Biliary tract cancers (BTCs), encompassing intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer, represent a heterogeneous group of aggressive malignancies with persistently poor outcomes [
1]. Worldwide, the incidence of cholangiocarcinoma has increased steadily over the past two decades, driven in part by the growing burden of chronic liver disease, metabolic dysfunction-associated steatotic liver disease, viral hepatitis, and alcohol-related liver injury [
2,
3]. Despite advances in diagnostic imaging, most patients are diagnosed with advanced, unresectable disease, limiting curative options and contributing to poor long-term survival. For more than a decade, gemcitabine plus cisplatin (GC) has remained the backbone of first-line systemic therapy for advanced BTC [
4]. Attempts to improve outcomes through cytotoxic chemotherapy intensification have yielded limited success. The phase III Southwest Oncology Group (SWOG) S1815 trial, which evaluated the addition of nab-paclitaxel to GC (gemcitabine, cisplatin, and nab-paclitaxel [GAP]), failed to demonstrate a statistically significant overall survival benefit in an unselected patient population, despite higher response rates [
5]. These results underscore the limitations of empiric treatment intensification in the absence of biologic stratification. More recently, the incorporation of immune checkpoint inhibitors into first-line therapy has modestly shifted the treatment paradigm. The phase III trial of durvalumab plus gemcitabine/cisplatin (TOPAZ-1) trial demonstrated a statistically significant, albeit modest, overall survival benefit with the addition of durvalumab to GC, establishing chemo-immunotherapy as a new standard of care [
6]. This finding was subsequently confirmed by the phase III trial of pembrolizumab plus gemcitabine/cisplatin (KEYNOTE-966), which showed a similar survival benefit when pembrolizumab was added to GC [
7]. Together, these trials validated immune checkpoint inhibition as a component of first-line therapy in BTC, but also highlighted the modest magnitude of benefit and the absence of predictive biomarkers to guide patient selection. Taken together, these experiences highlight a fundamental challenge in BTC management. The modest survival gains observed with treatment escalation likely reflect meaningful benefit confined to a biologically defined subset of patients. However, the absence of tools to prospectively identify these individuals hinders further progression and dilutes the therapeutic impact at the population level, masking benefit in responsive patients and exposing non-responders to unnecessary toxicity. These observations underscore the limitations of uniform intensification and support biomarker-guided approaches to align therapy with tumor biology.
In BTC, biomarker development has focused on the identification of actionable oncogenic drivers. Large-scale genomic profiling efforts led to the discovery of fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase 1 mutations in subsets of intrahepatic cholangiocarcinoma, directly enabling the development and regulatory approval of matched targeted therapies [
8,
9]. These advances have transformed the management of molecularly defined patient subsets and firmly established genomic stratification as a cornerstone of precision oncology in BTC. However, the vast majority patients do not harbor targetable alterations, and predictive biomarkers for chemotherapy or immunotherapy response remain elusive. In major chemoimmunotherapy trials, including TOPAZ-1 and KEYNOTE- 966, benefit was largely independent of programmed death-ligand 1 expression, tumor mutational burden, or other conventional immune biomarkers. Similarly, SWOG S1815 demonstrated that response rate improvements with GAP (31% vs. 21% in GC,
P=0.03) did not translate into a survival benefit, raising the possibility that intrinsic resistance mechanisms offset cytotoxic intensification in molecularly defined subsets. Collectively, these findings highlight a fundamental gap in BTC management. Despite growing recognition of its molecular heterogeneity, therapeutic decision-making for cytotoxic and immunotherapy regimens remains largely biomarker-agnostic. Overcoming this limitation will require a shift from single-gene markers to pathway-based and molecular subtype-informed approaches that more accurately reflect the biological determinants of treatment response and resistance.
Against this backdrop, the study by Kim et al. [
10] represents an important advance by systematically interrogating genomic determinants of benefit from GAP versus GC in advanced BTC. Rather than focusing on individual gene alterations, the investigators adopted a pathway-level framework, classifying tumors according to activation of oncogenic pathways using clinically annotated, pathogenic genomic events. Their central finding is that activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling is associated with a lack of benefit from nab-paclitaxel–containing chemotherapy. Among patients treated with GAP, PI3K pathway activation was associated with inferior progression-free and overall survival, whereas no such association was observed in patients receiving GC alone. Conversely, patients lacking PI3K pathway activation derived meaningful benefit from the addition of nab-paclitaxel, establishing a clear treatment–biomarker interaction. These findings reframe the interpretation of SWOG S1815. Rather than indicating that GAP is broadly ineffective, the results suggest that therapeutic benefit was diluted by the absence of biomarker-based patient stratification in a biologically heterogeneous population. In this context, PI3K pathway activation emerges as a negative predictive biomarker for chemotherapy intensification, offering a biologically plausible explanation for the neutral overall survival outcome observed in the trial.
The relevance of PI3K pathway activation as a predictive biomarker is further supported by its alignment with biologically distinct genomic subgroups of cholangiocarcinoma defined by differences in cell of origin, oncogenic signaling, and tumor microenvironment [
2]. Activation of the PI3K/AKT/mTOR pathway frequently co-occurs with molecular features associated with aggressive behavior, increased proliferation, and therapeutic resistance [
11-
13]. Such tumors exhibit enhanced survival signaling, reduced apoptotic priming, and altered mitotic checkpoint control, biological properties that plausibly attenuate the cytotoxic effects of microtubule-targeting agents such as nab-paclitaxel. In contrast, tumors lacking PI3K/AKT/mTOR pathway activation may remain more reliant on intact mitotic stress responses, rendering them more susceptible to taxane-based treatment intensification. Although the current evidence is associative, anchoring treatment response to subtype-linked biological programs advances the field beyond descriptive genomics and toward functionally informed patient stratification using clinical sequencing data, pending validation in future studies.
The identification of PI3K pathway activation as a determinant of chemotherapy resistance opens several rational avenues for future mechanistically aligned clinical investigation. One obvious strategy is the prospective exclusion of PI3K-activated tumors from nab-paclitaxel–containing regimens, thereby sparing patients unnecessary toxicity while enriching for those most likely to benefit. In parallel, evaluating the efficacy of chemo-immunotherapy in the context of PI3K pathway activation may enable further refinement of precision treatment strategies through molecular stratification. More ambitiously, these findings support the exploration of rational combination strategies incorporating PI3K/AKT/mTOR inhibitors such as alpelisib or inavolisib (PI3Kα inhibitor), as well as capivasertib (AKT inhibitor) [
14]. Preclinical data across multiple tumor types suggest that PI3K inhibition can restore sensitivity to taxanes and enhance apoptotic priming [
15,
16]. In BTC, combining PI3K pathway inhibitors with chemotherapy, or potentially with chemo-immunotherapy, may overcome intrinsic resistance mechanisms and expand the number of patients who benefit from treatment intensification. Importantly, the biomarker framework described in the current study provides a clear blueprint for such trials. Rather than empiric combination therapy, PI3K inhibitors could be deployed selectively in biomarker-defined subsets, enabling more efficient trial design and clearer biological interpretation of outcomes.
Beyond immediate therapeutic implications, this study reinforces a broader message that resonates across BTC research: meaningful progress will require improved disease classification, standardized surveillance strategies, and subtype-specific prevention and treatment approaches. As epidemiologic studies increasingly link cholangiocarcinoma to chronic liver disease and metabolic risk factors, integrating molecular stratification with clinical risk profiling becomes imperative. Future efforts should aim to align epidemiologic insights, molecular subtypes, and therapeutic vulnerabilities into a cohesive framework that enables earlier detection, rational prevention strategies, and personalized treatment selection. The current biomarker study exemplifies this direction by demonstrating how pathway-level genomic information can inform chemotherapy decision-making and reinterpret negative clinical trials.
In conclusion, as the incidence of BTC continues to rise and therapeutic gains remain modest, moving from empiric treatment intensification toward biomarker-guided strategies based on clinically available sequencing data has become increasingly necessary. Therefore, the study by Kim et al. [
10], along with other similar approaches, carries the promise of providing an important foundation for that shift, offering both mechanistic insight and a practical path toward precision therapy in BTC.
FOOTNOTES
-
Authors’ contribution
S.H.L. and J.S.L. conceived the editorial. S.H.L. drafted the initial manuscript. A.O.K. provided clinical interpretation of biliary tract cancer treatment and trial implications. J.S.L. provided conceptual guidance on biomarker-driven precision oncology and revised the manuscript. All authors critically reviewed the manuscript, approved the final version, and agree to be accountable for the work.
-
Acknowledgements
This work was supported by the National Institutes of Health/National Cancer Institute (NIH/NCI) under award numbers R01CA237327, P50CA217674, and P30CA016672 (to JSL), and by a National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT; 2023R1A2C10073311212982036810102) (to SHL).
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
gemcitabine plus cisplatin
phase III trial of pembrolizumab plus gemcitabine/cisplatin
mechanistic target of rapamycin
phosphoinositide 3-kinase
phase III trial of durvalumab plus gemcitabine/cisplatin
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