Precision medicine in patients with advanced biliary tract cancer

To determine whether a program of molecular profiling and matching targeted therapy in advanced biliary tract cancer improves patient outcomes.

We reviewed all patients with advanced biliary tract cancer treated in our institution between 2015 and 2021 with a molecular profile available. We compared overall survival and growth modulation index (study primary endpoints) according to the absence or presence of targetable alterations and to the treatment received after profiling.

Of 313 patients with a molecular profile, 146 (46.6%) harbored at least one targetable alteration; 77 patients (24.6%) received molecular targeted agents (molecularly matched therapy group), 37 (11.8%) received conventional therapy (unmatched therapy group), and 32 (10.2%) were not treated. No targetable alterations were found in 167 patients (53.4%); 126 patients (40.3%) received conventional therapy (no-alteration group) and 41 (13.1%) were not treated. Overall survival was longer in the molecularly matched therapy group (median, 28.0 months [95%CI 24.8-36.7]) than in unmatched therapy (18.0 months [95%CI 15.7-26.6]; HR 1.80 [95%CI 1.17-2.78]; p=0.011) and no-alteration (22.9 months [95%CI 19.7-26.3]; HR 1.55 [95%CI 1.12-2.16]; p=0.008) groups. A growth modulation index ≥1.33 was observed in 49% (CI, 38%-61%) of the patients in the molecularly matched therapy group versus 34% (CI, 26%-42%) in the unmatched therapy and no-alteration groups combined (p=0.024). Molecularly matched therapy group patients had better progression-free survival and clinical benefit rate than patients in the unmatched therapy and no-alteration groups.

Identifying targetable alterations and providing molecularly matching therapy in 25% of patients was associated with improved outcomes in advanced biliary tract cancer.

Molecular profiling has become an increasingly important component of the management of advanced biliary tract cancer (BTC), a disease characterized by substantial molecular heterogeneity and a growing number of actionable alterations. In this retrospective study of 313 patients with advanced BTC who underwent molecular profiling, nearly half harbored an alteration considered targetable according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Patients who received a matched molecular targeted therapy had longer overall and progression-free survival, as well as higher growth modulation index, objective response, and clinical benefit rates, than patients treated with conventional therapy, whether or not a targetable alteration was identified. These findings support the clinical relevance of identifying actionable alterations and ensuring access to matched therapies in advanced BTC. The results are particularly relevant to physicians involved in the multidisciplinary management of BTC and support early, systematic molecular profiling, ideally before substantial attrition occurs during successive treatment lines. They also highlight that genomic profiling alone is insufficient: timely access to appropriate molecular targeted agents, including through clinical trials, is essential for the potential clinical benefit of precision oncology. The findings may therefore inform the organization of molecular testing and referral pathways and support the development of clinical trial portfolios addressing the range of actionable alterations encountered in BTC. However, these results should not be interpreted as demonstrating a causal survival benefit from molecular profiling or matched therapy. The study was retrospective and single-center, molecular testing was performed at variable time points, and residual selection and immortal time biases cannot be excluded despite the use of comparator groups and multivariable analyses. The findings therefore warrant prospective confirmation. Ongoing randomized studies evaluating molecularly guided treatment in advanced BTC should help determine the clinical benefit and optimal timing of precision oncology strategies in routine practice.

This retrospective, single-center study shows that among 313 patients with advanced biliary tract cancer, at least one tumor gene alteration amenable to matched targeted therapy was found in 146 patients (46.6%). Overall survival was longer in the matched therapy group (median, 28.0 months) than in the unmatched therapy group (18.0 months) and the no-alteration group (22.9 months). Identifying targetable alterations and matching therapy accordingly seems associated with improved outcomes in patients with advanced biliary tract cancer.