Meeting
2020 Gastrointestinal Cancers Symposium
Genetic variants involved in bromodomain-containing protein 4 (BRD4) regulating pathway to predict outcomes in patients with metastatic colorectal cancer: Results from FIRE3 and MAVERICC trials.
Authors
Jingyuan Wang
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
Jingyuan Wang , Yi Xiao , Fotios Loupakis , Sebastian Stintzing , Hiroyuki Arai , Francesca Battaglin , Shivani Soni , Wu Zhang , Christoph Mancao , Chiara Cremolini , Volker Heinemann , Alfredo Falcone , Joshua Millstein , Heinz-Josef Lenz
Organizations
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, Istituto Toscano Tumori, Pisa, Italy, Medical Department, Division of Hematology, Oncology, and Tumor Immunology (CCM), Charité Universitätsmedizin, Berlin, Germany, Chiba Cancer Center, Chibashi, Japan, Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USC Keck School of Medicine, Los Angeles, CA, F. Hoffmann-La Roche Ltd., Basel, Switzerland, Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy, University Hospital Munich, LMU Munich, Munich, Germany, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy, Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA
Research Funding
Other Foundation
National Cancer Institute (grant number P30CA014089), The Gloria Borges WunderGlo Foundation-The Wunder Project, Dhont Family Foundation, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund and Call to Cure Fund
Background: BRD4 plays an important role in transcription, DNA repair and drug resistance. High expression and polymorphisms of BRD4 regulating pathways were reported to be related to worse prognosis in colorectal cancer. Therefore, we hypothesized that genetic variants in BRD4 regulating pathway may predict first-line treatment outcome in mCRC pts. Methods: The impact on outcome of 22 SNPs in 7 genes involved in BRD4 regulating pathway (BRD4, SIPA1, MYC, 53BP1, H2AX, BATF, CD47) was analyzed through the OncoArray, a customized array manufactured by Illumina, on genomic DNA from blood samples of pts enrolled in 2 randomized trials. MAVERICC FOLFIRI/bevacizumab (bev) arm served as discovery cohort (N = 107), FIRE3 FOLFIRI/bev arm as validation (N = 107) and FOLFIRI/cetuximab (cet) arm as control (N = 129). Results: In the discovery cohort, right(R)-sided pts with BRD4 rs4808272 any G allele (N = 46) showed significantly shorter PFS (9.5 vs 18 m) compared to carriers of A/A (N = 21) in both uni- and multi-variable analysis (p < .01); R-sided pts carrying any T allele of BATF rs7161377 (N = 50) showed longer PFS (12.3 vs 6.8 m) compared to carriers of C/C (N = 14) in univariate analysis (p < .05) and had a strong trend in multivariable analysis (p = .06). These findings were all validated in R-sided pts in FIRE3 bev arm (BRD4 rs4808272, PFS 9.8 vs 18.7 m; BATF rs7161377, PFS 15.1 vs 4.2 m) in uni- (both p < .01) and multi-variable (p = .08 and p < .05 respectively) analysis. No significant association was observed in the control arm. Interestingly, pts carrying CD47 rs3206652 any C allele (N = 13) only showed significant longer PFS (9.0 vs 3.0 m, univariable p < .01 and multivariable p = .07) in the R-sided pts of FIRE3 cet cohort, but no association was observed in the bev-based treatment. Conclusions: Our study demonstrates for the first time that BRD4 and BATF polymorphisms may predict outcomes of bev-based treatment in R-sided mCRC pts; Meanwhile CD47 polymorphism could predict outcomes of cet-based treatment in R-sided mCRC pts. This finding supports a possible role of BRD4 regulating pathway in contributing to resistance to anti-VEGF/EGFR treatment.
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Abstract Details
Session Type
Poster Session
Session Title
Poster Session C: Anal and Colorectal Cancer
Track
Colorectal Cancer,Anal Cancer
Sub Track
Tumor Biology, Biomarkers, and Pathology
Citation
J Clin Oncol 38, 2020 (suppl 4; abstr 232)
Abstract #
232
Poster Bd #
L10
Abstract Disclosures
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