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 Jul:152:193-203. doi: 10.1016/j.ejca.2021.04.038. Epub 2021 Jun 8.

Abstract

Background: Young women receiving chemotherapy for early breast cancer (EBC) have a high probability for ovarian failure, defined by chemotherapy-induced amenorrhea (CIA) as a surrogate. CIA is insufficiently reliable and reproducible. We analysed chemotherapy-induced ovarian failure (CIOF) by assessing hormone parameters, CIA, and antral follicle count (AFC).

Methods: Blood samples of women aged ≤45 years treated with anthracycline/taxane-based chemotherapy for EBC from four neoadjuvant/adjuvant trials were collected at baseline, at the end of treatment (EOT), and at 6, 12, 18, and 24 months after EOT. Centrally assessed oestradiol (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. Further analyses included CIA, regain of premenopausal hormone levels, and disease-free survival (DFS) also in subgroups.

Results: Six hundred ninety-six patients aged ≤45 years 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. Of those, 32.7% (48/147) regained premenopausal hormone levels after 6 months, 57.9% (66/114) regained premenopausal hormone levels after 12 months, 83.0% (73/88) regained premenopausal hormone levels after 18 months, and 89.2% (74/83) regained premenopausal hormone levels after 24 months. After 24 months, 72.4% (21/29) of patients without CIOF and 100% (14/14) with CIOF had low AMH levels. Four-year DFS without CIOF versus CIOF was 65.9% versus 84.6% (hazard ratio [HR] = 2.09, 95% confidence interval [CI]: 1.37-3.19; P < 0.001); in hormone receptor positive 61.8% versus 87.5% (HR = 2.69, 95% CI: 1.57-4.60; P < 0.001); in <30 years 68.3% versus 92.6% (HR = 4.87, 95% CI: 1.05-22.63; P = 0.026).

Conclusion: Most premenopausal women experienced CIOF after chemotherapy for EBC. After 2 years, nearly all regain premenopausal hormone levels. CIOF was associated with better DFS, especially in patients with hormone receptor-positive EBC or aged <30 years.

Keywords: Chemotherapy-induced amenorrhea; Chemotherapy-induced ovarian failure; Early breast cancer; Ovarian reserve; Young women.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Breast Neoplasms / blood
  • Breast Neoplasms / mortality
  • Breast Neoplasms / therapy*
  • Chemotherapy, Adjuvant / adverse effects
  • Chemotherapy, Adjuvant / methods
  • Disease-Free Survival
  • Female
  • Follicle Stimulating Hormone / blood
  • Humans
  • Middle Aged
  • Neoadjuvant Therapy / adverse effects*
  • Neoadjuvant Therapy / methods
  • Premenopause / blood
  • Premenopause / drug effects
  • Primary Ovarian Insufficiency / blood
  • Primary Ovarian Insufficiency / chemically induced
  • Primary Ovarian Insufficiency / epidemiology*
  • Randomized Controlled Trials as Topic
  • Risk Assessment / statistics & numerical data
  • Risk Factors
  • Young Adult

Substances

  • Follicle Stimulating Hormone