Analysis of mutational profiles and their correlation with organ-specific metastases in MSS and <i>BRAF</i> wt colorectal cancer (mCRC).

Abstract

3556 Background: In BRAF wt/ MSS mCRC, the mechanisms driving distinct metastatic dissemination patterns remain unclear. Understanding them is crucial, as dissemination profiles influence therapeutic strategies, such as immunotherapy for patients (pts) without liver metastasis (mets) or locoregional approaches and liver transplantation for those with liver-limited disease. NGS advances provide genomic data, offering opportunities to identify predictive signatures that link molecular profiles to metastatic patterns. This study investigates mutational profiles to uncover correlations with organ-specific mets in pts treated at our institution. Methods: This study included pts with unresectable MSS/ BRAF wt mCRC treated at Vall d’Hebron Hospital (2010–2020). Pts were grouped into three clinical categories based on metastatic patterns: liver-limited disease (LLD), exclusively extrahepatic disease (EXTRAHEP), and hepatic and extrahepatic disease (BOTH). Molecular analyses were performed using NGS prescreening data available at our institution. Mutations were grouped in two approches: (1) by biological significance using cancer hallmark genes from published datasets (Zhang, Front Genet 2020; Sondka, Nat Rev Cancer 2018), and (2) by molecular pathways based on the Sanchez-Vega dataset ( Cell 2018). Statistical analyses were conducted using R version 4.3.2. Results: A total of 1,026 pts were included (204 LLD, 297 EXTRAHEP, and 525 BOTH), with molecular analyses performed on 360 samples (35% overall; 31.8%, 39.7%, and 33.7%, in each group, respectively). The median number of genes with pathogenic mutations per sample differed significantly between groups: 2.28 in LLD, 2.44 in EXTRAHEP, and 2.65 in BOTH (p = 0.01). BOTH showed significantly greater increase than LLD in mutated genes associated with five of the ten analyzed hallmarks: activation of invasion and mets, resistance to cell death, evasion of growth suppressors, sustaining proliferative signaling, and replicative immortality. Compared to EXTRAHEP, BOTH also had more mutations in invasion and mets activation and proliferative signaling (adjusted p-value &lt; 0.05 for all the hallmarks mentioned). For pathway associations, WNT pathway activation was higher in BOTH than EXTRAHEP (p = 0.004), driven by more frequent APC mutations in BOTH (82% vs. 69%, adj. p = 0.049). Conclusions: This study provides evidence that pts with both hepatic and extrahepatic disease exhibit enrichment in five cancer hallmarks and the WNT pathway compared to other metastatic patterns. This suggests the tumor's potential to adapt to diverse microenvironments. Despite the statistical significance, the magnitude of the observed differences in mutated genes is not yet clinically useful. These findings highlight the need for collaborative efforts to develop mutational profiles that predict organotropism and guide therapy.