VEGF-A, VEGFR1 and VEGFR2 single nucleotide polymorphisms and outcomes from the AGITG MAX trial of capecitabine, bevacizumab and mitomycin C in metastatic colorectal cancer.

Abstract

The phase III MAX clinical trial randomised patients with metastatic colorectal cancer (mCRC) to receive first-line capecitabine chemotherapy alone or in combination with the anti-VEGF-A antibody bevacizumab (± mitomycin C). We utilised this cohort to examine whether single nucleotide polymorphisms (SNPs) in VEGF-A, VEGFR1, and VEGFR2 are predictive of efficacy outcomes with bevacizumab or the development of hypertension. Genomic DNA extracted from archival FFPE tissue for 325 patients (69% of the MAX trial population) was used to genotype 16 candidate SNPs in VEGF-A, VEGFR1, and VEGFR2, which were analysed for associations with efficacy outcomes and hypertension. The VEGF-A rs25648 'CC' genotype was prognostic for improved PFS (HR 0.65, 95% CI 0.49 to 0.85; P = 0.002) and OS (HR 0.70, 95% CI 0.52 to 0.94; P = 0.019). The VEGF-A rs699947 'AA' genotype was prognostic for shorter PFS (HR 1.32, 95% CI 1.002 to 1.74; P = 0.048). None of the analysed SNPs were predictive of bevacizumab efficacy outcomes. VEGFR2 rs11133360 'TT' was associated with a lower risk of grade ≥ 3 hypertension (P = 0.028). SNPs in VEGF-A, VEGFR1 and VEGFR2 did not predict bevacizumab benefit. However, VEGF-A rs25648 and rs699947 were identified as novel prognostic biomarkers and VEGFR2 rs11133360 was associated with less grade ≥ 3 hypertension.

• Authors: Fiona Chionh, Val Gebski, Sheren J Al-Obaidi, Jennifer K Mooi, Maressa A Bruhn, Chee K Lee, Anderly C Chüeh, David S Williams, Andrew J Weickhardt, Kate Wilson, Andrew M Scott, John Simes, Jennifer E Hardingham, Timothy J Price, John M Mariadason, Niall C Tebbutt
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 1238 (01 24 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35075138 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Antineoplastic Agents
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Receptors, Vascular Endothelial Growth Factor

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Australia (epidemiology)
• Carcinoma (drug therapy, genetics, mortality)
• Colorectal Neoplasms (drug therapy, genetics, mortality)
• Female
• Humans
• Hypertension (genetics)
• Male
• Middle Aged
• Pharmacogenomic Variants
• Polymorphism, Single Nucleotide
• Receptors, Vascular Endothelial Growth Factor (genetics)
• Vascular Endothelial Growth Factor A (genetics)