Gene polymorphisms predict toxicity to neoadjuvant therapy in patients with rectal cancer.

BACKGROUND Toxicity from neoadjuvant chemoradiation therapy (NT) increases morbidity and limits therapeutic efficacy in patients with rectal cancer. The objective of this study was to determine whether specific polymorphisms in genes associated with rectal cancer response to NT were correlated with NT-related toxicity. METHODS One hundred thirty-two patients with locally advanced rectal cancer received NT followed by surgery. All patients received 5-fluorouracil (5-FU) and radiation (RT), and 80 patients also received modified infusional 5-FU, folinic acid, and oxaliplatin chemotherapy (mFOLFOX-6). Grade ≥3 adverse events (AEs) that occurred during 5-FU/RT and during combined 5-FU/RT + mFOLFOX-6 were recorded. Pretreatment biopsy specimens and normal rectal tissues were collected from all patients. DNA was extracted and screened for 22 polymorphisms in 17 genes that have been associated with response to NT. Polymorphisms were correlated with treatment-related grade ≥3 AEs. RESULTS Overall, 27 of 132 patients (20%) had grade ≥3 AEs; 18 patients had a complication associated only with 5-FU/RT, 3 patients experienced toxicity only during mFOLFOX-6, and 6 patients had grade ≥3 AEs associated with both treatments before surgery. Polymorphisms in the genes x-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), xeroderma pigmentosum group D (XPD), and tumor protein 53 (TP53) were associated with grade ≥3 AEs during NT (P < .05). Specifically, 2 polymorphisms—an arginine-to-glutamine substitution at codon 399 (Q399R) in XRCC1 and a lysine-to-glutamine substitution at codon 751 (K751Q) in XPD—were associated with increased toxicity to 5-FU/RT (P < .05), and an arginine-to-proline substitution at codon 72 (R72P) in TP53 was associated with increased toxicity to mFOLFOX-6 (P = .008). CONCLUSIONS Specific polymorphisms in XRCC1, XPD, and TP53 were associated with increased toxicity to NT in patients with rectal cancer. The current results indicated that polymorphism screening may help tailor treatment for patients by selecting therapies with the lowest risk of toxicity, thus increasing patient compliance. Cancer 2013. © 2012 American Cancer Society.