June 2021: Chemotherapy-induced ovarian failure in young women with early breast cancer

Young women (aged ≤45 years) receiving chemotherapy for early breast cancer have a high probability for ovarian failure, defined by chemotherapy-induced amenorrhea (CIA) as a surrogate. CIA is difficult to distinguish from physiologically induced amenorrhea, especially in patients whose age makes it plausible. CIA is insufficiently reliable and reproducible. This study analyzed chemotherapy-induced ovarian failure (CIOF) by assessing hormone parameters, antral follicle count (AFC) and CIA.

Blood samples of women aged ≤45 years treated with anthracycline/taxane-based chemotherapy for EBC from four neo-(adjuvant) trials (GeparSixto, GeparSepto, GAIN-2 and GENEVIEVE) were collected at baseline, at the end of treatment (EOT), and at 6, 12, 18, and 24 months after EOT. Centrally assessed estradiol (cutoff <52.2 ng/L) and follicle-stimulating hormone (cutoff >12.4IU/L) were used to define CIOF for patients with baseline premenopausal hormone levels, anti-Müllerian hormone (AMH), and AFC to assess ovarian reserve. In addition CIA, regain of premenopausal hormone levels and disease-free survival (DFS) were also evaluated.

A total of 696 patients had premenopausal hormone levels at baseline. Overall, 85.1% (592/696) experienced CIOF at EOT, and 147 of 592 had further hormone measurements after EOT. Older patients, dose-dense/dose-intensified regimen and longer treatment were associated with a higher rate of CIOF. Regained premenopausal hormone levels were detected in 32.7% (48/147) after 6 months, 57.9% (66/114) after 12 months, 83.0% (73/88) after 18 months, and 89.2% (74/83) after 24 months. After 24 months, 72.4% (21/29) of patients without CIOF and 100% (14/14) with CIOF had low AMH levels. Estimated 4-year DFS rates were 65.9% in women without CIOF compared to 84.6% in women with CIOF (HR=2.09 [95% CI 1.37-3.19]; p<0.001); in women with hormone receptor-positive breast cancer 61.8% versus 87.5% (HR=2.69 [95%CI 1.57-4.60]; p<0.001) and 68.3% in women aged <30 years compared to 92.6% in women aged ≥30 years (HR=4.87 [95% CI 1.05-22.63]; p=0.026). Each 10 IU/L increase in FSH values was associated with a reduction in the risk for a DFS event of 9% (HR10unit=0.91 [95% CI 0.87-0.96]; P<0.001). Overall survival was significantly improved only in patients with hormone-receptor-positive disease.

In conclusion, most premenopausal patients aged 45 years experience CIOF after chemotherapy for early breast cancer. After 2 years, more than 70% regained premenopausal hormone levels, but in only one-third, the ovarian reserve was not diminished. CIOF was associated with better DFS, especially in patients with hormone receptor-positive EBC or aged <30 years. The degree of ovarian suppression was linked to prognosis. This study provides new and important information useful for clinicians to counsel premenopausal patients about the risk of ovarian suppression and diminishing of ovarian reserve after chemotherapy for early breast cancer.

Furlanetto J, Marmé F, Seiler S, et al. Chemotherapy-induced ovarian failure in young women with early breast cancer: Prospective analysis of four randomised neoadjuvant/adjuvant breast cancer trials. Eur J Cancer. 2021;152:193-203.

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