PLoS ONE (Jan 2020)

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

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

DOI
https://doi.org/10.1371/journal.pone.0239439
Journal volume & issue
Vol. 15, no. 9
p. e0239439

Abstract

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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.