Ruth M. O’Regan, MD
While age remains a major risk factor for breast cancer, with nearly 80% of new cases occurring in women aged 50 years and older, women diagnosed at a younger age generally have poorer outcomes. This is partly because premenopausal women are more likely to have triple-negative breast cancer, which tends to be more aggressive than other types, but some studies have also shown that younger women with estrogen receptor–positive cancers “do worse than patients who are older,” Ruth M. O’Regan, MD, reported at the 19th Annual Lynn Sage Breast Cancer Symposium.1 Dr. O’Regan is Professor and Division Chief, Hematology and Medical Oncology, University of Wisconsin, Madison.
Focus on Endocrine Therapy
Triple-negative breast cancer is generally treated the same for younger and older patients, Dr. O’Regan said, and that is also true for HER2-positive breast cancer. “What can we do differently for premenopausal patients as opposed to postmenopausal patients? It really comes down to hormone receptor–positive breast cancer,” Dr. O’Regan said. “The focus really has to be on endocrine therapy recommendations, which differ based on menopausal status.”
A meta-analysis of premenopausal women who received ovarian function suppression to prevent chemotherapy-induced premature ovarian failure showed that patients who had ovarian suppression were less likely to have ovarian failure compared to patients who did not and were more likely to be able to get pregnant, she said.2
Ovarian suppression was not shown to negatively affect outcome. One study “showed that it actually may be beneficial in improving disease-free survival,” Dr. O’Regan said. In the Prevention of Early Menopause Study (POEMS) study, patients with estrogen receptor–negative breast cancer randomized to standard chemotherapy with the gonadotropin-releasing hormone (GnRH) agonist goserelin (Zoladex) had significant improvement in 4-year disease-free survival—89% vs 78% for those receiving chemotherapy alone.3
“Overall, the message here is this therapy seems to be safe. I think it is a reasonable option for patients with estrogen receptor–negative and estrogen receptor–positive breast cancers if they want to maintain fertility,” Dr. O’Regan said.
Improving outcomes for premenopausal women with hormone receptor–positive early-stage breast cancer “is a somewhat controversial area,” Dr. O’Regan noted. A combined analysis looked at two pivotal trials—the Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT)—both involving premenopausal women with hormone receptor–positive early breast cancer.4 In TEXT, women received the GnRH agonist triptorelin (Trelstar) and either exemestane or tamoxifen for 5 years. Chemotherapy was optional. In SOFT, women who remained premenopausal 6 months after chemotherapy or for whom -tamoxifen alone was considered suitable treatment received tamoxifen alone or ovarian function suppression with either -tamoxifen or exemestane for 5 years. Most recurrences occurred in women previously treated with chemotherapy.5
Adjuvant treatment with exemestane plus ovarian suppression had a profound impact on freedom from breast cancer and distant recurrence in patients who received chemotherapy but not in those who did not.
Ovarian suppression is associated with menopausal symptoms. These toxicities “unfortunately can lead to lack of adherence,” Dr. O’Regan said, and nearly 20% of the women in these trials who were under age 35 stopped endocrine therapy.6
Guidelines for Ovarian Function Suppression
Given these toxicities with ovarian function suppression, “We need a better way for working out which patients need this approach.” For patients under age 35, “there was a clear benefit, certainly for exemestane plus ovarian suppression, but also for tamoxifen plus ovarian suppression.”
According to the National Comprehensive Cancer Network’s NCCN Guidelines® for the addition of ovarian function suppression: “A balanced discussion of the risks and benefits associated with ovarian suppression is critical. Aromatase inhibitor or tamoxifen for 5 years plus ovarian suppression should be considered, based on the SOFT and TEXT clinical trial outcomes for premenopausal women with higher-risk cancers.”
Dr. O’Regan commented: “In the molecular era, this definition of high risk seems rather empiric. We need more robust biomarkers to help us make these decisions.”
Search for Biomarkers
Some “interesting analyses” have been done with SOFT and TEXT data to try to find surrogate markers, Dr. O’Regan noted. One analysis looking at progesterone receptor expression found that patients with low levels of progesterone receptor expression who received chemotherapy had a clear benefit from exemestane plus ovarian suppression. “As the progesterone receptor levels started increasing, however, there was not much difference between the arms in the trial,” she said. An analysis looking at Ki67 as a surrogate marker found the benefit of ovarian function suppression restricted to patients with high levels of Ki67 who received chemotherapy.
Although “premenopausal patients with high-risk breast cancers do better with a more intense endocrine therapy, we are not quite sure how to define high risk,” Dr. O’Regan remarked. ■
DISCLOSURE: Dr. O’Regan has received research support from and is an advisor for Pfizer.
1. O’Regan RM: Adjuvant considerations in premenopausal women. 2017 Lynn Sage Breast Cancer Symposium. Presented September 14, 2017.
2. Lambertini M, et al: Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients. Ann Oncol 26:2408-2419, 2015.
3. Moore HCF, et al: Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med 372:923-932, 2015.
4. Pagani W, et al: Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 371:107-118, 2014.
5. Francis PA, et al: Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 372:436-446, 2015.
6. Saha P, et al: Treatment efficacy, adherence, and quality of life among women younger than 35 years in the International Breast Cancer Study Group TEXT and SOFT adjuvant endocrine therapy trials. J Clin Oncol 35:3113-3122, 2017.