Understanding homologous recombination repair deficiency in biliary tract cancers: clinical implications and correlation with platinum sensitivity.

BACKGROUND: Biliary tract cancers (BTCs) exhibit high mortality rates and significant heterogeneity in both clinical and molecular characteristics. This study aims to molecularly characterize a cohort of patients with BTC, with a specific focus on genomic alterations within homologous recombination repair (HRR) genes in a real-world setting. PATIENTS AND METHODS: We carried out a retrospective analysis on 256 patients with BTC treated at five Austrian centers and one German comprehensive cancer center between 2016 and 2023 utilizing comprehensive genomic profiling platforms to assess HRR status and its correlation with clinical outcomes after platinum-based chemotherapy. RESULTS: A total of 67 patients (27.5%) exhibited HRR gene mutations (HRRm), with the most common pathogenic alterations in BAP1 (9%), ARID1A (7.8%), and ATM (6.1%). Time to failure of the first-line strategy (TFS) between patients with HRRm and non-HRRm treated with platinum agents was 7.9 and 6.7 months, respectively [hazard ratio (HR) 0.89; P = 0.49]. The overall survival (OS) estimates at 6, 18, and 24 months were 82%, 45%, and 39% in the HRRm group (median 16.01 months) and 81%, 42%, and 22% in the HRR group (median 15.68 months), respectively (Fleming-Harrington test P = 0.0004; log-rank P = 0.022). Significance did not persist in the multivariate analysis (HR 0.72; 95% confidence interval 0.489-1.059; P = 0.095). An interaction between HRRm status and molecular-informed therapeutic strategies in later lines was noted. In the second-line treatment, OS following an irinotecan-based regimen was comparable to re-exposure to platinum-based agents (12.36 versus 10.13 months; HR 0.92; P = 0.85). No better outcome was noted for patients with HRRm versus patients with non-HRRm with second-line platinum agents (HR 1.45; P = 0.35). CONCLUSIONS: Patients with HRRm with BTC showed a potential advantage in OS following platinum-based first-line chemotherapy, presumably attributed to enhanced opportunities for targetable coalterations. Further investigation is needed to outline HRR within the scope of BTCs and detail a clinically meaningful sensitivity to platinum agents or targeted approaches with poly (ADP-ribose) polymerase (PARP) inhibitors.

Bevacizumab mitigates codon-specific effects of trifluridine/tipiracil on efficacy outcome parameters in metastatic colorectal cancer.

BACKGROUND: Molecular informed therapy changed treatment patterns of metastatic colorectal cancer (mCRC). Recently KRAS G12, the most prevalent RAS mutation in mCRC, was investigated to be a negative predictive marker for the efficacy of trifluridine/tipiracil (FTD/TPI). Whether this proposed selectivity remains when FTD/TPI is combined with bevacizumab remains elusive. We aimed to describe the efficacy of FTD/TPI + bevacizumab depending on the RAS mutational status in a real-world population. PATIENTS AND METHODS: Patients from five different cancer centers in Austria who received FTD/TPI + bevacizumab in any treatment line having available information on their molecular profile were eligible. Data were retrospectively collected by chart review. Survival data were compared using log-rank test. Multivariate Cox regression models included several established covariates. RESULTS: One hundred and twenty-three patients with mCRC were included in this study. Median overall survival (OS) was highly similar in the RAS wild type (WT) [9.63 months (95% confidence interval [CI] 8.055-13.775 months)] and the RAS mutant cohorts [8.78 months (95% CI 8.055-11.014 months)], which was confirmed in a multivariable model adjusting for potential confounders; hazard ratio (HR): 1.05 (95% CI 0.618-1.785; P = 0.857). In addition, no effect of KRAS G12 status on patient outcome was observed. In detail, OS was 8.88 months (95% CI 7.332-12.921 months) in patients with KRAS G12 mutation, compared to 9.47 months (95% CI 8.088-11.375 months) in patients with RAS WT/no-KRAS G12 disease [HR: 0.822 (95% CI 0.527-1.282; P = 0.387)]. CONCLUSION: This real-world study indicates that the efficacy of FTD/TPI + bevacizumab is independent of RAS mutational status and that bevacizumab may therefore mitigate the potentially limited efficacy of FTD/TPI monotherapy in the KRAS G12-mutated population.

Novel pyrazole compounds for pharmacological discrimination between receptor-operated and store-operated Ca(2+) entry pathways.

BACKGROUND AND PURPOSE: Pyrazole derivatives have recently been suggested as selective blockers of transient receptor potential cation (TRPC) channels but their ability to distinguish between the TRPC and Orai pore complexes is ill-defined. This study was designed to characterize a series of pyrazole derivatives in terms of TRPC/Orai selectivity and to delineate consequences of selective suppression of these pathways for mast cell activation. EXPERIMENTAL APPROACH: Pyrazoles were generated by microwave-assisted synthesis and tested for effects on Ca(2+) entry by Fura-2 imaging and membrane currents by patch-clamp recording. Experiments were performed in HEK293 cells overexpressing TRPC3 and in RBL-2H3 mast cells, which express classical store-operated Ca(2+) entry mediated by Orai channels. The consequences of inhibitory effects on Ca(2+) signalling in RBL-2H3 cells were investigated at the level of both degranulation and nuclear factor of activated T-cells activation. KEY RESULTS: Pyr3, a previously suggested selective inhibitor of TRPC3, inhibited Orai1- and TRPC3-mediated Ca(2+) entry and currents as well as mast cell activation with similar potency. By contrast, Pyr6 exhibited a 37-fold higher potency to inhibit Orai1-mediated Ca(2+) entry as compared with TRPC3-mediated Ca(2+) entry and potently suppressed mast cell activation. The novel pyrazole Pyr10 displayed substantial selectivity for TRPC3-mediated responses (18-fold) and the selective block of TRPC3 channels by Pyr10 barely affected mast cell activation. CONCLUSIONS AND IMPLICATIONS: The pyrazole derivatives Pyr6 and Pyr10 are able to distinguish between TRPC and Orai-mediated Ca(2+) entry and may serve as useful tools for the analysis of cellular functions of the underlying Ca(2+) channels.