Abstract 1342: Polymorphisms in genes involved in mitophagy pathway predict clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from TRIBE and FIRE3 phase III trials
Authors: Zhang Stephanie , Millstein Joshua , Cao Shu , Battaglin Francesca , Tokunaga Ryuma , Soni Shivani , Lo Jae Ho , Ning Tricia , Zagonel Vittorina , Cremolini Chiara , Stintzing Sebastian , Loupakis Fotios , Falcone Alfredo , Heinemann Volker , Lenz Heinz-Josef 
Published: August 2019

Abstract
Background: Mitophagy is the selective degradation of mitochondria by autophagy. Recent studies are suggesting that dysregulation of mitophagy pathway contributes to neoplastic progression and drug resistance in various types of tumors, includes colorectal cancer. We hypothesized genetic variants in mitophagy pathway genes may predict clinical outcome in mCRC pts treated with bevacizumab-based chemotherapy.
Methods: Genomic DNA extracted from blood samples of pts enrolled in two independent randomized phase III trials, TRIBE and FIRE3. 16 SNPs from 4 mitopahgy pathway genes (PINK1, BNIP3, NIX and PARK2), which were selected based on frequency and function, were genotyped by PCR-based direct DNA sequencing. The associations between SNPs and clinical outcomes were analyzed using chi-square test for tumor response, and the Kaplan-Meier curves and Cox regression for PFS and OS.
Results: A total of 451 pts were included in the analysis. TRIBE FOLFIRI/bevacizumab (bev) arm served as discovery cohort (n = 215, median PFS/OS: 9.7/26.2 mo), FIRE3 FOLFIRI/bev arm as validation cohort (n = 107, mPFS/OS: 11.5/31.4 mo). In the discovery cohort, pts carrying the BNIP3 rs4450 C/C variant showed an increased tumor response rate compared to pts with any T allele (65.3% vs 50.5%, p = 0.032); this finding was consistent in overall pts in FIRE3 cohort, pts with BNIP3 rs4550 C/C genotype had increased tumor response rate compared to pts with any T allele (75% vs 53.8%, p = 0.024). Additionally, in the discovery cohort, pts with BNIP3 rs11556626 any C allele showed a longer PFS (12.7 vs 9.5 mo) and OS (49.1 vs 25.6 mo) compared to pts with A/A variant in both univariate (PFS: HR = 0.52; 95%CI 0.34-0.81; p = 0.002) (OS: HR = 0.50; 95%CI 0.31-0.81; p = 0.004) and multivariable analysis (PFS:HR =0.46; 95%CI 0.28-0.76; p=0.002) (OS:HR =0.45; 95%CI 0.27-0.76; p=0.003).
Conclusions: Our results demonstrated for the first time that mitophagy pathway gene BNIP3 polymorphism may have a predictive value in mCRC pts treated with bevacizumab based chemotherapy. This finding supports a possible role of mitophagy BNIP3 genes in contributing to resistance to antiVEGF treatment.
Citation Format: Stephanie Zhang, Joshua Millstein, Shu Cao, Francesca Battaglin, Ryuma Tokunaga, Shivani Soni, Jae Ho Lo, Tricia Ning, Vittorina Zagonel, Chiara Cremolini, Sebastian Stintzing, Fotios Loupakis, Alfredo Falcone, Volker Heinemann, Heinz-Josef Lenz. Polymorphisms in genes involved in mitophagy pathway predict clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from TRIBE and FIRE3 phase III trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1342.