Insights into the impact of chromosome 3p mutations in advanced renal cell carcinoma treated with immune-based combinations or targeted therapy: A single-center experience

Background: Immune-based combinations have transformed first-line treatment for metastatic renal cell carcinoma (mRCC), but reliable biomarkers for patient selection remain elusive. Chromosome 3p mutations (e.g., VHL, PBRM1, SETD2, BAP1) have shown inconsistent prognostic and predictive value. This retrospective study assessed the prognostic impact of tissue-based biomarkers, focusing on 3p mutations in mRCC. Patients and methods: A single-center retrospective analysis included mRCC patients treated with immunocombinations or tyrosine kinase inhibitors (TKIs). We evaluated mutations in 14 genes, including VHL, PBRM1, SETD2, and BAP1. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Prognostic factors were analyzed using univariate and multivariate models. Results: Among the included 38 patients, the most common mutations were in VHL (45 %), PBRM1 (42 %), and SETD2 (26 %), with these latter more frequent in males (p = 0.012). Most patients (74 %) received immune-based combinations; 26 % received TKIs. SETD2 mutations were associated with primary refractoriness (30 %). Median OS was not reached; brain metastases (p = 0.001) and BAP1 mutations (p = 0.025) predicted worse OS, while PBRM1 mutations trended toward improved OS (p = 0.845). Median PFS was 14.1 months. Higher tumor grade (p = 0.038) and worse ECOG PS (p = 0.008) negatively impacted PFS, while 3p mutations showed no significant effect on PFS. Conclusions: ECOG PS and brain metastases were confirmed as poor prognostic factors. VHL and PBRM1 mutations may suggest a better prognosis, while SETD2 and BAP1 mutations portend worse outcomes. Larger studies are needed to confirm these findings.