Response to Klar and Adams

The optimal endocrine treatment for perimenopausal women with amenorrhea postchemotherapy is a matter of debate, as these women were excluded from most large, randomized clinical trials. In addition, ovarian function may recover causing aromatase inhibitor (AI) treatment to be ineffective.

Based on nationwide data from the Netherlands Cancer Registry, we showed that chemotherapy-treated breast cancer patients diagnosed between 45 and 50 years of age, who are at an increased risk for chemotherapy-induced amenorrhea, have an improved overall and recurrence-free survival with increasing AI treatment duration.

As pointed out by Klar and Adams (1), differences exist between guidelines regarding types of chemotherapy schedules. The National Comprehensive Cancer Network guidelines consider women with node-negative, hormone receptor-positive and HER2-negative breast cancer, with Oncotype DX breast cancer recurrence scores of 16 or higher as candidates for chemotherapy with docetaxel–cyclophosphamide (TC), among others (2). According to the Dutch guidelines, however, many of these women will not receive adjuvant chemotherapy (ie, node-negative [N0] patients with tumors that are grade 1 and 3 cm or less, grade 2 and 2 cm or less, or grade 3 and 1 cm or less) (3). Therefore, the TC schedule has never really gained popularity among Dutch oncologists, unless anthracycline-containing schedules were contraindicated. As a result, only 3 of 2295 (0.1%) women included in our study were treated according to the TC schedule. It is important to realize, however, that 71.8% (1647 of 2295) of the women included in our study had N+ disease and, as a result, would not have been candidates for the TC schedule because of its inferiority compared with an anthracycline-containing schedule in women with N+ disease (4).

A woman’s risk for chemotherapy-induced amenorrhea and subsequent ovarian function recovery postchemotherapy is determined by, among others, her age at diagnosis, baseline fertility, and chemotherapy regimen received. Comparable rates of chemotherapy-induced amenorrhea (exceeding 70%) have been observed among women aged older than 40 years at diagnosis after anthracycline-based and cyclophosphamide-methotrexate-fluorouracil schedules (5). The literature on ovarian function recovery in relation to different chemotherapy schedules, however, is sparse. Therefore, we agree with Klar and Adams (1) that a less gonadotoxic schedule, like TC, may put its recipient at an increased risk for ovarian function recovery during AI treatment. Interpretation and comparison of study results on chemotherapy-induced amenorrhea and ovarian function recovery are complicated because of the heterogeneity in patient characteristics and the multitude of definitions and assays used .

Because of the observed benefit of AI treatment in chemotherapy-treated women 45-50 years of age in the BIG 1-98 trial as well as in our study, we encourage medical oncologists to not withhold AIs merely because of the increased risk for ovarian function recovery (6). Ideally, we would be able to identify in advance which women will experience ovarian function recovery. Unfortunately, a robust and reliable biomarker is still unavailable. Until that time, we agree with Klar and Adams that all AI-treated women with chemotherapy-induced amenorrhea should be assessed for the return of menses combined with serial monitoring of gonadotropin and estradiol levels. In case of ovarian function recovery, ovarian function suppression should be added (1).

Funding

This work was supported by grants from the Netherlands Organization for Health Research and Development (Project number 836021019), A Sister’s Hope, and De Vrienden van UMC Utrecht.

Notes

Role of the funders: None of the funders had any influence on data interpretation or manuscript preparation, review, or approval.

Disclosures: SCL reports grants from ZonMw and A Sister’s Hope during the conduct of the study. SCL is an advisory board member for AstraZeneca, Cergentis, IBM, Pfizer, and Roche and received grants from AstraZeneca, Eurocept-pharmaceuticals, Genentech, Novartis, Pfizer, Roche, Tesaro, and Immunomedics. In addition, SCL received nonfinancial support from Genentech, Novartis, Roche, Tesaro and Immunomedics and other from AstraZeneca, Pfizer, Cergentis, IBM and Bayer outside of this study. In addition, SCL received institutional research grants and institutional nonfinancial support. All remaining authors have declared no conflicts of interest.

Author contributions: Conceptualization: GMHED, MH, SCL. Funding acquisition: SCL. Project administration: GMHED. Supervision: SCL. Writing—original draft: GMHED. Writing—review & editing: GMHED, KJ, MH, SCL.

Data Availability

Not applicable.