Relevance of sex and PER2 SNPs for predicting irinotecan tolerability in cancer patients.

Abstract

416 Background: Advances in understanding the mechanisms underlying diseases and drug responses are creating increasing opportunities to offer safer and more effective treatments to individual patients (pts). Biomarkers are needed for predicting likelihood of therapeutic safety and efficacy in each individual pt. Down-regulation of core clock gene PER2 in tumors predicted for poor survival in pts with metastatic colorectal cancer (Jacobelli. J Clin Oncol. 26: 2008 May 20 suppl; abstr 11032). Methods: A clinical data base and tissue bank involving primary tumor (T) and healthy adjacent colon mucosa (C) from 139 pts treated with circadian-shaped or standard infusion of (A)-single-agent irinotecan (63 pts) or (B) in combination with oxaliplatin and 5FU (76 pts) for previously-treated metastatic colorectal cancer was established and tissues were collected. Clinical relevance of constitutive or acquired single nucleotide polymorphisms (SNPs) for 5 metabolism (ABCB1, ABCB2, CES2, TOP1, UGT1A1) and for two PER2 SNP's (A4572G and C3968T). Results: No acquired mutation in the genes analysed was found (100% T and C concordance). The incidence of grade 3-4 toxic event of any kind was significantly lower in women as compared to men in A population(39% vs 76%, p=0.007) and in A+B population (p=0.05), independently from other factors (p=0.02) this difference is lost if you consider only B population where oxaliplatin is added (p=0.5). No SNP in metabolism genes predicted for toxicity in this cohort. Conversely, SNPs in core clock gene PER2 (1 pt with A4572G and 4 pts C3968T) were significantly associated with higher incidence of G3-4 toxicity (100% in polymorphic pts. vs 17.2% in wild type pts, p=0.01). Conclusions: Irinotecan tolerability is sex dependent and woman has significative low incidence of toxic effects. We demonstrated for the first time an association between constitutive SNPs in a core clock gene and toxicity, further supporting the relevance of the circadian timing system in chemotherapy tolerability. Moreover, our findings are in good agreement with data in mice, supporting the hypothesis that sex determines two chronotoxicity classes in patients with metastatic colorectal cancer. No significant financial relationships to disclose.