AMPK variant, a candidate of novel predictor for chemotherapy in metastatic colorectal cancer: A meta-analysis using TRIBE, MAVERICC and FIRE3.

Tokunaga, Ryuma; Cao, Shu; Naseem, Madiha; Battaglin, Francesca; Lo, Jae Ho; Arai, Hiroyuki; Loupakis, Fotios; Stintzing, Sebastian; Puccini, Alberto; Berger, Martin D.; Soni, Shivani; Zhang, Wu; Mancao, Christoph; Salhia, Bodour; Mumenthaler, Shannon M; Weisenberger, Daniel J; Liang, Gangning; Cremolini, Chiara; Heinemann, Volker; Falcone, Alfredo; ... (2019). AMPK variant, a candidate of novel predictor for chemotherapy in metastatic colorectal cancer: A meta-analysis using TRIBE, MAVERICC and FIRE3. International journal of cancer, 145(8), pp. 2082-2090. Wiley-Blackwell 10.1002/ijc.32261

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AMP-activated protein kinase (AMPK) is a key sensor of energy homeostasis and regulates cell metabolism, proliferation and chemotherapy/radiotherapy sensitivities. This study aimed to explore the relationship between the AMPK pathway-related single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with metastatic colorectal cancer (mCRC). We analyzed a total of 884 patients with mCRC enrolled in three randomized clinical trials (TRIBE, MAVERICC and FIRE-3: where patients were treated with FOLFIRI, mFOLFOX6 or FOLFOXIRI combined with bevacizumab or cetuximab as the first-line chemotherapy). The association between AMPK pathway-related SNPs and clinical outcomes was analyzed across the six treatment cohorts, using a meta-analysis approach. Our meta-analysis showed that AMPK pathway had significant associations with progression-free survival (PFS; p < 0.001) and overall survival (OS; p < 0.001), but not with tumor response (TR; p = 0.220): PRKAA1 rs13361707 was significantly associated with favorable PFS (log HR = -0.219, SE = 0.073, p = 0.003), as well as PRKAA1 rs10074991 (log HR = -0.215, SE = 0.073, p = 0.003), and there were suggestive associations of PRKAG1 rs1138908 with unfavorable OS (log HR = 0.170, SE = 0.083, p = 0.041), and of UBE2O rs3803739 with unfavorable PFS (log HR = 0.137, SE = 0.068, p = 0.042) and OS (log HR = 0.210, SE = 0.077, p = 0.006), although these results were not significant after false discovery rate adjustment. AMPK pathway-related SNPs may be predictors for chemotherapy in mCRC. Upon validation, our findings would provide novel insight for selecting treatment strategies.

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