Abstract 5546: Impact of DNA repair and apoptosis gene polymorphisms on clinical outcome in head and neck cancer patients treated with radiotherapy

Abstract Introduction: The effects of single nucleotide polymorphisms (SNPs) in DNA repair (ERCC1, ERCC2, ERCC5, XRCC1) and apoptosis genes (TP53, MDM2) on response rate, survival and toxicity were tested in a group of squamous cell head and neck cancer (SCCHN) patients receiving a radiotherapy (RT)-based treatment. Materials and Methods: A retrospective cohort of 122 locally advanced SCCHN patients non-eligible for surgery, treated by RT (N=38) or chemoRT (CRT, N=84) between 1992 and 2006 was selected. The following SNPs were analyzed on tumor DNA: ERCC1 259Lys>Thr (rs735482), ERCC2 751Lys>Gln (rs13181), ERCC5 46His C>T (rs1047768), XRCC1 399Arg>Gln (rs25487), TP53 72Arg>Pro (rs1042522) and MDM2 309T>G (rs2279744). Tumor response 6 months after treatment cessation (ORR), progression-free survival (PFS), cancer-specific survival (CSS) and RT-related toxicity (G0-2 vs G3-4 according to CTCAE v4.0) were assessed. Results: ORR was 70%. Median PFS was 15.8 months and median CSS was 33.1 months. In total, 104/114 patients (91 %) experienced RT-related G3-4 toxicity at any time. 99/122 (81 %) patients had acute side-effects (during RT), among them 46 had epithelitis. 98/116 (85%) developed an early G3-4 DMEX toxicity (dysphagia, mucocitis, epithelitis and/or xerostomia up to 3 months after end of RT). 29/95 patients (31%) developed any G3-4 late toxicity (3 months after end of RT), with skin fibrosis for 3 patients and xerostomia for 13 patients. No relationship was found between any SNPs and ORR, PFS or CSS. The presence of the G allele of MDM2 or the Thr allele of ERCC1 were associated with a higher risk of early DMEX. Focusing on each toxicity separately, MDM2 GG genotype was related to a higher risk of acute G3-4 epithelitis. The ERCC5 TT genotype was associated with more frequent G3-4 late cervical skin fibrosis or xerostomia. Conclusion: SNPs in ERCC1 and ERCC5 DNA repair genes, as well as MDM2 apoptosis gene may influence RT-induced toxicity. Genotypes and G3-4 toxicity G0-2G3-4RR (95% CI)Global pEarly DMEXMDM2 309T>GTT113110.018TG3491.28 (1.05-1.55)GG3181.16 (0.90-1.49)Early DMEXERCC1 259Lys>ThrLys/Lys166810.038Lys/Thr + Thr/Thr1311.20 (1.06-1.35)Acute EpithelitisMDM2 309T>GTT2241910.037TG40140.59 (0.33-1.03)GG10121.23 (0.74-2.05)Late Skin FibrosisERCC5 46His C>TCC280Not assessable0.012CT450TT203Late XerostomiaERCC5 46His C>TCC23510.023CT4320.25 (0.05-1.20)TT1761.46 (0.51-4.18) Citation Format: Marie-Christine Etienne-Grimaldi, Delphine Borchiellini, Laurence LLorca, Jean-Louis Formento, Patricia Formento, Yann Château, Gérard Milano. Impact of DNA repair and apoptosis gene polymorphisms on clinical outcome in head and neck cancer patients treated with radiotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5546. doi:10.1158/1538-7445.AM2014-5546