A Nine-Gene Signature for Predicting the Response to Preoperative Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer.

In Ja Park,Chang Min Kim,Jin Young Park,Bilal Mustafa,Yong Bae Seo,Luigi Buonaguro,Gun-Do Kim,Jinpyo Kim,Yun Suk Yu,Hyun Deok Noh,Sung-Min Ahn,Adnan Ahmad Ansari,Seung-Mo Hong,Chang-Sik Yu,Mi-Ju Kim,Yeon Wook Kim

doi:10.3390/cancers12040800

Abstract

Preoperative chemoradiotherapy (PCRT) and subsequent surgery is the standard multimodal treatment for locally advanced rectal cancer (LARC), albeit PCRT response varies among the individuals. This creates a dire necessity to identify a predictive model to forecast treatment response outcomes and identify patients who would benefit from PCRT. In this study, we performed a gene expression study using formalin-fixed paraffin-embedded (FFPE) tumor biopsy samples from 156 LARC patients (training cohort n = 60; validation cohort n = 96); we identified the nine-gene signature (FGFR3, GNA11, H3F3A, IL12A, IL1R1, IL2RB, NKD1, SGK2, and SPRY2) that distinctively differentiated responders from non-responders in the training cohort (accuracy = 86.9%, specificity = 84.8%, sensitivity = 81.5%) as well as in an independent validation cohort (accuracy = 81.0%, specificity = 79.4%, sensitivity = 82.3%). The signature was independent of all pathological and clinical features and was robust in predicting PCRT response. It is readily applicable to the clinical setting using FFPE samples and Food and Drug Administration (FDA) approved hardware and reagents. Predicting the response to PCRT may aid in tailored therapies for respective responders to PCRT and improve the oncologic outcomes for LARC patients.

Highlights

Advanced rectal cancer (LARC) is described as an invasive rectal tumor with unresectable margins involving the mesorectal fascia and clinically suspicious lymph nodes [1,2]
78%, 86% and 83% respectively, Zuo et al described the gene combination based on RNA sequencing, showing lower performances in Area under the curve (AUC) of three-year and five-year survival rates, which were 0.711 and 0.683 respectively, Palma et al reported the genetic signature based on qRT-PCR, showing lower performance in sensitivity, specificity and accuracy which were 60%, 100% and 85% respectively; (2) gene expression analysis was performed using formalin-fixed paraffin-embedded (FFPE) samples and Food and Drug Administration (FDA)-approved hardware and reagents; and (3) the nine-gene signature was validated in larger cohorts than those used in previous studies [23,24,25]
We developed a nine-gene signature using DEG analysis, followed by k-fold cross validation and logistic regression models that robustly predicted the response to Preoperative chemoradiotherapy (PCRT) in patients with

Summary

Introduction

Advanced rectal cancer (LARC) is described as an invasive rectal tumor with unresectable margins involving the mesorectal fascia and clinically suspicious lymph nodes (lateral pelvic lymph nodes) [1,2]. PCRT is associated with two adverse effects in non-responders: (1) radiation therapy is associated with long-term complications that affect the quality of life of patients; and (2) delayed surgical resection due to PCRT may lead to local and distant tumor spread [17,18]. These outcomes have prompted extensive efforts to develop biomarkers for predicting the response to PCRT in LARC patients, which would enable the selection of responders who would benefit from PCRT [19]

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Conclusion