Abstract P2-09-26: Circadian Clock Genes in Primary Breast Cancer: Strong Predictors of Pathologic Response on Neoadjuvant Chemotherapy:

Abstract Background: Circadian clocks involve 15 specific genes, which control cell cycle, apoptosis, DNA repair and metabolism. Circadian disruption is associated with both an increased risk of breast cancer, and poor survival in patients (pts) with metastatic cancer (IARC#98; Innominato et al. Cancer Res 2009). Objective: to provide first evidence of clinical relevance of clock genes expression for the therapeutic sensitivity of primary breast cancer. Method: Affymetrix Hgu133plus2 microarrays data were derived from 189 primary breast cancers. All the pts had non metastatic disease and were registered in multicenter Phase II trial of neoadjuvant chemotherapy with epirubicin-cyclophosphamide (4 courses) then docetaxel ± herceptin (4 courses). In this study, negative hormonal receptor status and limited tumor size predicted for pathological complete response rate (pCR) (Pierga JY, et al Breast Cancer Res Treat. 2010).The expression data of 15 core clock genes, within the whole tumor transcriptome, were related both to tumor mitotic index (MI) and estrogen receptors (ESR1), and to chemotherapy-induced pCR. Statistical validation involved T-test statistics, with corrections for multiple testing. Results: In the tumor biopsy obtained before treatment onset, both Per2 and Cry2 expressions correlated positively with ESR1 (r≥0.43; P<0.001) and inversely with (MI (r≤−0.28; P<0.007). In addition, a positive correlation was found for Dec 1 with ESR1 (r=0.65, P<0.001). The mean expressions of Per2, Cry2 and Dec 1 before chemotherapy were lower in the 32 pts who subsequently achieved pathologic complete response (pCR) as compared to the 157 who did not (P<0.001). No other clock gene expression was significantly related to pCR. The odds ratio confirmed the decreased chance of achieving pCR with increased expression of clock genes Per2, Cry2 or Dec1. Clock gene expression and pCR Conclusion: Low expressions of three core genes in the negative loop of the molecular circadian clock strongly predicted for the induction of a pathologic complete response of primary breast cancer with neoadjuvant chemotherapy. While circadian clock disruption seems to constitute a poor prognostic factor in cancer patients, our data suggest that the downregulation of core circadian genes in tumors significantly enhances susceptibility to chemotherapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-26.