Biliary tract cancer (BTC) accounts for 10%-15% of all primary liver cancers in adults and includes tumors of the gallbladder and biliary tree. BTC is less common in Western populations but occurs more frequently in Asia. Notably, the incidence of intrahepatic cholangiocarcinoma has been rising worldwide, driven in part by metabolic disorders such as obesity, diabetes, and liver cirrhosis. The disease is often diagnosed at an advanced stage, contributing to dismal 5-year survival rates of just 5%-15%. Against this backdrop, discussions on refining diagnosis and therapy are highly relevant. At the 36^th ASCOMOS, Dr. Wong Yoke Fui, clinical oncologist at the National Cancer Institute, Putrajaya, shared insights on the evolving role of biomarkers in guiding treatment for BTC.

While BTC is not among the ten most common cancers in Malaysia, over 600 cases are diagnosed nationwide annually, and Dr. Wong’s center has reported a rising trend of about 50 new cases each year in recent years. Surgical resection remains the mainstay of curative treatment, and while there is no randomized evidence supporting neoadjuvant therapy, adjuvant chemotherapy with capecitabine—or, in selected Asian practice, TS-1 (tegafur + gimeracil + oteracil potassium)—is recommended following surgery. Dr. Wong emphasized that positive surgical margins still confer poor prognosis, underscoring the need for effective systemic therapy.

In the first-line (1L) setting, she revisited pivotal chemotherapy data. The phase 3 ABC-02 trial, which enrolled 410 patients with advanced BTC established gemcitabine + cisplatin (GemCis) as the standard of care, with overall survival (OS) superior to gemcitabine alone. Since then, multiple attempts have sought to improve outcomes. The Japanese JCOG1113 trial randomized 354 patients with unresectable or recurrent BTC to GemCis vs. gemcitabine + TS-1, showing similar survival but distinct side-effect patterns. Dr. Wong reminded clinicians “that tolerability and access remain practical drivers of regimen choice”. The phase 3 MITSUBA trial suggested improved response rates with the addition of TS-1, although its greater toxicity limited uptake. By contrast, the phase 3 SWOG 1815 trial testing a GemCis triplet failed to show a survival benefit, and the randomized phase 2/3 PRODIGE 38 of modified FOLFIRINOX proved both toxic and ineffective. Taken together, these efforts illustrate the limits of intensifying chemotherapy—with GemCis and gemcitabine + TS-1 as the regimens showing positive signals in the 1L setting.

Building on this foundation, immunotherapy has started to reshape the treatment landscape. The phase 3 TOPAZ-1 trial, which randomized 685 patients with advanced BTC across 17 countries evaluated durvalumab with GemCis and showed a survival benefit compared with chemotherapy alone. Dr. Wong highlighted that the 3-year OS rate was 14.6% with durvalumab vs. 6.9% with chemotherapy, remarking, “A 10% difference may not look much. But bear in mind BTC is a hard-to-treat tumor, hence that 10% does make a difference in our population.” Tumor responses were also more frequent and more durable with the addition of durvalumab. Similarly, the phase 3 KEYNOTE-966 trial, which enrolled 1,069 patients worldwide, investigated pembrolizumab + GemCis, reporting a median OS of 12.7 months vs. 10.9 months (HR=0.83; 95% CI: 0.72-0.95), though progression-free survival (PFS) gains remained modest. While no biomarker currently guides immunotherapy selection in BTC, both combinations represent meaningful progress in a setting long defined by limited options.

Beyond 1L, treatment decisions increasingly hinge on molecular profiling. Dr. Wong stressed that nearly 40% of BTCs harbor actionable genetic alterations, and that testing should ideally be performed before or during 1L therapy to allow timely planning. Among the most clinically relevant are IDH1 mutations and FGFR2 fusions or rearrangements, both ranked at the highest levels on the European Society For Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT), which stratifies genomic alterations by clinical relevance.

These molecularly defined subgroups have been the focus of pivotal clinical trials testing novel targeted agents. The phase 3 ClarIDHy trial with ivosidenib demonstrated nearly doubled PFS for patients with IDH1 mutations compared with placebo (2.7 months vs. 1.4 months), offering an oral targeted option in the second-line (2L) setting. For patients with FGFR2 alterations, phase 2 studies such as FIGHT-202 (pemigatinib) and FOENIX (futibatinib) reported objective responses in roughly 40% of patients, a striking contrast to the limited benefits historically seen with chemotherapy. These data underscore how molecular insights are beginning to carve out precision paths in BTC care.

Dr. Wong also touched on the potential role of liquid biopsy. Circulating tumor DNA (ctDNA) may serve as a non-invasive biomarker for detecting minimal residual disease (MRD), monitoring recurrence, and providing real-time insights into tumor evolution when tissue is scarce or urgent decisions are needed. While still investigational, ctDNA holds promise to eventually complement tissue-based testing and refine the practice of precision oncology.

In closing, Dr. Wong emphasized that despite incremental advances, BTC remains a challenging disease with poor outcomes. Reliable biomarkers to guide patient selection for combination therapy are lacking, but ongoing research continues to expand therapeutic possibilities. The integration of molecular profiling into routine practice, alongside judicious use of chemotherapy and immunotherapy, is gradually shifting BTC care from a purely chemo-centric paradigm toward biomarker-guided precision treatment.