Lacking Immunotherapy Biomarkers for Biliary Tract Cancer: A Comprehensive Systematic Literature Review and Meta-Analysis

Abstract

Background: Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential in order to identify those patients who may benefit most from this novel treatment option. Here, we propose a systematic literature review and a meta-analysis of PD-1, PD-L1, and other immune-related biomarker expression levels in patients with BTC. Methods: Prisma guidelines were followed for this systematic review and meta-analysis. Eligible studies were searched on PubMed. Studies published between 2017 and 2022, reporting data on PD-1/PD-L1 expression and other immune-related biomarkers in patients with BTC, were considered eligible. Results: A total of 61 eligible studies were identified. Despite the great heterogeneity between 39 studies reporting data on PD-L1 expression, we found a mean PD-L1 expression percentage (by choosing the lowest cut-off per study) of 25.6% (95% CI 21.0 to 30.3) in BTCs. The mean expression percentages of PD-L1 were 27.3%, 21.3%, and 27.4% in intrahepatic cholangiocarcinomas (iCCAs—15 studies), perihilar–distal CCAs (p/dCCAs—7 studies), and gallbladder cancer (GBC—5 studies), respectively. Furthermore, 4.6% (95% CI 2.38 to 6.97) and 2.5% (95% CI 1.75 to 3.34) of BTCs could be classified as TMB-H and MSI/MMRd tumors, respectively. Conclusion: From our analysis, PD-L1 expression was found to occur approximately in 26% of BTC patients, with minimal differences based on anatomical location. TMB-H and MSI molecular phenotypes occurred less frequently. We still lack a reliable biomarker, especially in patients with mismatch-proficient tumors, and we must need to make an effort to conceive new prospective biomarker discovery studies.

Changes in L-phenylalanine concentration is a risk factor for NSCLC patients who received PD-1 Ab treatment: a case-control study

“…Xiaoli et al found that the serum L-phenylalanine level in patients with esophageal cancer was signi cantly higher than that in healthy controls, whereas tyrosine levels were signi cantly lower than those in healthy controls (13). Cheng et al found that serum L-phenylalanine concentration in patients with NSCLC was signi cantly elevated (7). Gabriella Cadoni et al found that high serum L-phenylalanine levels in head and neck cancer patients were associated with increased risk of advanced disease and reduced overall survival (OS)(46).…”

“…However, if the patient's PD-L1 expression was negative, it is di cult to predict the e cacy of PD-1/PD-L1 inhibitors in patients(6). Based on our clinical ndings, even patients who do not express PD-1/PD-L1 can bene t from immunotherapy (7), whereas some patients with > 50% PD-1/PD-L1 expression still develop early treatment resistance. Therefore, the use of PD-1/PD-L1 expression alone to predict or evaluate treatment response is inaccurate.…”

Evaluating the Therapeutic Potential of Durvalumab in Adults with Locally Advanced or Metastatic Biliary Tract Cancer: Evidence to Date

“…10,38 Evidence at this point would suggest that those with MSI-H tumors or tumors with high tumor mutation burden (TMB-H) may have better response to immunotherapy, however, these markers may be seen in a minority of patients. [39][40][41][42][43] In fact, MSI-H and/or deficient mismatch repair (dMMR) may be seen in 2-2.5% of BTCs and TMB-H may be seen in <5% of BTCs. 43,44 Expression of PD-L1 may be most common, seen in approximately 25% of tumors.…”

“…[39][40][41][42][43] In fact, MSI-H and/or deficient mismatch repair (dMMR) may be seen in 2-2.5% of BTCs and TMB-H may be seen in <5% of BTCs. 43,44 Expression of PD-L1 may be most common, seen in approximately 25% of tumors. 43 In TOPAZ-1, in patients with PD-L1 tumor area positivity ≥1%, those who received durvalumab had numerically longer survival compared to those who received placebo with chemotherapy, although did not achieve statistical significance (HR = 0.79, 95% CI = 0.61-1.00).…”

“… 43 , 44 Expression of PD-L1 may be most common, seen in approximately 25% of tumors. 43 In TOPAZ-1, in patients with PD-L1 tumor area positivity ≥1%, those who received durvalumab had numerically longer survival compared to those who received placebo with chemotherapy, although did not achieve statistical significance (HR = 0.79, 95% CI = 0.61–1.00). 26 Similarly, in KEYNOTE-966, those with PD-L1 combined positive score ≥1 who received pembrolizumab trended towards longer overall survival compared to those who received placebo but, again, did not reach statistical significance (HR = 0.85, 95% CI = 0.72–1.00).…”