Angiogenesis genotyping and clinical outcome during regorafenib treatment in metastatic colorectal cancer patients

Abstract

Regorafenib monotherapy is a potential option for metastatic colorectal cancer patients. However, the lack of predictive factors and the severe toxicities related to treatment have made its use in clinical practice challenging. Polymorphisms of VEGF and its receptor (VEGFR) genes might regulate angiogenesis and thus potentially influence outcome during anti-angiogenesis treatment such as regorafenib. Aim of our study was to evaluate the role of VEGF and VEGFR genotyping in determining clinical outcome for colorectal cancer patients receiving regorafenib. We retrospectively collected clinical data and samples (tumour or blood) of 138 metastatic colorectal cancer patients treated with regorafenib. We analysed the correlation of different VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs) with patients’ progression-free survival (PFS) and overall survival (OS). Results from angiogenesis genotyping showed that only VEGF-A rs2010963 maintained an independent correlation with PFS and OS. Among clinical factors only ECOG PS was independently correlated with OS, whereas no correlation with PFS was evident. Grouping together those results allowed further patients stratification into 3 prognostic groups: favourable, intermediate and unfavourable. VEGF-A rs2010963 genotyping may represent an important tool for a more accurate selection of optimal candidates for regorafenib therapy.

Impact of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) single nucleotide polymorphisms on outcome in gastroenteropancreatic neuroendocrine neoplasms

“…showed also a correlation with the presence of ascites in an Indian ovarian cancer patients [ 33 ]. Furthermore, our group has previously demonstrated the predictive role of rs2010963 in patients with renal cell carcinoma treated with sunitinib [ 29 ] and has also confirmed this role in patients with hepatocellular carcinoma treated with sorafenib [ 34 ] and in metastatic colorectal cancer patients treated with regorafenib [ 35 ]. Thus proving that it is an independent factor for both progression-free survival and overall survival.…”

Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study

“…Several efforts are currently ongoing to define gene signatures 6 and biomarkers of response to anti-angiogenic drug in CRC and other cancers 7 ; however, validation of these biomarkers will only determine their use in clinical practice. While recent studies using tissue 8 and plasma 9 10 have attempted to elucidate the response and resistance mechanisms to regorafenib, the search for a clinically useful biomarker has been largely unsuccessful. A growing body of preclinical evidence suggests strong anti-angiogenic and pro-apoptotic effects of regorafenib 11–14 with clinical data demonstrating that drug activity is independent of the tumour’s mutational status.…”

Clinical outcome and molecular characterisation of chemorefractory metastatic colorectal cancer patients with long-term efficacy of regorafenib treatment

“…Many parameters have been investigated, both clinical and biological, such as Eastern Cooperative Oncology Group (ECOG) performance status (PS) (ie, 0 vs 1), lactic dehydrogenase, neutrophil:lymphocyte ratio, platelet count, the rs2010963 SNP of VEGF-A, ANG-2, interleukin-6 (IL-6), IL-8, PIGF, sTie-1, sVEGFR-1, VEGF-A, VEGF-C, VEGF-D, VEGF-A-121, BMP-7, M-CSF, SDF-1, TIMP-2 and VWF without conclusive results. 7–9 …”