Gradishar, WJ

1036 Background: Approximately 30% of human cancers have mutated Ras genes that produce proteins that remain in an active state causing uncontrolled proliferative signals. Post-translational modification of Ras include farneyslation catalyzed by FT. Tipifarnib (R115777) is an oral FTI active against human tumor cell lines and exhibiting modest single agent activity in pts with previously treated MBC. A previous phase I trial reported that CT inhibited farneyslation in peripheral blood mononuclear cells without affecting the pharmacokinetics of either agent. Objective: To evaluate objective response rate (ORR) of CT in taxane refractory MBC and to secondarily evaluate associated toxicity and progression-free survival (PFS). Methods: Pt with measurable MBC, previously treated (rx) with an anthracycline and relapse on a taxane or within 30 days (d). Study rx: T- 300 mg, po BID × 14 d plus C- 1,000 mg/m2, po BID × 14 d, followed by 7 d rest. Tumor reassessment was repeated q 3 cycles. The study was designed to detect improvement in ORR from 25% with C alone to 40% for the CT combination (90.5% power; type I error rate of 9.9%; 21 responses in 64 eligible pt needed to be promising. Results: 66/71 pt are available for primary analysis. Median age 50 yrs. Performance status: 0–1, 100%. ORR: PR-4.8% (3/62) [95% CI 0.01, 0.13], SD - 21% (13/62) [ 95% CI 0.12, 0.33]. Median survival - 10.6 months. Toxicity (%): anemia - 8(G3/4), neutropenia - 30 (G3/4), thrombocytopenia - 8 (G3/4), HFS-8 (G3), nausea/vomiting - 11(G3), diarrhea - 8 (G3), sensory neuropathy - 5 (G3). Conclusion: CT in taxane -refractory MBC has low antitumor activity without excessive toxicity. More mature data, including PFS, will be presented. No significant financial relationships to disclose.

Abstract Background: Intrinsic breast cancer subtypes determined by the PAM50 assay are reported to be prognostic independent of standard clinicopathological variables. The CALGB (Alliance) 9741 adjuvant trial randomized treatment in a 2×2 factorial design to (i) 2-wk (dose dense; DD) vs 3-wk therapy and (ii) sequential vs concurrent doxorubicin, cyclophosphamide, paclitaxel (A>T>C vs AC>T). DD therapy improved disease-free survival and overall survival (OS) (Citron et al. JCO 2003.). A significant interaction between intrinsic breast cancer subtypes and the use of DD therapy was hypothesized. Methods: C9741 was conducted in collaboration with ECOG, NCCTG, and SWOG. Biospecimens were collected from 1652 of 2005 subjects. Multiplexed gene expression profiling (NanoString Technologies, Inc) generated PAM50 subtype calls (luminal A, luminal B, HER2-enriched, basal-like), risk of relapse (ROR) score, and proliferation score for 1321 cases (80%). Excluded samples were due to insufficient tumor (n = 181) or RNA (n = 150). The primary endpoint was relapse-free survival (RFS). The primary analysis to determine if the clinical benefit of DD therapy is dependent on intrinsic subtype was conducted as a test of interaction in a Cox proportional hazards model (3 degrees of freedom, df; alpha=0.05). Similar analyses were performed for ROR score and proliferation score as continuous measures of risk (1 df). PAM50 subtype, ROR score, and proliferation score were evaluated in separate multivariate models adjusting for number of positive nodes, menopausal status, dose density, and sequence of therapy. Results: Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete dataset (HR = 1.20; 95%CI 0.99–1.44) with a median follow-up of 12.3 yrs. Subtype analysis identified 32% luminal A (n = 417), 26% luminal B (n = 341), 20% HER2-enriched (n = 267), and 22% basal-like (n = 296). Intrinsic subtypes were prognostic of RFS (p < 0.0001) irrespective of treatment assignment with HRs relative to the luminal A subgroup of 1.50 (luminal B), 1.70 (HER2-enriched) and 1.66 (basal-like). No subtype specific treatment effect on RFS was identified (p = 0.44). ROR scores (range 0–100, median 60) were also prognostic of RFS (HR = 1.12 for a 10-unit change; 95% CI 1.07–1.18; p < 0.0001), but no association with DD therapy benefit was seen (p = 0.58). Similar results were obtained for the proliferation score, for OS as a secondary endpoint, and from multivariate models with clinical covariates. Conclusion: The prognostic value of PAM50 subtype, ROR score, and proliferation score remains highly significant in patients treated with contemporary adjuvant anthracycline and taxane based chemotherapy. Intrinsic subtype did not predict for improved survival with the 2-wk DD vs 3-wk treatment schedule; we hypothesize that this is because the prognostic differences by subtype outweighed the modest but significant clinical benefit of DD chemotherapy administration for the overall population. Planned clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize systemic therapy regimens based on the expected risk of distant recurrence. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-01.