Use of the XRCC1 single nucleotide polymorphism to predict pathologic complete response to neoadjuvant chemoradiation in stage II/III rectal cancer.

Abstract

409 Background: The X-ray repair cross-complementing protein 1 (XRCC1) gene plays an important role in DNA damage repair; and the R194W and R399Q single nucleotide polymorphisms (SNPs) are associated with attenuated DNA repair activity. Our objective was to determine whether XRCC1 SNPs were associated with response to neoadjuvant chemoradiation therapy (CRT) in rectal cancer patients. Methods: We conducted a prospective multicenter phase II trial to investigate the effect of additional chemotherapy with a longer CRT-to-surgery interval on treatment response in patients with rectal cancer. Paired normal and rectal cancer tissues were prospectively collected from enrolled patients (n=110). DNA was extracted from normal rectal mucosa and analyzed for XRCC1 R194W and R399Q by polymerase chain reaction and sequencing. Each SNP was compared to response to CRT. Response to CRT was determined by a central pathologist. Results: Of the 110 patients, 25% (n=27) achieved a pathologic complete response (pCR). We examined the XRCC1 R194W SNP and observed that the allelic frequency of patients with the R/R genotype was 84% (n=92), the R/W genotype was 14% (n=16), the W/W genotype was 1% (n=2). By Fisher's Exact test, patients harboring either the R/W or W/W genotype, had a significantly higher rate of pCR compared to patients with the R/R genotype (44% vs. 21%, respectively; p=0.04). We then examined the R399Q SNP and observed that the allelic frequency of patients with the R/R genotype was 34% (n=37), the R/Q genotype was 49% (n=54), and the Q/Q genotype was 17% (n=19). In contrast, the detection of XRCC1 R399Q SNPs was not associated with pCR. Conclusions: We demonstrate that XRCC1 R194W SNP is associated with increased rate of pCR in our prospective multi-center trial. Although the detection of XRCC1 R399Q SNP is not associated with pCR, the detection of XRCC1 SNPs that predict treatment response may help identify patients who are unlikely to respond to CRT and therefore may potentially avoid treatment-associated morbidities. No significant financial relationships to disclose.