene, and exemestane. When we consider any preventive intervention, we need to look at both the risk and the benefit expected. Because the median followup in the Goss study was only 3 years, the long-term side effects of exemestane are not well established in this setting.
Report prepared by Matt Stenger
The selective estrogen-receptor modulators tamoxifen and raloxifene (Evista) are available for chemoprevention of breast cancer in women at increased risk of disease but are rarely used due to fears of serious adverse effects; there is an increased risk of endometrial cancer with tamoxifen and an increased risk of thromboembolism with both agents. The aromatase inhibitor exemestane (Aromasin) was recently shown to reduce the risk of invasive cancer in women at moderate risk, with no serious toxic effects and minimal changes in quality of life (QOL).1
In a double-blind trial, 4,560 postmenopausal women aged 35 years or older who were at moderate risk of breast cancer were randomized to receive exemestane (25 mg/day; n = 2,285) or placebo (n = 2,275).1 Patients had to have at least one of the following risk factors: age ≥ 60 years, Gail 5-year risk score (chance in 100 of developing invasive breast cancer) > 1.66%, prior atypical ductal hyperplasia (ADH) or lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS), or ductal carcinoma in situ (DCIS) treated with mastectomy. The primary endpoint of the trial was incidence of invasive breast cancer, with the trial being designed to detect a 65% relative reduction in risk with exemestane. The trial was event-driven, with patients continuing to receive study treatment for a planned maximum duration of 5 years or until occurrence of a breast event, neoplastic disease, cardiovascular event, or unacceptable toxicity.
The two study groups were well matched for baseline characteristics and risk factors. The median age was 62.5 years in the exemestane group vs 62.4 years in the placebo group, with 67.6% vs 69.1% being ≥ 60 years of age. The median body mass index values were 27.9 vs 28.1 kg/m2. The Gail model score was > 1.66% in 40.7% vs 39.8%; 48.8% vs 49.5% were aged ≥ 60 years (as a risk factor); 8.1% vs 8.3% had ADH, ALH, or LCIS on biopsy; and 2.5% vs 2.5% had DCIS treated with mastectomy. The median Gail score was 2.3% in both groups, with 57.8% vs 57.1% having a score > 2.0%. Prior use of menopausal hormone therapy; bone mineral density; history of clinical fracture; cardiovascular risk factors; and use of bisphosphonates, lipid-lowering drugs, and cardiovascular drugs were similar in the two groups. At the time of the clinical data cutoff, 33% of women randomized to receive exemestane and 29% of those randomized to receive placebo were no longer taking the study medication. About 5% in each group had completed treatment. The primary reason for discontinuation of treatment was toxicity, which resulted in discontinuation in 15.4% of exemestane recipients and 10.8% of placebo recipients (P < 0.0001). Patient refusal of treatment resulted in discontinuation in 6.9% vs 6.0% (P = not significant).
At a median follow-up of 35 months, invasive breast cancer had occurred in 11 exemestane recipients and 32 placebo recipients, representing a significant 65% reduction in annual incidence with exemestane(0.19% vs 0.55%; hazard ratio [HR], 0.35; P = 0.002; Figure 1). Exemestane was also associated with a lower incidence in the combined endpoint of invasive breast cancer or DCIS (20 vs 44 cases), with a significant 53% reduction in annual incidence (0.35% vs 0.77%; HR, 0.47; P = 0.004). Fewer cases of DCIS (9 vs 14) and the combined endpoint of ADH, ALH, or LCIS (4 vs 11 cases) occurred in the exemestane group, although the reduction in annual incidence of these outcomes did not reach statistical significance (0.16% vs 0.24%; HR, 0.65; P = 0.31 for DCIS; 0.07% vs 0.20%; HR, 0.36; P = 0.08 for ADH, ALH, or LCIS). Exemestane appeared to demonstrate consistent superiority over placebo in the subgroups included in the planned subgroup analysis (Figure 1). The number needed to treat to prevent 1 case of invasive breast cancer with exemestane was 94 over 3 years and 26 over 5 years (although few women had completed 5 years of therapy at data cutoff).
Adverse events of any grade were slightly more common with exemestane (88% vs 85%; P = 0.003). By grade, 21% vs 25% were grade 1; 42% vs 39% were grade 2; 24% vs 19% were grade 3; and 1% vs 1% were grade 4. Table 1 shows the incidence of adverse events that occurred in 5% or more of women, with a difference between groups of 1% or more, and the incidence of toxicities specified as secondary endpoints. Although there were statistically significant differences between groups for some adverse events, the absolute percentage differences were usually small. Menopausal symptoms were frequent and somewhat more common with exemestane. The most frequent adverse events were hot flashes (40% vs 32%; P < 0.001) and joint pain (30% vs 27%; P = 0.04); arthritis was also more common with exemestane (11% vs 9%; P = 0.01). There were no differences between groups in clinical fracture rates, new diagnoses of osteoporosis, new prescriptions for bisphosphonates, cardiovascular events, or rates of other cancers or time to detection of other cancers. There were 19 deaths in each group, with causes consisting of breast cancer in 1 exemestane recipient vs 0 placebo recipients, other cancers in 10 patients vs 12 patients, cardiovascular causes in 5 vs 4, and other causes in 3 vs 3. None of the deaths was considered treatment-related.
Health-related and menopausespecific QOL were assessed by the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and the Menopause-Specific QOL questionnaire. When distributions of worsened, stable, and improved scores were compared, no differences in health-related QOL between groups were found. Women taking exemestane had an overall 7% worsened menopause-related QOL compared with those taking placebo.
Reference
1. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.
COMMENTARY
An aromatase inhibitor for breast cancer prevention: a promising option with barriers to resolve
D. Lawrence Wickerham, MD, Drexel University College of Medicine, Philadelphia, PA
The first results of the National Cancer Institute of Canada Clinical Trials Group (NCIC–CTG) MAP-3 trial, a randomized doubleblind placebo-controlled study of the aromatase inhibitor (AI) exemestane, was presented at the June 2011 meeting of the American Society of Oncology1 and was published in the New England Journal of Medicine.2 They represent good news for postmenopausal women at increased risk for developing breast cancer.
With a median follow-up of 35 months, the exemestane-treated women had a 65% (0.19% vs 0.55%; hazard ratio, 0.35; 95% confidence interval, 0.18 to 0.70; P = 0.002) reduction in the incidence of invasive breast cancer. A total of 4,560 postmenopausal women from the United States, Canada, Spain, and France entered this study between 2004 and 2010. All the women were at increased risk, which was determined based on age 60 years or older, prior breast biopsy showing atypical hyperplasia or lobular carcinoma in situ (LCIS), prior ductal carcinoma in situ (DCIS) treated by mastectomy, or a Gail model risk score of greater than 1.66% of developing breast cancer over the next 5 years.
Concerns and barriers amid the good news
Although I have heard my colleagues express some concerns about the trial results, I find most of their issues to be relatively minor. The median follow-up is only about 3 years, and relatively few of the trial participants have completed 5 years of therapy. However, the results are highly statistically significant and are in keeping with the data in adjuvant therapy trials, where the AIs appear to have a durable benefit in reducing new primary cancers of the opposite breast. At the time of analysis, only 43 invasive breast cancers had been diagnosed— 11 in the exemestane-treated group and 32 in the placebo group.
With the estimated reduction in invasive breast cancer of 65%, again estimated from treatment trials and compared with an untreated control, it takes relatively few events to confirm the reduction in invasive breast cancer, which was the primary endpoint. The women were carefully followed and had annual mammograms. The cancers that did occur in both groups were small, early-stage tumors, making a survival benefit almost impossible to document; however, the study was not designed to demonstrate such a finding.
In addition, the treatment assignments were unblinded, the women were informed of their current treatment, and the placebo group was offered the opportunity to cross over to exemestane. These actions make follow-up analyses less meaningful, but the study officials should be applauded for this approach. Although individuals enter trials such as MAP- 3 with the hope that it will benefit them, they understand that if new information concerning their care options becomes available, they will be informed.
There will be barriers to the routine use of exemestane for risk reduction. First, it has not yet been approved for this use by the US Food and Drug Administration, so insurance coverage may not apply. The drug is scheduled to become available generically in the near future, but it currently costs $300-plus per month.
Second, AIs reduce estrogen levels in postmenopausal women to almost zero; that is an effective way to treat and now prevent breast cancer. However, AIs are associated with potential side effects and toxicities, which can be a barrier to their use. Use of AIs can reduce bone density and may result in bone fractures. In MAP-3, bone density measures were obtained at study entry but not routinely during the trial. During treatment, reports of a diagnosis of osteoporosis were balanced in both groups, and fracture rates were similar. Here, the short follow-up and patient selection may have been factors. With prolonged use of AIs, the bone loss can be cumulative. The development of osteoporosis in women who start with normal bone density is low, but for women who already have lowbone mass, other prevention options may be a better first choice. Following AI-treated women with periodic bone density studies and the use of bisphosphonates to blunt the bone impact is an additional approach but further adds to the cost of treatment.
Third, the biggest problem with exemestane may be that to obtain the 65% risk reduction, the drug must be taken on a daily basis. Among the most common side effects of the AIs are troubling arthralgias and myalgias; these problems are the most common reason for women discontinuing AIs during the treatment of breast cancer, and in MAP-3, almost one-third of the exemestane-treated women had stopped taking their medication. That fact does not impact the trial results, which achieved the risk reduction despite the drop-offs, but for those women who stop their medication early, it is unlikely they will achieve substantial risk reduction. In addition, medication adherence within trials is often better than in the real world, due to patients volunteering and being committed to the trial plus the trial investigators monitoring and encouraging adherence. Similar adherence rates can be achieved outside research studies, but they require effort and reinforcement at each follow-up visit.
Patients with DCIS
Participants with a history of DCIS treated by mastectomy were eligible for MAP-3 and appear to have a risk reduction benefit similar in magnitude to other trial participants. However, it would be premature to begin to use exemestane in the adjuvant treatment of patients with receptor-positive DCIS. That step should await the results of two adjuvant AI trials in DCIS that have completed accrual—IBIS II (International Breast Cancer Intervention Study) and NSABP (National Surgical Adjuvant Breast and Bowel Project) B-35—both of which compare anastrozole with tamoxifen in patients with receptor-positive DCIS treated by lumpectomy. Exemestane did reduce the number of cases of DCIS that were diagnosed, although that reduction did not reach statistical significance. However, given the overall sample size and the median follow-up, the lack of significance is not surprising and is unlikely to be clinically important.
Overall, the MAP-3 results are impressive and demonstrate that exemestane should be included with tamoxifen and raloxifene as an effective option for breast cancer prevention.
References
1. Goss PE, Ingle JN, Ales-Martinez J, et al. Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—a randomized, placebo-controlled clinical trial. J Clin Oncol 2011;29:LBA504.
2. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.
WHAT'S NEW, WHAT'S IMPORTANT
Jame Abraham, MD, Editor
Breast cancer is the most common cancer in women. The National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 studies both showed that selective inhibition of estrogen receptors with such drugs as tamoxifen or raloxifene (Evista) can decrease the incidence of breast cancer by about 50% in women who are at high risk of developing breast cancer based on the Gail risk model. Several studies in postmenopausal patients have shown that aromatase inhibitors are effective agents for the treatment of breast cancer when used in the metastatic, neoadjuvant, or adjuvant setting. The study by Paul Goss and colleagues described here has shown, for the first time, that exemestane, a steroidal aromatize inhibitor, can decrease the incidence of breast cancer by 65% in high-risk, postmenopausal patients.
So what do we tell our patients? In postmenopausal women who are at high risk of developing breast cancer, per the Gail risk criteria, we now have three drugs available: tamoxifen, raloxifene, and exemestane. When we consider any preventive intervention, we need to look at both the risk and the benefit expected. Because the median followup in the Goss study was only 3 years, the long-term side effects of exemestane are not well established in this setting.
Report prepared by Matt Stenger
The selective estrogen-receptor modulators tamoxifen and raloxifene (Evista) are available for chemoprevention of breast cancer in women at increased risk of disease but are rarely used due to fears of serious adverse effects; there is an increased risk of endometrial cancer with tamoxifen and an increased risk of thromboembolism with both agents. The aromatase inhibitor exemestane (Aromasin) was recently shown to reduce the risk of invasive cancer in women at moderate risk, with no serious toxic effects and minimal changes in quality of life (QOL).1
In a double-blind trial, 4,560 postmenopausal women aged 35 years or older who were at moderate risk of breast cancer were randomized to receive exemestane (25 mg/day; n = 2,285) or placebo (n = 2,275).1 Patients had to have at least one of the following risk factors: age ≥ 60 years, Gail 5-year risk score (chance in 100 of developing invasive breast cancer) > 1.66%, prior atypical ductal hyperplasia (ADH) or lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS), or ductal carcinoma in situ (DCIS) treated with mastectomy. The primary endpoint of the trial was incidence of invasive breast cancer, with the trial being designed to detect a 65% relative reduction in risk with exemestane. The trial was event-driven, with patients continuing to receive study treatment for a planned maximum duration of 5 years or until occurrence of a breast event, neoplastic disease, cardiovascular event, or unacceptable toxicity.
The two study groups were well matched for baseline characteristics and risk factors. The median age was 62.5 years in the exemestane group vs 62.4 years in the placebo group, with 67.6% vs 69.1% being ≥ 60 years of age. The median body mass index values were 27.9 vs 28.1 kg/m2. The Gail model score was > 1.66% in 40.7% vs 39.8%; 48.8% vs 49.5% were aged ≥ 60 years (as a risk factor); 8.1% vs 8.3% had ADH, ALH, or LCIS on biopsy; and 2.5% vs 2.5% had DCIS treated with mastectomy. The median Gail score was 2.3% in both groups, with 57.8% vs 57.1% having a score > 2.0%. Prior use of menopausal hormone therapy; bone mineral density; history of clinical fracture; cardiovascular risk factors; and use of bisphosphonates, lipid-lowering drugs, and cardiovascular drugs were similar in the two groups. At the time of the clinical data cutoff, 33% of women randomized to receive exemestane and 29% of those randomized to receive placebo were no longer taking the study medication. About 5% in each group had completed treatment. The primary reason for discontinuation of treatment was toxicity, which resulted in discontinuation in 15.4% of exemestane recipients and 10.8% of placebo recipients (P < 0.0001). Patient refusal of treatment resulted in discontinuation in 6.9% vs 6.0% (P = not significant).
At a median follow-up of 35 months, invasive breast cancer had occurred in 11 exemestane recipients and 32 placebo recipients, representing a significant 65% reduction in annual incidence with exemestane(0.19% vs 0.55%; hazard ratio [HR], 0.35; P = 0.002; Figure 1). Exemestane was also associated with a lower incidence in the combined endpoint of invasive breast cancer or DCIS (20 vs 44 cases), with a significant 53% reduction in annual incidence (0.35% vs 0.77%; HR, 0.47; P = 0.004). Fewer cases of DCIS (9 vs 14) and the combined endpoint of ADH, ALH, or LCIS (4 vs 11 cases) occurred in the exemestane group, although the reduction in annual incidence of these outcomes did not reach statistical significance (0.16% vs 0.24%; HR, 0.65; P = 0.31 for DCIS; 0.07% vs 0.20%; HR, 0.36; P = 0.08 for ADH, ALH, or LCIS). Exemestane appeared to demonstrate consistent superiority over placebo in the subgroups included in the planned subgroup analysis (Figure 1). The number needed to treat to prevent 1 case of invasive breast cancer with exemestane was 94 over 3 years and 26 over 5 years (although few women had completed 5 years of therapy at data cutoff).
Adverse events of any grade were slightly more common with exemestane (88% vs 85%; P = 0.003). By grade, 21% vs 25% were grade 1; 42% vs 39% were grade 2; 24% vs 19% were grade 3; and 1% vs 1% were grade 4. Table 1 shows the incidence of adverse events that occurred in 5% or more of women, with a difference between groups of 1% or more, and the incidence of toxicities specified as secondary endpoints. Although there were statistically significant differences between groups for some adverse events, the absolute percentage differences were usually small. Menopausal symptoms were frequent and somewhat more common with exemestane. The most frequent adverse events were hot flashes (40% vs 32%; P < 0.001) and joint pain (30% vs 27%; P = 0.04); arthritis was also more common with exemestane (11% vs 9%; P = 0.01). There were no differences between groups in clinical fracture rates, new diagnoses of osteoporosis, new prescriptions for bisphosphonates, cardiovascular events, or rates of other cancers or time to detection of other cancers. There were 19 deaths in each group, with causes consisting of breast cancer in 1 exemestane recipient vs 0 placebo recipients, other cancers in 10 patients vs 12 patients, cardiovascular causes in 5 vs 4, and other causes in 3 vs 3. None of the deaths was considered treatment-related.
Health-related and menopausespecific QOL were assessed by the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and the Menopause-Specific QOL questionnaire. When distributions of worsened, stable, and improved scores were compared, no differences in health-related QOL between groups were found. Women taking exemestane had an overall 7% worsened menopause-related QOL compared with those taking placebo.
Reference
1. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.
COMMENTARY
An aromatase inhibitor for breast cancer prevention: a promising option with barriers to resolve
D. Lawrence Wickerham, MD, Drexel University College of Medicine, Philadelphia, PA
The first results of the National Cancer Institute of Canada Clinical Trials Group (NCIC–CTG) MAP-3 trial, a randomized doubleblind placebo-controlled study of the aromatase inhibitor (AI) exemestane, was presented at the June 2011 meeting of the American Society of Oncology1 and was published in the New England Journal of Medicine.2 They represent good news for postmenopausal women at increased risk for developing breast cancer.
With a median follow-up of 35 months, the exemestane-treated women had a 65% (0.19% vs 0.55%; hazard ratio, 0.35; 95% confidence interval, 0.18 to 0.70; P = 0.002) reduction in the incidence of invasive breast cancer. A total of 4,560 postmenopausal women from the United States, Canada, Spain, and France entered this study between 2004 and 2010. All the women were at increased risk, which was determined based on age 60 years or older, prior breast biopsy showing atypical hyperplasia or lobular carcinoma in situ (LCIS), prior ductal carcinoma in situ (DCIS) treated by mastectomy, or a Gail model risk score of greater than 1.66% of developing breast cancer over the next 5 years.
Concerns and barriers amid the good news
Although I have heard my colleagues express some concerns about the trial results, I find most of their issues to be relatively minor. The median follow-up is only about 3 years, and relatively few of the trial participants have completed 5 years of therapy. However, the results are highly statistically significant and are in keeping with the data in adjuvant therapy trials, where the AIs appear to have a durable benefit in reducing new primary cancers of the opposite breast. At the time of analysis, only 43 invasive breast cancers had been diagnosed— 11 in the exemestane-treated group and 32 in the placebo group.
With the estimated reduction in invasive breast cancer of 65%, again estimated from treatment trials and compared with an untreated control, it takes relatively few events to confirm the reduction in invasive breast cancer, which was the primary endpoint. The women were carefully followed and had annual mammograms. The cancers that did occur in both groups were small, early-stage tumors, making a survival benefit almost impossible to document; however, the study was not designed to demonstrate such a finding.
In addition, the treatment assignments were unblinded, the women were informed of their current treatment, and the placebo group was offered the opportunity to cross over to exemestane. These actions make follow-up analyses less meaningful, but the study officials should be applauded for this approach. Although individuals enter trials such as MAP- 3 with the hope that it will benefit them, they understand that if new information concerning their care options becomes available, they will be informed.
There will be barriers to the routine use of exemestane for risk reduction. First, it has not yet been approved for this use by the US Food and Drug Administration, so insurance coverage may not apply. The drug is scheduled to become available generically in the near future, but it currently costs $300-plus per month.
Second, AIs reduce estrogen levels in postmenopausal women to almost zero; that is an effective way to treat and now prevent breast cancer. However, AIs are associated with potential side effects and toxicities, which can be a barrier to their use. Use of AIs can reduce bone density and may result in bone fractures. In MAP-3, bone density measures were obtained at study entry but not routinely during the trial. During treatment, reports of a diagnosis of osteoporosis were balanced in both groups, and fracture rates were similar. Here, the short follow-up and patient selection may have been factors. With prolonged use of AIs, the bone loss can be cumulative. The development of osteoporosis in women who start with normal bone density is low, but for women who already have lowbone mass, other prevention options may be a better first choice. Following AI-treated women with periodic bone density studies and the use of bisphosphonates to blunt the bone impact is an additional approach but further adds to the cost of treatment.
Third, the biggest problem with exemestane may be that to obtain the 65% risk reduction, the drug must be taken on a daily basis. Among the most common side effects of the AIs are troubling arthralgias and myalgias; these problems are the most common reason for women discontinuing AIs during the treatment of breast cancer, and in MAP-3, almost one-third of the exemestane-treated women had stopped taking their medication. That fact does not impact the trial results, which achieved the risk reduction despite the drop-offs, but for those women who stop their medication early, it is unlikely they will achieve substantial risk reduction. In addition, medication adherence within trials is often better than in the real world, due to patients volunteering and being committed to the trial plus the trial investigators monitoring and encouraging adherence. Similar adherence rates can be achieved outside research studies, but they require effort and reinforcement at each follow-up visit.
Patients with DCIS
Participants with a history of DCIS treated by mastectomy were eligible for MAP-3 and appear to have a risk reduction benefit similar in magnitude to other trial participants. However, it would be premature to begin to use exemestane in the adjuvant treatment of patients with receptor-positive DCIS. That step should await the results of two adjuvant AI trials in DCIS that have completed accrual—IBIS II (International Breast Cancer Intervention Study) and NSABP (National Surgical Adjuvant Breast and Bowel Project) B-35—both of which compare anastrozole with tamoxifen in patients with receptor-positive DCIS treated by lumpectomy. Exemestane did reduce the number of cases of DCIS that were diagnosed, although that reduction did not reach statistical significance. However, given the overall sample size and the median follow-up, the lack of significance is not surprising and is unlikely to be clinically important.
Overall, the MAP-3 results are impressive and demonstrate that exemestane should be included with tamoxifen and raloxifene as an effective option for breast cancer prevention.
References
1. Goss PE, Ingle JN, Ales-Martinez J, et al. Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—a randomized, placebo-controlled clinical trial. J Clin Oncol 2011;29:LBA504.
2. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381–2391.
WHAT'S NEW, WHAT'S IMPORTANT
Jame Abraham, MD, Editor
Breast cancer is the most common cancer in women. The National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 studies both showed that selective inhibition of estrogen receptors with such drugs as tamoxifen or raloxifene (Evista) can decrease the incidence of breast cancer by about 50% in women who are at high risk of developing breast cancer based on the Gail risk model. Several studies in postmenopausal patients have shown that aromatase inhibitors are effective agents for the treatment of breast cancer when used in the metastatic, neoadjuvant, or adjuvant setting. The study by Paul Goss and colleagues described here has shown, for the first time, that exemestane, a steroidal aromatize inhibitor, can decrease the incidence of breast cancer by 65% in high-risk, postmenopausal patients.
So what do we tell our patients? In postmenopausal women who are at high risk of developing breast cancer, per the Gail risk criteria, we now have three drugs available: tamoxifen, raloxifene, and exemestane. When we consider any preventive intervention, we need to look at both the risk and the benefit expected. Because the median followup in the Goss study was only 3 years, the long-term side effects of exemestane are not well established in this setting.