Molecular and genomic predictors of response to single-agent doxorubicin (ADR) versus single-agent docetaxel (DOC) in primary breast cancer (PBC).

Abstract

502 Background: ADR and DOC improve disease-free survival (DFS) of PBC, but patients (pts) who actually obtain a benefit with either of these agents cannot be identified. Predictors of response to ADM and DOC are necessary. Methods: ER, PR, Ki-67, topoIisomerase IIα protein (topoII), tau and p27 proteins, bcl-2, EGFR, and CK 5/6 (all determined by IHC), topoIIα and her2 gen alterations (by FISH) and a genomic profiling (PAM50/claudin low classifier, using Agilent 44K microarrays) were studied as predictors of response to ADR (75mg/m2 × 4 cy) vs DOC (100mg/m2 × 4 cy) q3w in a neoadjuvant phase II study in pts with PBC (www.ClinTrials.gov, NCT 00123929). Pathological responses (PatRes) and residual cancer burden (RCB) were estimated according to Symmans et al. (J Clin Oncol 25:4414,2007). PCR+class I were considered good PatRes. Multivariable logistic regression analysis was used to determine the odds ratio to response. Results: 204 pts (104 ADR, 100 DOC) were analyzed. PatRes were 19% (ADR) vs 20% (DOC), p=1.0. In multivariate analysis, high topoII expression (but not topoII gene alterations) and ER+ status (for ADM) and ER+ status and tumor size (T) >5cm (for DOC) were associated with poorer PatRes. The odd ratios of PatRes for ADR were 10.4 (95% CI 2.0-55.1) for normal vs high topoII (p=0.006) and 4.6 (95% CI 1.4-15.3) for ER—; vs ER+ tumors (p=0.012); and for DOC 8.3 (2.25-30.73) for ER— vs ER+ tumors (p=0.001) and 13.9 (3.4-56.3) for T≤5 cm vs >5cm (p<0.001). Genomic profiles were possible in 94 pts. Basal-like tumors were selectively sensitive to DOC and resistant to ADR; no differences were seen in other subtypes. Conclusions: Normal topoIIα protein expression and ER-negative status were predictive of response to ADR, while ER-negative status and T≤5cm were predictive of response to DOC. Basal-like tumors are sensitive to DOC and resistant to ADR. Good PatRes (PCR+I) RCB (mean) Genomic subtype ADR DOC P* ADR DOC P* Luminal A 1/12 (8%) 0/5 (0%) NS 3.386 2.839 NS Luminal B 2/14 (14%) 0/11 (0%) NS 2.378 2.806 NS HER2-enriched 1/5 (20%) 2/5 (40%) NS 2.822 1.670 NS Basal 0/7 (0%) 5/9 (56%) 0.034 3.245 1.626 0.039 Claudin low 3/12 (25%) 1/5 (20%) NS 2.626 2.538 NS Normal 1/4 (25%) 2/5 (40%) NS 2.183 2.821 NS Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration University Genomics