Single Mutations And Mutated Gene Families As Predictors Of Response To Neoadjuvant Chemoradiation In Locally Advanced Rectal Cancer

Abstract

Neoadjuvant chemoradiation (CRT) followed by surgical resection is the standard of care for patients with locally advanced rectal cancer (LARC), but as many as 30% of patients respond poorly to treatment. We sought to determine if tumor mutations in LARC were predictors of patient response to neoadjuvant CRT. Tumor mutations were considered both singly and after organizing related mutations into functionally-defined gene families. Thirty-nine patients with T3-4NanyM0 or TanyN1-2M0 LARC were enrolled in this IRB-approved prospective study. All patients underwent staging via endorectal ultrasound (EUS) and/or pelvic MRI. Patients received 5-6 weeks of CRT consisting of 5-fluorouracil/capecitabine with concomitant external beam radiation. Patient response to treatment was considered complete if either a complete clinical response (CCR) or a pathological complete response (PCR) was attained. Patient response to treatment was considered poor if little or no tumor destruction was observed in a surgical specimen. Tissue obtained from EUS was analyzed with targeted genomic sequencing. Mutated genes present in 5 or more patients were then categorized into 7 functionally-defined families as follows: 1) cytokines and growth factors, 2) transcription factors, 3) cell differentiation markers, 4) protein kinases, 5) translocated cancer genes, 6) oncogenes, and 7) tumor suppressors. Five patients were excluded from analysis because they died, discontinued treatment or were lost to follow-up. The median age at diagnosis for the remaining 34 patients was 57 (26-81). Seven patients (20.5%) had a complete response to CRT (2 with CCR, 5 with PCR), and 5 patients (15%) had a poor response. Twenty-five mutated genes were identified in at least 5 patients, including most commonly APC (n = 31), TP53 (n = 29), and ZNF217 (n = 14). Neither the mean number of mutations nor any of the 25 mutated genes considered singly predicted the likelihood of a complete or a poor treatment response. Of the 25 mutated genes identified, 17 could be classified into one of 7 functionally-defined gene families. The group of transcription factors composed of 5 related mutated genes (ARID1B, CIC, KMT2D, TP53, ZNF217) predicted a poor response to CRT (p = 0.002). Twenty-five frequently mutated genes were identified in patients undergoing neoadjuvant CRT for LARC. Neither a complete response (20.5% of patients) nor a poor response (15% of patients) was predicted by any single gene mutation or by the total number of mutated genes. The gene family of transcription factors composed of 5 mutated genes was found to predict a poor response to neoadjuvant CRT. Data such as these may allow identification of poorly responding tumors prior to treatment, thereby increasing the response rate to neoadjuvant CRT in select patients.