Adjuvant Chemotherapy in Premenopausal Breast Cancer Patients is Effective by Means Other than Ovarian Function Suppression

Summary

In order further to clarify the role of endocrine mechanisms mediating the effect of adjuvant systemic therapy in patients with operable breast cancer, we analysed the incidence of amenorrhoea and its association with outcome in a cohort of 1127 premenopausal women included in a randomised trial. There were 4 distinct subpopulations defined by nodal status and therapy: in a group with node-negative disease (552 patients), one course of cytotoxic drugs was compared to no adjuvant chemotherapy. In a group with metastatic nodes (575 patients), a single course of cytotoxic therapy was compared with a prolonged treatment (6 or 7 courses). Amenorrhoea was defined as having no menstrual bleeding for a 3-month interval within the first 9 months after surgery. Amenorrhoea was observed in 21% of the 199 patients with N-negative breast cancer who received no adjuvant therapy, in 31% of the 353 N-negative patients who had a single course of cytotoxic therapy and in 31% of the 188 patients with N-positive disease who had the same short-duration therapy as compared to 68% of the 387 patients who had a prolonged adjuvant therapy. Amenorrhoea was associated with a prolonged disease- free survival (DFS) only in the patients with prolonged cytotoxic therapy: 4-year DFS % (+ s.e.) was 68% + 3% vs 61% + 5%, for the amenorrhoea and the no-amenorrhoea groups, respectively (p=0.05). On the other hand, the comparison between the effects of prolonged therapy upon outcome versus the short perioperative course (the direct comparison of the trial carried out within the node- positive population) showed a much larger treatment effect. The 4-year DFS% was 66% as compared to 38% (p<0.0001).

We conclude that cytotoxic-induced amenorrhoea is associated with a better outcome, but that this effect is difficult to observe due to the non cytotoxic-induced amenorrhoea rate, which is substantial in a patient population with breast cancer. The influence of amenorrhoea upon outcome is of small magnitude and it is unlikely that the effect of cytotoxics to reduce relapse and mortality rates in premenopausal women with breast cancer is primarily due to an ovarian suppression-mediated mechanism.