RTOG0617 to Externally Validate Blood Cell ERCC1/2 Genotypic Signature as a Radiosensitivity Biomarker for Both Tumor and Normal Tissue for Individualized Dose Prescription

Abstract

According to our previous finding of single Institutional data, a single nucleotide polymorphisms (SNPs) signature in DNA repair pathway genes ERCC1/ERCC2 may serve as a radiosensitivity biomarker for both tumor and normal tissue in patients with non-small cell lung cancer (NSCLC), and patients can be classified as sensitive or resistant accordingly for differential radiation dose interaction. Using patients enrolled in RTOG0617 a phase III randomized study on radiation dose, here we aimed to externally validate the above findings: i.e. patients with a sensitive genotype have better survival in the low-dose (60Gy) arm, while patients with a resistant genotype have better survival in the high-dose (74Gy) arm. Patients enrolled in RTOG0617 clinical trial with blood samples available for analysis were eligible to this study. DNA samples for genotyping were extracted from buffy-coat that were collected before commencement of treatment. A mass array system was used for genotyping. According to our previous finding, this study only analyzed rs11615 in ERCC1 and rs238406 in ERCC2 in the nucleotide excision repair (NER) pathway. Patients with CC-type in ERCC1-rs11615 and GG-type in ERCC2-rs238406 were classified as radio-resistant, and the remaining as radio-sensitive. Log rank test and Cox regression model were used for survival analysis. A total of 321 patients were eligible, with 275 of them had both ERCC1 and ERCC2 SNPs genotyped. The median follow-up was 68 (95% CI, 61-72) months. Among 163 assigned to 60 Gy arms, 67 patients carrying the resistant genotype had a median OS of 22 (16-29) months, comparing to a median OS of 31 (25-46) months for the sensitive genotype (P = 0.076, HR = 1.4 [95%CI: 0.96-2.01]). In 112 patients treated with 74 Gy, 36 patients carrying the resistant signature had a median survival of 31 (95% CI, 20-52) months, significantly better than a median OS of 20 (95% CI, 13-26) months in those carrying the sensitive signature (p = 0.025, HR = 0.59 [95% CI: 0.37-0.94]). The interaction between radio-sensitivity and RT dose group was significant (p = 0.004), suggesting that the ERCC1/2 SNP signature’s prognostic value significantly differed in 60Gy and 74Gy patients. This study of RTOG0617 phase III trial patients validated ERCC1/2 SNP signature as a radiosensitivity biomarker of both tumor and normal tissue, which explained the fact that high dose radiation decreased survival in patients treated with high dose radiation when they carry a radiation sensitive genotype in DNA repair pathway. While further prospective validation study with larger sample size may be needed, this study confirms the possibility of personalized dose prescription according to testing of genotypic signature of DNA repair pathway.