MEDROXYPROGESTERONE ACETATE ADDITION OR SUBSTITUTION FOR TAMOXIFEN INADVANCED TAMOXIFEN-RESISTANT BREAST-CANCER - A PHASE-III RANDOMIZED TRIAL

Purpose: To determine whether a strategy of adding medroxyprogesterone acetate (MPA) to tamoxifen (TAM) is superior to the substitution of M PA for TAM among women with advanced breast cancer and disease progres sing on TAM. To assess the patterns or response and subsequent progres sion in sites and tissues according to prior involvement and treatment . Patients and Methods: Two-hundred-fifteen postmenopausal women with advanced breast cancer pro gressing on TAM after receiving TAM for at least six months were randomized: 109 to add MPA 500 mg/day orally (TA M + MPA), and 106 to stop TAM and to substitute MPA. Results: There we re no significant differences between groups with respect to complete plus partial response rates: TAM + MPA 10%, MPA 9%, median time to pro gression TAM + MPA 3.0 months, MPA 4.5 months, or median overall survi val, TAM + MPA 17.2 months, MPA 18.4 months. In a multivariate model, prognostic factors significant for a shorter time to disease progressi on were worse for performance status, involvement of more than one tis sue, prior radiotherapy, and shorter time fram recurrence after primar y therapy to randomization. Adjusting for these factors, treatment wit h TAM + MPA was associated with a higher relative risk for disease pro gression, with ct hazards ratio of 1.31, but this was not significant (95% confidence interval, 0.98 to 1.74; P = .067). However, in an expl oratory analysis, the time to disease progression, among patients with progesterone receptor positive (PR+) tumors, was 6.3 months with MPA versus 2.9 months with TAM + MPA, with a hazards ratio of 1.92 (95% co nfidence interval, 1.12 to 3.32; P = .02). There was a significant int eraction, P = .04, between PR status and treatment, indicating an adva ntage to treatment substitution for those who have PR+ tumors. Tumor r esponse occurred in 14% of assessed metastatic sites. Subsequent progr ession occurred in a new tissue alone in 13% of patients, in both new and previously involved (old) tissues in 76%, and in old tissues only in 11%. In 23% of patients, progression occurred only at a new site, i n 50% at both old and new sites, and in 27% only at old sites. No sign ificant differences in the patterns of response or progression were se en in the different treatment groups. Conclusion: Among women with bre ast cancer whose disease is progressing after at least six months of t reatment with TAM, there is no advantage to maintaining TAM when MPA i s to be given. An overall effect of treatment on the pattern of failur e at old sites or at new sites or tissues cannot be discerned. (C) 199 7 by American Society of Clinical Oncology.