Abstract
Angiogenesis pathway genes show substantial genetic variability causing inter-individual differences in responses to anti-angiogenic drugs. We examined 20 single nucleotide polymorphisms (SNPs) in 13 of these genes to predict tumour response and clinical outcome measured as progression free survival (PFS) and overall survival (OS) in 57 patients with metastatic colorectal cancer (mCRC) given bevacizumab plus chemotherapy. SNPs were detected (iPLEX® Assay) in genomic DNA extracted from formalin-fixed paraffin-embedded tumour specimens. The variant allele CD39 rs11188513 was associated with a good tumour response (p = 0.024). Patients homozygous for the wild-type allele FGF2 rs1960669 showed a median PFS of 10.95 months versus 5.44 months for those with at least one variant allele-A (HR 3.30; 95% CI: 1.52–7.14; p = 0.001). Patients homozygous for wild-type MMP9 rs2236416 and rs2274755 showed a median PFS of 9.48 months versus 6 and 6.62 months, respectively, for those with at least one variant allele (p = 0.022, p = 0.043, respectively). OS was also lengthened to 30.92 months (p = 0.034) in carriers of wild-type ANGPT1 rs2445365 versus 22.07 months for those carrying at least one variant allele-A. These gene variants were able to predict clinical outcome and tumour response in mCRC patients given bevacizumab-based therapy.
Highlights
Colorectal cancer (CRC) is the fourth most common cancer and the fifth leading cause of cancer death worldwide, with an estimated 1.85 million new cases and 861,663 deaths recorded in 2018 [1]
We examined whether several single-nucleotide polymorphisms (SNPs) in the major vascular endothelial growth factor (VEGF)-dependent and independent angiogenic pathway genes A2BR, ANGPT1, ANGPT-2, CCL5, CD39, EDN1, FGF2, IGF1, MKNK1, MMP9, NT5E, TOP1 and VEGF-A could correlate with treatment efficacy and clinical outcomes in metastatic colorectal cancer (mCRC) patients receiving BVZ in combination with CT
Following CT+BVZ, several studies have shown increases in the response rate, progression-free survival and overall survival in patients with mCRC compared to patients not treated with BVZ [7,8,9,11,12] and a significantly improved pathologic complete response (pCR) in breast cancer patients [24]
Summary
Colorectal cancer (CRC) is the fourth most common cancer and the fifth leading cause of cancer death worldwide, with an estimated 1.85 million new cases and 861,663 deaths recorded in 2018 [1]. Metastasis is the most lethal characteristic of CRC and accounts for 90% of all deaths registered in colon cancer patients [2]. Metastatic CRC (mCRC) is a complex disease that is largely influenced by lifestyle and dietary factors, and is linked to socioeconomic status. The management of this disease requires new-age practices in a predictive, preventive, and personalized medicine (PPPM) approach [1]. Recent studies have suggested that inter-individual genetic variations may significantly affect an individual’s predisposition to and risk of developing mCRC [3]. There is increasing evidence that single nucleotide polymorphisms (SNPs) may be used
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