The probability of long-term amenorrhea is similarly high in all premenopausal breast cancer patients age 35 years and older who undergo chemotherapy, regardless of whether they carry a BRCA1 or BRCA2 mutation.
Age at treatment and use of tamoxifen were important predictors of chemotherapy-induced amenorrhea in a multicenter survey of 1,954 premenopausal women aged 26-47 with invasive breast cancers and BRCA1 or BRCA2 mutations. In the absence of chemotherapy, however, tamoxifen alone was not associated with the onset of long-term amenorrhea.
The findings indicate that all women are at risk of chemotherapy-induced amenorrhea and BRCA1 or BRCA2 status per se should not be an indication for referral to a fertility clinic, according to Dr. Adriana Valentini of the Women’s College Research Institute, Toronto, and her colleagues in the Hereditary Breast Cancer Clinical Study Group.
Breast cancer patients who wish to preserve fertility should be aware of the synergistic impact of chemotherapy and tamoxifen on inducing long-term amenorrhea and possibly menopause, the researchers said. The study was published online Aug. 26 in the Journal of Clinical Oncology.
The researchers compared age of amenorrhea onset after breast cancer diagnosis for women who were and were not treated with chemotherapy, alone or with tamoxifen. Chemotherapy-induced amenorrhea was defined as 2 or more years of amenorrhea, with no resumption of menses, commencing within 2 years of initiating chemotherapy (J. Clin. Oncol. 2013 Aug. 26 [doi:10.1200/JCO.2012.47.7893]).
Patients were selected from a database of 13,004 BRCA1 and BRCA2 mutation carriers and 2,451 noncarriers at one of 62 participating centers in seven countries. The women sought testing for BRCA1 and BRCA2 mutations because of a personal or family history of breast or ovarian cancer. They were diagnosed with invasive breast cancer between 26 and 47 years of age and were premenopausal at the time of diagnosis.
In total, 1,954 BRCA carriers with breast cancer were eligible; 1,506 (77%) carried a BRCA1 mutation, 436 (22%) carried a BRCA2 mutation, and 12 (0.6%) carried both mutations.
Of the 1,954 carrier patients, 1,426 received chemotherapy and 35% of them experienced long-term amenorrhea. Of the 528 women who did not receive chemotherapy, 5.3% developed long-term amenorrhea.
The study also included 167 noncarrier women with breast cancer as a comparison group; 100 of these women (59%) received chemotherapy, and 49% developed chemotherapy-induced amenorrhea.
The probabilities of chemotherapy-induced amenorrhea were 7.2% for women diagnosed at or before age 30 years, 33% for women diagnosed at age 31-44 years, and 79% for women diagnosed after age 45 years (P trend greater than or equal to .001).
Tamoxifen was give to 478 carrier patients, and 410 (86%) received both tamoxifen and chemotherapy. Their probability of induced amenorrhea was 52%, compared with 29% for those who did not receive tamoxifen (P less than or equal to .001).
The probability of chemotherapy-induced amenorrhea was significantly higher for BRCA2 carriers than for BRCA1 carriers (46.8% v 32.7%; P less than or equal to .001). By age 38 years, 50% of BRCA2 carriers were expected to experience amenorrhea after chemotherapy, compared with the age of 40 years expected for BRCA1 carriers.
Among all women who reached age 56 years, the mean age of menopause was 45.4 years for those who received chemotherapy and resumed menses, and 49 years for those who did not receive chemotherapy (P less than or equal to .001), a difference of 3.6 years.
Among women who had a BRCA1 mutation and reached age 56 years, the mean age of menopause was 45.5 years for those who received chemotherapy and 48.7 years for those who did not receive chemotherapy (P less than or equal to .001).
Among women who had a BRCA2 mutation and reached age 56 years, the mean age of menopause was 45.2 years for those who received chemotherapy and 49.9 years for those who did not receive chemotherapy (P less than or equal to .003).
The study was supported by the Canadian Breast Cancer Research Alliance, the Canadian Cancer Research Society Research Initiative, Fonds de Recherche en Sante´ du Que´ bec, and National Institutes of Health Grant No. R01 CA74415. The authors reported having no potential conflicts of interest.