Impact of Taxanes, Endocrine Therapy, and Deleterious Germline BRCA Mutations on Anti-müllerian Hormone Levels in Early Breast Cancer Patients Treated With Anthracycline- and Cyclophosphamide-Based Chemotherapy

Abstract

Background: Limited evidence exists on the impact of adding a taxane, using endocrine therapy and carrying a deleterious germline BRCA mutation on ovarian reserve measured by anti-müllerian hormone (AMH) levels of young breast cancer patients receiving (neo)adjuvant cyclophosphamide- and anthracycline-based chemotherapy. Methods: This is a biomarker analysis including young (≤ 40 years) early breast cancer patients with known germline BRCA mutational status and available prospectively collected frozen plasma samples before and after chemotherapy. Chemotherapy consisted of either six cycles of FEC (5 fluorouracil 500 mg/m 2 , epirubicin 100 mg/m 2 , cyclophosphamide 500 mg/m 2 ) or three cycles of FEC followed by three cycles of docetaxel (D, 100 mg/m 2 ). Endocrine therapy consisted of tamoxifen (±GnRH agonists). AMH levels at baseline, 1 and 3 years after diagnosis were compared according to type of chemotherapy (FEC only vs. FEC-D), use of endocrine therapy (yes vs. no) and deleterious germline BRCA mutations (mutated vs. negative). Results: Out of 148 included patients, 127 (86%) received D following FEC chemotherapy, 90 (61%) underwent endocrine therapy, and 35 (24%) had deleterious germline BRCA mutations. In the whole cohort, AMH levels drastically dropped 1 year after diagnosis ( p < 0.0001) with a slight but significant recovery at 3 years ( p < 0.0001). One year after diagnosis, patients treated with FEC only had higher median AMH levels than those who received FEC-D (0.22 vs. 0.04 μg/L, p = 0.0006); no difference was observed at 3 years (0.06 and 0.18 μg/L, p = 0.47). Patients under endocrine therapy had significantly higher AMH levels than those who did not receive this treatment 1 year after diagnosis (0.12 vs. 0.02 μg/L; p = 0.008), with no difference at 3 years (0.11 and 0.20 μg/L, p = 0.22). AMH levels were similar between BRCA -mutated and BRCA -negative patients at baseline (1.94 vs. 1.66 μg/L, p = 0.53), 1 year (0.09 vs. 0.06 μg/L, p = 0.39) and 3 years (0.25 vs. 0.16 μg/L; p = 0.43) after diagnosis. Conclusions: In breast cancer patients receiving FEC chemotherapy, adding D appeared to negatively impact on their ovarian reserve in the short-term; no further detrimental effect was observed for endocrine therapy use and presence of a deleterious germline BRCA mutation.

Burning Questions in the Oncofertility Counseling of Young Breast Cancer Patients

“…Similar AMH levels at baseline (1.94 vs 1.66 µg/L, P = .53), 1 year (0.09 vs 0.06 µg/L, P = .39) and 3 years (0.25 vs 0.16 µg/L, P = .43) after diagnosis were observed between breast cancer patients with and without BRCA mutations. 14 Taken together, the available albeit limited evidence does not suggest an increased risk of treatment-induced gonadotoxicity in young patients with breast cancer carrying a BRCA mutation (Table 1). However, a potential negative impact of BRCA mutations on women's reproductive potential even before starting anticancer therapies cannot be excluded.…”

“…Similar AMH levels at baseline (1.94 vs 1.66 µg/L, P = .53), 1 year (0.09 vs 0.06 µg/L, P = .39) and 3 years (0.25 vs 0.16 µg/L, P = .43) after diagnosis were observed between breast cancer patients with and without BRCA mutations. 14 …”

“…11 More recently, the potential further negative gonadotoxic effect of adding a taxane to cyclophosphamide-and anthracycline-based chemotherapy has been reported. [12][13][14][15] The improved prognosis for breast cancer patients makes survivorship issues an area of crucial importance with an increased attention needed toward the development of potential anticancer treatment-related long-term side-effects, including gonadal failure and infertility in young patients. 16 Therefore, fertility preservation and family planning are crucial issues to be addressed in all young women of reproductive age with a newly diagnosed cancer.…”

“… 11 More recently, the potential further negative gonadotoxic effect of adding a taxane to cyclophosphamide- and anthracycline-based chemotherapy has been reported. 12 - 15 …”

Gender-specific aspects related to type of fertility preservation strategies and access to fertility care

“…Anticancer therapies may have potential detrimental effects on the gonadal function and fertility potential of young patients. [3][4][5][6][7] Treatment-induced gonadotoxicity is of concern to many young patients with newly diagnosed cancer. [8][9][10][11][12] According to the available guidelines on the topic, all patients with cancer diagnosed during their reproductive years should be provided a proper oncofertility counselling before starting anticancer treatments.…”