Advanced ovarian cancer: Is residual disease after debulking surgery affected by genetics factors involved in angiogenesis and immunity pathways?

Abstract

Abstract Background The residual disease (RD) after debulking surgery is one of the strongest prognostic factors in ovarian cancer (OC) patients. Despite surgical efforts, most patients do not achieve optimal cytoreduction (R0) even in high-volume centres. The interplay between cancer-promoted angiogenesis and host immune-system could foster cancer dissemination, reducing the likelihood of surgical eradication. The aim of this study was to assess whether the presence of germline polymorphisms in genes involved in angiogenesis and immunity pathways was predictive of R0. Methods A cohort of 230 patients with stage III-IV, high grade epithelial OC treated with debulking surgery and platinum-based therapy without bevacizumab, was retrospectively enrolled. A panel of 192 single nucleotide polymorphisms (SNPs) in 34 angiogenesis and immune system-related genes was analyzed with Illumina GoldenGate Genotyping Assay. Log-additive, dominant and recessive genetic models were evaluated using a multivariate logistic regression adjusted for type of surgery (i.e. primary or interval). False discovery rate (FDR) test Results Thirteen SNPs were significantly associated with RD. Among them, MMP3-rs569444, TLR3-rs5743303 and VEGFA-rs2146323 passed the FDR filter. Patients carrying the variant alleles of MMP3-rs569444 (OR\xa0=\xa02.52, 95%CI 1.42-4.47, p\xa0=\xa00.0326) and VEGFA-rs2146323 (OR\xa0=\xa01.83, 95%CI 1.21-2.75, p\xa0=\xa00.0375) showed an increased risk of RD. Conversely, TLR3-rs5743303 carriers were more likely to achieve R0 (OR\xa0=\xa00.43, 95%CI 0.27-0.7, p\xa0=\xa00.0004). Conclusions Angiogenesis and the immune-system competence are key players in OC growth and could influence the burden of RD. In our cohort, individual polymorphisms on angiogenesis (VEGFA), extracellular matrix degradation (MMP3) and innate immunity activation (TLR3) pathways were independent predictive factors of RD. These markers, whether validated, might underline the role of host genetics factors in predicting R0. Moreover, if VEGFA-rs2146323 variant carriers could benefit the most from bevacizumab appears as an intriguing question. Legal entity responsible for the study Toffoli Giuseppe. Funding Has not received any funding. Disclosure F. Puglisi: Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eisai; Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self): Pierre Fabre; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Takeda; Research grant / Funding (self): AstraZeneca. All other authors have declared no conflicts of interest.