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

Abstract

Background Toxicity from neoadjuvant chemoradiation therapy (NT) increases morbidity and limits therapeutic efficacy in patients with rectal cancer. Our objective was to determine whether specific polymorphisms in genes associated with rectal cancer response to NT correlate with NT-related toxicity. Methods One hundred thirty-two patients with locally advanced rectal cancer were treated with NT followed by surgery. All patients received 5-fluorouracil (5-FU) and radiation (RT), and 80 patients also received modified FOLFOX-6 (mFOLFOX-6) chemotherapy. Grade ≥3 adverse events (AEs) that occurred during 5-FU/RT and 5-FU/RT+mFOLFOX-6 were recorded. Pretreatment biopsies and normal rectal tissue were collected from all patients. DNA was extracted and screened for 22 polymorphisms in 17 genes associated with response to NT. Polymorphisms were correlated with treatment-related Grade ≥3 AEs. Results Overall 27 of 132 (20%) patients had Grade ≥3 AEs; 24 of 132 (18%) patients had Grade ≥3 AEs during 5-FU/RT, 9 of 80 (11%) patients had Grade ≥3 AEs during mFOLFOX-6, and 6 (5%) patients had Grade ≥3 AEs during both 5-FU/RT and mFOLFOX-6. Polymorphisms in XRCC1, XPD, and TP53 were associated with Grade ≥3 AEs during NT (p<0.05). Specifically, the XRCC1 Q399R and XPD K751Q polymorphisms were associated with increased toxicity to 5-FU/RT (p<0.05), and the TP53 R72P polymorphism was associated with increased toxicity to mFOLFOX-6 (p=0.008). Conclusion Specific polymorphisms in XRCC1, XPD, and TP53 are associated with increased toxicity to NT in rectal cancer. Polymorphism screening may help tailor treatment for patients by selecting therapies with the lowest risk of toxicity thus increasing patient compliance.

Single Nucleotide Polymorphism TGFβ1 R25P Correlates with Acute Toxicity during Neoadjuvant Chemoradiotherapy in Rectal Cancer Patients

“…The previously reported association of toxicity with the SNPs of interest was based on an autosomal dominant mode of inheritance, comparing patients with 1 or 2 minor alleles with those with none (7, 8). Therefore, our analysis was performed in the same fashion.…”

“…The DNA was of good quality, as assessed by spectrophotometry. The SNPs XRCC1 R399Q (rs25487), XPD K751Q (rs13181), and TGFβ1 R25P (rs1800471), identified in previous studies (7, 8), were assessed using iPLEX SNP Genotyping with the MassArray platform (Sequenom, San Diego, CA).…”

“…Our group and others have investigated the association of SNPs with acute CRT-induced toxicity in rectal cancer patients in an attempt to identify factors that diminish the full efficacy of neoadjuvant treatment and adversely affect patient quality of life (7, 8). Previously, our group screened 132 rectal cancer patients for 22 SNPs in 17 genes.…”

“…Of the 22 SNPs, 2 were correlated with toxicity during CRT that was grade ≥3 ( P <.05), according to the Common Terminology Criteria for Adverse Events (CTCAE). These 2 SNPs were an arginine-to-glutamine substitution at codon 399 (Q399R) in XRCC1 and a lysine-to-glutamine substitution at codon 751 (K751Q) in XPD (7). Additionally, another group of researchers screened 163 rectal cancer patients for 9 SNPs in TGFβ1 .…”

AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin

“…The T allele has been strongly associated with toxicity in locally advanced rectal cancer patients treated with 5-Fu and radiotherapy. 49 It has also been associated with an increased risk of severe gastrointestinal toxicity in lung cancer patients treated with cisplatin-based chemotherapy, 50 and CRC patients with the C/C genotype experienced less neurotoxicity after adjuvant oxaliplatin. 20 Lee et al 20 further showed that the onset of neurotoxicity was significantly later for patients with the C/C genotype.…”