Chinese expert consensus on molecular diagnostics in hepatobiliary cancers — 2024 edition

The role of molecular diagnostics has become increasingly important in the clinical diagnosis, treatment protocol development, efficacy evaluation and prognosis of hepatobiliary cancers. Several clinical trials conducted in China and beyond have concentrated on specific molecular targets or signaling pathways, yielding promising results. Consequently, integrating molecular testing into the clinical management of hepatobiliary cancers may offer enhanced therapeutic options, potentially improving patient survival and quality of life.

According to the 2023 guidelines from the National Comprehensive Cancer Network (NCCN), hepatobiliary cancers have been reclassified. Against that backdrop, a team of experts in China established a consensus for classifying hepatobiliary cancers that aligns with the NCCN guidelines, categorizing this group of cancers into hepatocellular carcinoma (HCC), combined hepatocellular-cholangiocarcinoma (cHCC-CCA), and biliary tract cancer (BTC), which primarily includes gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC).

The consensus underscores the importance of personalized treatment, particularly by considering various patient-specific factors, as highlighted by Yinying Lu from The Fifth Medical Center of PLA General Hospital in Beijing. The expert panel has refined the classification criteria to enable a more targeted approach to treatment.

Additionally, they have compiled a comprehensive update on the latest advancements in molecular marker research related to hepatobiliary cancers, including studies on relevant proteins and nucleic acids. This update provides a thorough overview of the clinical significance of these markers and the revised guidelines for their application.

The consensus findings, published in the KeAi Journal of Liver Research, serve as a basis for the standardization and enhancement of clinical applications of molecular diagnostics for hepatobiliary tumors, summarized, as follows:

1. Clinical applications of molecular markers in targeted therapy for hepatobiliary cancers

Recommendation 1: Testing for IDH mutations in patients with unresectable or metastatic BTC is recommended. For second-line therapy, ivosidenib is recommended for patients with unresectable or metastatic BTC harboring IDH1-activating mutations (recommendation grade: 1A).

Recommendation 2: Testing for FGFR2 fusion or rearrangement is recommended for patients with unresectable or metastatic BTC. In second-line therapy, pemigatinib (recommendation grade: 1A), futibatinib, derazantinib (recommendation grade: 2B), and erdafitinib (recommendation grade: 3B) are recommended for patients with unresectable or metastatic BTC positive for FGFR2 fusion or rearrangement.

Recommendation 3: Testing for BRAF V600E mutation in patients with unresectable or metastatic BTC is recommended. For second-line therapy, dabrafenib combined with trametinib is recommended for patients with unresectable or metastatic BTC harboring BRAF V600E mutations (recommendation grade: 2B).

Recommendation 4: Testing for HER2 (ERBB2) overexpression or amplification is recommended for patients with unresectable or metastatic BTC. For second-line therapy, pertuzumab plus trastuzumab (recommendation grade: 2C), trastuzumab deruxtecan (recommendation grade: 2C), or zanidatamab (recommendation grade: 2B) are recommended for patients with unresectable or metastatic BTC with HER2 overexpression or amplification.

Recommendation 5: Testing for RET fusion or rearrangement is recommended for patients with unresectable or metastatic BTC and HCC. For first- or second-line therapy in CCA, pralsetinib or selpercatinib is recommended for patients with unresectable or metastatic CCA harboring RET fusions (recommendation grade: 3C). In second-line therapy for HCC, selpercatinib is recommended for unresectable or metastatic HCC with RET fusions (recommendation grade: 3C).

Recommendation 6: Testing for NTRK fusion is recommended for patients with unresectable or metastatic BTC and HCC. Larotrectinib and entrectinib are recommended for those with unresectable or metastatic BTC and HCC harboring NTRK fusions when first-line therapy fails (recommendation grade: 3C).

Recommendation 7: Testing for NRG1 fusion is recommended for patients with unresectable or metastatic BTC. In second-line therapy, zenocutuzumab is recommended for patients with unresectable or metastatic BTC and HCC harboring NRG1 fusions (recommendation grade: 3C).

Recommendation 8: For patients with HCC and BTC requiring systemic treatment, testing for KRAS hotspot mutations is recommended. If KRAS G12C or G12D mutations are detected after failure of conventional treatments, participation in relevant clinical trials, such as those involving sotorasib, is advisable based on available data and evidence (recommendation grade: 3C).

Recommendation 9: Testing for MET overexpression or amplification is recommended for patients with HCC and BTC requiring systemic treatment. If MET overexpression or amplification is identified in patients with HCC or BTC who have failed conventional systemic therapy, cabozantinib or crizotinib may be considered a potential treatment option for subsequent-line treatment strategies (recommendation grade: 3C).

Recommendation 10: Based on current clinical evidence, isolated testing for TP53 mutations and PI3K/mTOR signaling pathway genes is not currently recommended for patients with HCC and BTC undergoing systemic therapy (degree of expert consensus: 100%).

Recommendation 11: For patients with HCC and BTC scheduled to receive systemic therapy, validated next-generation sequencing (NGS) is recommended to detect HR repair gene mutation status, including both somatic and germline mutations. However, individual HRD defect status testing is not recommended. For patients with advanced metastatic HCC or BTC who have failed conventional treatment and possess pathogenic or suspected pathogenic HR repair gene mutations, particularly BRCA1 and BRCA2, PARPi therapy may be considered (recommendation grade: 3C).

Recommendation 12: IHC detection, FISH, and NGS can be used to assess gene overexpression, determine gene fusion or rearrangement, and detect single nucleotide variants (SNVs), respectively. Combined testing of multiple genes is highly significant for guiding treatment. Therefore, NGS techniques are recommended for detecting the mutations listed in Table 1 in liver and BTC tissue samples, particularly in cases where tissue samples are limited.

2. Molecular markers related to immunotherapy in hepatobiliary cancers

Recommendation 13: Routine screening for PD-L1 expression to select the optimal population for PD-1/PD-L1 monoclonal antibody therapy in hepatobiliary cancers is not currently recommended. However, considering the role of PD-L1 as a predictive biomarker for immunotherapy in various solid tumors, its significance in hepatobiliary cancers should be further explored in combination with clinical practice and clinical trials (degree of expert consensus: 100%).

Recommendation 14: MSI-H and dMMR are critical biomarkers for predicting the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in solid tumors, including hepatobiliary cancers. MSI/dMMR testing is recommended for patients with inoperable or advanced disease. PCR-CE is recommended for microsatellite status testing and IHC for dMMR testing. In addition, MSI and MMR genes can be tested using a certified NGS panel in laboratories accredited by Clinical Laboratory Improvement Amendments (CLIA), College of American Pathologists (CAP), and CNAS-CL02:2023 (equivalent to ISO 15189:2022) (degree of expert consensus: 100%).

Recommendation 15: Given the favorable efficacy of ICIs in patients with MSI-H, patients with advanced hepatobiliary cancers and MSI-H are recommended to initiate treatment with relevant ICIs as early as possible. For patients with a family history of tumors, particularly those with BTC, the genetic risk of Lynch syndrome must be excluded using NGS. In patients with unresectable or metastatic BTC having MSI-H/dMMR, pembrolizumab is recommended as first- or second-line treatment (recommendation grade: 2A), and dostarlimab is recommended as second-line treatment (recommendation grade: 2B). In patients with unresectable or metastatic HCC who have MSI-H/dMMR, dostarlimab is recommended as a second-line treatment (recommendation grade: 2B).

3. TMB and immunotherapy

Recommendation 16: Although TMB is a biomarker used to predict the efficacy of ICIs in various solid tumors, no unified standard has been established for the TMB algorithm. Thus, patients with unresectable or metastatic hepatobiliary cancers are recommended to undergo TMB testing using NGS. In patients with unresectable or metastatic BTC with TMB-H, nivolumab plus ipilimumab for first-line or second-line treatment (recommendation grade: 2B) and pembrolizumab for second-line treatment (recommendation grade: 2B) should be considered. For patients with unresectable or metastatic HCC and TMB-H, nivolumab plus ipilimumab is recommended as the first- or second-line treatment (recommendation grade: 2B).

Recommendation 17: For BTC, IHC is recommended to detect HER2, MET, and MMR; FISH to detect FGFR2, RET, NTRK, and NRG1 fusions or rearrangements; and first-generation sequencing to detect IDH1/2, BRAF V600E, and KRAS hotspot mutations. NGS is recommended as a comprehensive test for TP53, HRD, TMB, and all other variants (degree of expert consensus: 100%).

4. Potential novel molecular markers for hepatobiliary tumors

Recommendation 18: Relevant clinical studies must be actively pursued when conditions allow for elucidating the clinical value of novel molecular markers in the early diagnosis of hepatobiliary cancers, prognostic monitoring, therapeutic efficacy prediction, treatment optimization, and development of new immunotherapy targets.

Contact author: Yinying Lu, Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China. E-mail: luyinying1973@163.com.

Funder: This work was funded by the National Natural Science Foundation of China (No. 82272956).

Conflict of interest: The authors declare that there is no conflicts of interest.

See the article: Ainiwaer A., et al., Chinese expert consensus on the clinical application of molecular diagnostics in hepatobiliary cancers (2024 edition), Liver Res, Volume 8, Issue 4, 2024, Pages  195-206, https://doi.org/10.1016/j.livres.2024.11.005.