Abstract
PurposeThere has been growing interest in using chemoradiation (CRT) for non-operative management of rectal cancer, and identifying patients who might benefit most from this approach is crucial. This study identified miRNAs (miRs) associated with clinical outcomes and treatment resistance by evaluating both pre- and post-CRT expression profiles.MethodsForty patients, 9 with pathologic complete response (pCR) and 31 with pathologic incomplete response (pIR) were included. MicroRNA was extracted from 40 pre-therapy tumor samples and 31 post-chemoradiation surgical samples with pathologic incomplete response (pIR). A generalized linear model was used to identify miRs associated with pCR. A linear mixed effects model was used to identify miRs differentially expressed before and after treatment. miR expression was dichotomized at the mean and clinical outcomes were evaluated using Cox proportional hazard modeling.ResultsNine miRs were associated with pCR (p<0.05), but none were significant after false discovery rate correction. Among patients with pIR, 68 miRs were differentially expressed between the pre and post-CRT groups (FDR p<0.05). Ingenuity pathway analysis (IPA) demonstrated multiple signaling networks associated with pIR, including p38MAPK, TP53, AKT, IL-6, and RAS. Increased let-7b was correlated with increased distant metastasis (DM), worse relapse-free survival (RFS), and worse overall survival (OS) (p<0.05).ConclusionsNo miRs were significantly correlated with pCR. We identified miRs that were differentially expressed between pre- and post-CRT tumor samples, and these miRs implicated multiple signaling pathways that may confer resistance to CRT. In addition, we identified an association between increased let-7b and worse clinical outcomes (DM, DFS, OS).
Highlights
Rectal adenocarcinoma accounts for almost 1/3 of all colorectal cancer, with approximately 40,000 new cases diagnosed each year, and rectal cancer is a major cause of cancer morbidity and mortality in the United States [1].Current treatment regimens include neo-adjuvant chemoradiation followed by surgical removal for locally advanced rectal cancer (T3-4 or node positive disease) [2, 3]
Nine miRs were associated with pathologic complete response (pCR) (p
Increased let-7b was correlated with increased distant metastasis (DM), worse relapse-free survival (RFS), and worse overall survival (OS) (p
Summary
Rectal adenocarcinoma accounts for almost 1/3 of all colorectal cancer, with approximately 40,000 new cases diagnosed each year, and rectal cancer is a major cause of cancer morbidity and mortality in the United States [1].Current treatment regimens include neo-adjuvant (preoperative) chemoradiation followed by surgical removal for locally advanced rectal cancer (T3-4 or node positive disease) [2, 3]. Given that the number of pelvic recurrences after pCR are very low, there has been growing interest in finding biomarkers that may predict which patients will have a complete clinical or pathologic response to chemoradiation, or who are at decreased risk of pelvic recurrence after chemoradiation [8, 9]. While NOM is controversial, the discovery of biomarkers that reliably predict response and recurrence rates after chemoradiation offers the potential to better select patients for this strategy. This NOM approach could potentially spare patients invasive, life-changing surgeries (especially for patients requiring permanent colostomies), and improve their quality of life if the risk of pelvic recurrence is low. Surgery could be used as a salvage option for patients who do have a pelvic recurrence
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