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

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

Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments

“…In patients with colorectal and lung cancer, high circulating activin A levels were associated with cancer cachexia [144,[147][148][149], along with an independent negative prognostic impact [144] and reduced chemotherapy response [148], although in some other cancers, decreased activin-signaling was also observed [150]. In addition, based on a study by Miyamoto et al, a polymorphism in the activin A gene (INHBA) was found to predict survival in refractory metastatic colorectal cancer patients treated with regorafenib [151].…”

FOXO3 polymorphisms influence the risk and prognosis of rhabdomyosarcoma in children

“…Evidence supported that the aberrant expression or dysfunction of FOXO3 was associated with various types of cancers including RMS ( 11 – 14 ). In addition, gene polymorphism of FOXO3 has been validated to influence various human disorders including cancer, such as pancreatic cancer, colorectal cancer, active tuberculosis, polycystic ovary syndrome, and acute lymphoblastic leukemia (ALL) ( 15 – 20 ). However, the association of FOXO3 polymorphisms with childhood RMS risk and outcome has never been reported.…”

Elevated INHBA Promotes Tumor Progression of Cervical Cancer

“… 4 , 6 Furthermore, genetic variations in the INHBA gene have been found to increase the risk of developing certain types of cancer. 7 The potential of INHBA as a therapeutic target for cancer treatment has also been explored, with some promising results in preclinical studies. 8 However, there are gaps in the current knowledge regarding the precise role of INHBA in cancer development and progression, as well as its potential as a target for cancer therapy.…”