Neprilysin Functional Genetic Polymorphism in NSCLC Progression Without PD-L1 Expression

Advanced NSCLC without driver mutations and low levels of PD-L1 can be treated in first line with platinum-based doublet chemotherapy and immunotherapy and/or anti-angiogenic drugs. However, there is a lack of biomarkers. Neprilysin (NEP) is encoded by MME gene and is implicated in oncogenesis, inhibiting angiogenesis via proteolysis of fibroblast growth factor-2. Previous studies showed that the functional polymorphism MME rs701109 C>T is associated with altered NEP expression. Our aim was to study the association of functional MME polymorphism according to PD-L1 expression in NSCLC progression. In this retrospective cohort study, 109 patients staged IIIA-IVB without actionable mutations were treated with first line platinum-based chemotherapy. Genotyping for MME rs701109 was performed by Real-Time PCR. The association between genetic polymorphism and time-to-outcome was tested using Kaplan-Meier curves and Log-rank test. Patients with tumour PD-L1 expression above 1% had longer progression-free-survival (PFS) when compared with those without expression (8.0 months, CI95% 5.7-10.3, versus 6.0 months, CI95% 3.0-9.0, p= 0.022). In patients without PD-L1 expression, the MME rs701109 homozygous C carriers had shorter PFS, compared with T carriers [median 4.0 months (CI 95% 1.9-6.1) versus 8.0 months (CI 95% 4.6-11.4), p= 0.033]. In conclusion, patients with CC genotype for MME rs701109 might have lower levels of NEP favouring a pro-angiogenic tumour microenvironment. This polymorphism opens new perspectives for its inclusion as a pharmacogenetic predictor of response to platinum-based chemotherapy in patients without PD-L1 expression.