title: Medroxyprogesterone acetate addition or substitution for tamoxifen in advanced tamoxifen-resistant breast cancer: a phase III randomized trial. Australian-New Zealand Breast Cancer Trials Group.
abstract: OBJECTIVE
  To determine whether a strategy of adding medroxyprogesterone acetate (MPA) to tamoxifen (TAM) is superior to the substitution of MPA for TAM among women with advanced breast cancer and disease progressing on TAM. To assess the patterns or response and subsequent progression in sites and tissues according to prior involvement and treatment.
  
  
  METHODS
  Two-hundred-fifteen postmenopausal women with advanced breast cancer progressing on TAM after receiving TAM for at least six months were randomized: 109 to add MPA 500 mg/day orally (TAM + MPA), and 106 to stop TAM and to substitute MPA.
  
  
  RESULTS
  There were no significant differences between the groups with respect to complete plus partial response rates: TAM + MPA 10%, MPA 9%, median time to progression TAM + MPA 3.0 months, MPA 4.5 months, or median overall survival, TAM + MPA 17.2 months, MPA 18.4 months. In a multivariate model, prognostic factors significant for a shorter time to disease progression were worse for performance status, involvement of more than one tissue, prior radiotherapy, and shorter time from recurrence after primary therapy to randomization. Adjusting for these factors, treatment with TAM + MPA was associated with a higher relative risk for disease progression, with a hazards ratio of 1.31, but this was not significant (95% confidence interval, 0.98 to 1.74; P = .067). However, in an exploratory 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% confidence interval, 1.12 to 3.32; P = .02). There was a significant interaction, P = .04, between PR status and treatment, indicating an advantage to treatment substitution for those who have PR+ tumors. Tumor response occurred in 14% of assessed metastatic sites. Subsequent progression 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, in 50% at both old and new sites, and in 27% only at old sites. No significant differences in the patterns of response or progression were seen in the different treatment groups.
  
  
  CONCLUSIONS
  Among women with breast cancer whose disease is progressing after at least six months of treatment with TAM, there is no advantage to maintaining TAM when MPA is to be given. An overall effect of treatment on the pattern of failure at old sites or at new sites or tissues cannot be discerned.
authors.affiliation: Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Australia. mjbyrne@cyllene.uwa.edu.au
authors.forename: M J
authors.initials: MJ
authors.lastname: Byrne
authors.forename: V
authors.initials: V
authors.lastname: Gebski
authors.forename: J
authors.initials: J
authors.lastname: Forbes
authors.forename: M H
authors.initials: MH
authors.lastname: Tattersall
authors.forename: R J
authors.initials: RJ
authors.lastname: Simes
authors.forename: A S
authors.initials: AS
authors.lastname: Coates
authors.forename: J
authors.initials: J
authors.lastname: Dewar
authors.forename: M
authors.initials: M
authors.lastname: Lunn
authors.forename: C
authors.initials: C
authors.lastname: Flower
authors.forename: P G
authors.initials: PG
authors.lastname: Gill
authors.forename: J
authors.initials: J
authors.lastname: Stewart
mesh_terms: D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000627:therapeutic use*; D008875:Middle Aged; D016016:Proportional Hazards Models; D011980:Receptors, Progesterone / Q000187:drug effects; D012306:Risk; D013629:Tamoxifen / Q000627:therapeutic use*; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011980:Receptors, Progesterone; D013629:Tamoxifen; D017258:Medroxyprogesterone Acetate