Abstract A01: Development and application of DNA Repair Dysregulation Score in predicting response to neoadjuvant therapy in patients with rectal cancer

Abstract

Abstract Purpose/Background: Neoadjuvant chemoradiation (nCRT) may lead to complete tumor regression in a proportion of patients and may offer the opportunity for organ-preserving strategies. Pretreatment prediction of tumor response to nCRT would allow identification of ideal candidates for this alternative treatment, avoiding the unnecessary detrimental effects of radiation for patients unlikely to develop complete response (CR). Dysregulation of DNA repair pathways is involved in several carcinogenetic processes of human cancers, including colorectal malignancies. The purpose of this study was to develop and test the performance of DNA Repair Dysregulation Score (DS) in the prediction of tumor response to neoadjuvant CRT by comparing gene expression profiles of patients with CR and incomplete response (IR) to nCRT. Methods/Interventions: 46 patients with T2-3N0-1M0 distal rectal cancer underwent pretreatment biopsy collection prior to nCRT. All patients underwent radiation and 5FU-based chemotherapy. Patients were divided in two groups: a training group composed of 25 patients (9 patients with CR and 16 patients with IR) and a validation group composed of 21 patients (8 patients CR and 13 patients with IR). We performed global gene expression analysis using RNA-seq in the training group to search for differentially expressed genes according to tumor response. To develop the DS, RNA-seq expression values in RPKM of upregulated genes among CR patients were multiplied by +1. Expression values for downregulated genes among IR patients were multiplied by -1. The sum of all expression values for all genes was used to determine individual DS for each patient. Average DS values between CR and IR were compared using Mann-Whitney test and ROC curve was used to estimate the predictive value of the score. To assess the predictive value of our DS, in an independent set of patients, we used qRT-PCR to evaluate gene expression of dysregulated DNA repair genes. Relative expression for dysregulated genes was calculated by ∆∆Ct method. Expression values for upregulated genes among CR patients were multiplied by +1 and expression values for downregulated genes among IR patients were multiplied by -1. The sum of all relative expression values for all genes was performed to determine individual score. Average DS values between CR and IR in this independent group were also compared using Mann-Whitney test and ROC curve was used to estimate the predictive value of the score. Results/Outcome: Using RNA-seq we identified 7 differentially expressed genes between CR and IR patients to develop the DS (XPA, XRCC3, ATRIP, UBE2A, NEIL2, XRCC4). The average DS value in the training group was 27 RPKM for CR and 14 for IR (p<0.001). The ROC curve resulted in an AUC of 0.94 with high sensitivity (87%) and specificity (100%) to predict response to nCRT using a cutoff of >19.5 for the prediction of response. The average DS score in the validation set was 11.5 for CR and 9.2 for IR (p<0.006). The ROC curve resulted in an AUC 0.85 with high sensitivity (62.5%) and specificity (92.3%) to predict response using a cutoff of >10.7 for the prediction or response. Conclusions: Our DS may provide accurate prediction of tumor response to nCRT and may be useful in clinical practice to optimized nCRT stratification and adopt organ-preserving strategies for selected patients. Citation Format: Leandro Jimenez, Fernanda Koyama, Jennifer DeVecchio, Mathew Kalady, Angelita Habr-Gama, Rodrigo Perez, Anamaria Camargo. Development and application of DNA Repair Dysregulation Score in predicting response to neoadjuvant therapy in patients with rectal cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A01.