A polymorphism in the cachexia-associated gene INHBA predicts efficacy of regorafenib in patients with refractory metastatic colorectal cancer.

Yuji Miyamoto,Sara Lonardi,Toshiharu Yamaguchi,Chiara Cremolini,Fotios Loupakis,Beatrice Borelli,Satoshi Okazaki,Wu Zhang,Filippo Pietrantonio,Shu Cao,Yan Ning,Dongyun Yang,Satoshi Matsusaka,Martin D Berger,Heinz-Josef Lenz,Marta Schirripa,Hideo Baba,Mitsukuni Suenaga

doi:10.1371/journal.pone.0239439

Abstract

Activin/myostatin signaling has a critical role not only in cachexia but also in tumor angiogenesis. Cachexia is a frequent complication among patients with advanced cancer and heavily pretreated patients. We aimed to evaluate the prognostic significance of cachexia-associated genetic variants in refractory metastatic colorectal cancer (mCRC) patients treated with regorafenib. Associations between twelve single nucleotide polymorphisms in 8 genes (INHBA, MSTN, ALK4, TGFBR1, ALK7, ACVR2B, SMAD2, FOXO3) and clinical outcome were evaluated in mCRC patients of three cohorts: a discovery cohort of 150 patients receiving regorafenib, a validation cohort of 80 patients receiving regorafenib and a control cohort of 128 receiving TAS-102. In the discovery cohort, patients with any G variant in FOXO3 rs12212067 had a significantly lower response rate (P = 0.031) and overall survival (OS) than those with a T/T in univariate analysis (4.5 vs. 7.6 months, hazard ratio [HR] = 1.63, 95% confidence interval [CI] = 1.09-2.46, P = 0.012). Among female patients, those with any G variant in INHBA rs2237432 had a significantly longer OS than those with an A/A in both univariate (7.6 vs. 4.3 months, HR = 0.57, 95%CI = 0.34-0.95, P = 0.021) and multivariable (HR = 0.53, 95%CI = 0.29-0.94, adjusted P = 0.031) analysis. This association was confirmed in female patients of the validation cohort, though without statistical significance (P = 0.059). Conversely, female patients with any G allele in the control group receiving TAS-102 did not show a longer OS. This was the first study evaluating the associations between polymorphisms in cachexia-associated genes and outcomes in refractory mCRC patients treated with regorafenib. Further studies should be conducted to confirm these associations.

Highlights

Regorafenib is a small molecule multikinase inhibitor that blocks protein kinases involved in tumor angiogenesis, oncogenesis and the tumor microenvironment [1]
Based on the clinical importance of cachexia signaling being potentially involved in angiogenesis, we evaluated the prognostic and predictive significance of cachexia-associated genetic variants in refractory metastatic colorectal cancer (mCRC) patients treated with regorafenib chemotherapy
Our findings present the first evidence that germline variations in the cancer cachexia pathway are associated with outcome in chemorefractory mCRC patients treated with regorafenib

Summary

Introduction

Regorafenib is a small molecule multikinase inhibitor that blocks protein kinases involved in tumor angiogenesis, oncogenesis and the tumor microenvironment [1]. Several investigators have attempted to identify molecular markers that predict the activity of regorafenib for the individualized treatment of patients with mCRC. Skeletal muscle mass is dynamically regulated by various extracellular signals, which activate distinct intracellular signaling processes [11]. INHBA and MSTN are potent negative regulators of muscle mass [12]. The binding of INHBA and MSTN to membrane receptors (ACVR1B, C, and ACVR2B) leads to the activation of SMAD-mediated signal transduction, promoting muscle protein degradation [13]. We reported that germline variants within the cancer cachexia pathway are associated with outcome in mCRC patients treated with bevacizumab-based chemotherapy [18]

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