Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response

Abstract

Background While there have been encouraging preliminary clinical results for immune checkpoint inhibitors (ICIs) in BTCs, it remains a challenge to identify the subset of patients who may benefit. In this study, we evaluated the efficacy of ICI treatment in patients with advanced BTCs, and explored potential biomarkers that are predictive of response. Methods The study enrolled 26 patients with advanced microsatellite stable BTCs (15 with gallbladder cancers [GCs] and 11 with intrahepatic cholangiocarcinoma [ICCs]) who received ICI treatment. Targeted next‐generation sequencing (NGS) was performed on tumor tissue samples collected from 17 patients. Clinical and genomic characteristics were assessed for the correlation with clinical outcome. Results Analysis of the baseline clinical characteristics showed that performance score (PS) of 0 was associated with a better prognosis than PS of 1 (HR = 1.08 × 109; 95% CI, 0∼Inf; P = .002). No significant correlations were found between clinical outcome and inflammation‐related indicators. NGS profiling of the available tumor tissues, revealed largely non‐overlapping somatic alterations between GCs and ICCs. Mutations in LRP1B (HR = 0.26; 95% CI, 0.06‐1.21; P = .067), ERBB2 (HR = 0.15; 95% CI, 0.02‐1.19; P = .04), or PKHD1 (HR < 0.01; 95% CI, 0‐Inf; P = .04) showed strong association with increased progression‐free survival (PFS) benefit. Subsequent analysis showed that alterations in the RTK‐RAS pathway were associated with improved outcomes (HR = 0.12; 95% CI, 0.02‐0.63; P = .003). Tumor mutation burden (TMB) was higher in patients with GC than those with ICC, and was associated with LRP1B mutations (P = .032). We found that patients with 19q amplification (19q Amp) and 9p deletion (9p Del) had poor PFS outcome (19q Amp, HR = 15.4; 95% CI, 2.7‐88.5; P < .001; 9p Del; HR = 4.88 × 109; 95% CI, 0‐Inf; P < .001), while those with chromosomal instability derived PFS benefit (HR = 0.24; 95% CI, 0.05‐1.17; P = .057). Conclusion Our study identified several potential clinical and genomic features that may serve as biomarkers of clinical response to ICIs in advanced BTCs patients. A larger sample size is required for further verification.

LRP1B: A Giant Lost in Cancer Translation

“…Consequently, the number of immunotherapy predictors described has been raising over the years, among which are included tumor mutation burden (TMB, a measurement of the number of mutations harbored by tumor cells), expression of immune checkpoint genes, microsatellite instability, and DNA mismatch repair defects [61,[116][117][118]. Recently, LRP1B mutation status was associated with improved patients' outcome to immunotherapy, being described as a biomarker for ICIs in multiple cancers such as melanoma, non-small cell lung cancer, prostate cancer, and advanced biliary tract cancer [58,79,89,119]. However, the exact mechanisms involved warrant further study.…”

Gallbladder Cancer: Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

“…Out of 92 articles, 30 were excluded due to: no data for adenocarcinoma of the gallbladder available (N = 12), overlapping cohorts (N = 8), the wrong type of article (N = 5), no genetic alteration frequency data available (N = 3), wrong study population (N = 1), and not written in English (N = 1). A total of 62 articles were included for final data extraction, describing a total of 3893 GBC samples from individual patients [ 18 , 19 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ,…”

“…Previous studies have shown that TMB-H is correlated with clinical response to immunotherapy in several tumors, including BTC, and that patients with TMB-H tumors can benefit from immune checkpoint inhibitors such as pembrolizumab [ 108 , 109 , 110 ]. In patients with GBC receiving immunotherapy, a higher objective response rate was observed for TMB-high tumors compared to TMB-low tumors (50% vs. 25%) [ 47 ]. Pembrolizumab has been FDA-approved for patients with TMB-H advanced solid cancers.…”

LRP1B mutation is associated with tumor HPV status and promotes poor disease outcomes with a higher mutation count in HPV-related cervical carcinoma and head & neck squamous cell carcinoma

“…Patients with poor biological behavior could then be identified and treated with individual therapies [16]. In particular, LRP1B mutation was identified as a biomarker for ICIs in melanoma, non-small cell lung cancer [17], prostate cancer [18], and advanced biliary tract cancer [19].…”