Age of Menopause Among Women Who Remain Premenopausal Following Treatment for Early Breast Cancer: Long-Term Results From International Breast Cancer Study Group Trials V and VI

Eur J Cancer. 2007 Jul;43(11):1646-53. doi: 10.1016/j.ejca.2007.04.006. Epub 2007 May 18.


Background: The likelihood of premature menopause has not been thoroughly explored in women who remain premenopausal after adjuvant chemotherapy for breast cancer.

Methods: We used data from the International Breast Cancer Study Group (IBCSG) Trials V and VI. Trial V enrolled 1407 eligible premenopausal women randomised to no systemic therapy (No CT) or 1 cycle of perioperative CMF-based chemotherapy (PeCT) if node negative, and 6 cycles of CMF-based chemotherapy postoperatively (CMFx6) or 1 cycle perioperative CMF-based chemotherapy plus CMFx6 postoperatively (CMFx7) if node positive. From Trial VI (a 2x2 factorial designed study of 3 versus 6 initial cycles of CMF and a reintroduction of three additional courses of CMF), we included 375 women randomised to receive only six initial cycles of CMF (CMFx6).

Findings: We excluded women who reported no menses during 12-24 months after randomisation (N=934), hysterectomy (N=16) or bilateral oophorectomy (N=8), or missing menses data (N=57), creating a cohort of 767 women; 540 women had been randomised to PeCT or no CT, 227 randomised to CMFx6 or 7. A Cox proportional hazards model revealed that CMFx6 or 7 (HR=2.03, p<0.0001) and temporary amenorrhea (HR=1.96, p<0.0001) were associated with premature menopause.

Interpretation: Women who remain premenopausal after 6 or 7 cycles of CMF-based chemotherapy have a higher likelihood of going through menopause at an earlier age than women who received little or no chemotherapy. Temporary cessation of menses appears to be a marker for earlier onset of menopause. These findings may assist women and clinicians when making treatment and reproductive decisions after a diagnosis of breast cancer.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Amenorrhea / chemically induced*
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Breast Neoplasms / drug therapy*
  • Cohort Studies
  • Cyclophosphamide / administration & dosage
  • Female
  • Fluorouracil / administration & dosage
  • Humans
  • Menopause / drug effects*
  • Methotrexate / administration & dosage
  • Middle Aged
  • Proportional Hazards Models


  • Cyclophosphamide
  • Fluorouracil
  • Methotrexate

Supplementary concepts

  • CMF regimen