Study Supports Comprehensive Genomic Profiling for Patients With Biliary Tract Cancer

As the treatment landscape for biliary tract cancer (BTC) expands, the clinical utility of comprehensive genomic profiling (CGP) to detect potential therapy targets warrants further research. A prospective study published in Frontiers in Oncology suggests that CGP can help with clinical decision-making and predict clinical outcomes in advanced BTC.

BTC, which encompasses cancers in the biliary tract—including intrahepatic and extrahepatic cholangiocarcinoma (ICC and ECC), gallbladder cancers, and ampullary cancer—has a 5-year survival rate lower than 15%. A lack of established early detection methods in tandem with a lack of curative therapies contribute to the poor prognosis patients with BTC face. With novel therapeutic strategies under investigation, review authors Takada, et al., aimed to evaluate the utility of CGP for patients with BTC and to identify genomic alterations that may help with prognostication.

The immunotherapy armamentarium for cancer overall has been growing, but combination gemcitabine and cisplatin chemotherapy is the current standard of care in advanced BTC. Recent research suggests that adding the immune checkpoint inhibitor (ICI) durvalumab to the gemcitabine-cisplatin regimen may be an effective approach, with a phase 3 study underway to confirm the benefit of adding durvalumab.

The FDA has already approved 2 novel targeted therapies: pemigatinib, a fibroblast growth factor receptor inhibitor; and ivosidenib, an isocitrate dehydrogenase 1 variant inhibitor. Tumor-agnostic ICIs and neurotrophic receptor tyrosine kinase (NTRK) inhibitors are also options in patients whose tumors fit certain genomic criteria. Human epidermal growth factor receptor-2 (EGFR-2)–targeted therapies for BTC with amplified Erb-B2 receptor tyrosine kinase 2 (ERBB2) is another emerging targeted therapy option. Overall, the increasing number of known targets and potentially applicable therapeutics supports the potential benefit of CGP in this patient population.

The study included 72 patients with advanced BTC at 5 hospitals in Japan who underwent CGP and met performance status and specimen eligibility criteria. Of these patients, 26 (36.1%) had ICC, 22 (30.6%) had ECC, 21 (29.2%) had gallbladder carcinoma, and 3 (4.2%) had ampullary carcinoma. The median patient age was 70 years, and all patients had undergone chemotherapy. Most samples (65.3%) were surgical specimens, but endoscopic ultrasound-guided fine needle aspiration and a cell block prepared from ascites were also feasible methods, the authors noted. In the study cohort, 66 samples underwent testing with F1CDx sequencing (91.7%), 5 were done with F1LCDx, and 1 (1.4%) was done with an NCC Oncopanel.

All patients in the cohort showed genomic alterations, with the most common being tumor protein p53, cyclin-dependent kinase inhibitor 2A (CDKN2A)or 2B (CDKN2B), and Kirsten rat sarcoma virus (KRAS) alterations. Of these patients, 42 (58.3%) had actionable genomic alterations and 14 (33.3%) had multiple actionable alterations. However, there were not distinct patterns associated with the 4 BTC subtypes as previous reports have suggested.

Eight (11.1%) of the 42 patients with actionable genomic alterations were treated with therapies matched to their genotypes in the second line or later. Gallbladder carcinoma patients with high TMB or MSI were given an ICI and experienced stable and progressive disease, respectively. Patients with ICC and an FGFR2 fusion gene were given pemigatinib, which elicited partial responses. Both treatments were covered by public insurance. Patients with high programmed death ligand 1 or 2 (PD-L1/PD-L2) expression, high TMB, breast cancer gene 2 (BRCA2) mutation or high ERBB2 expression received investigational agents.

Genomic alterations found in the study cohort were not significantly associated with clinical features or overall survival (OS), except in the case of CDKN2A or CDKN2B loss predicting poor prognosis and shorter OS in patients with ICC. Clinical features did not correlate to OS in most cases, although OS in patients with gallbladder carcinoma was notably shorter than OS in patients with ECC. The authors noted that normally, gallbladder carcinoma patients face a more positive prognosis than those with ICC or ECC, but the patients in the study cohort represent a cohort of patients with advanced cancer who did not respond to typical therapies.

While the study had a limited number of patients and no definitive conclusion, the findings support the use of CGP in clinical decision-making for advanced BTC.

“Although the Japanese health insurance system does not allow CGP before initial treatment, performing CGP in an earlier phase of therapy may improve clinical outcomes,” the authors wrote. “Further efforts are needed to delineate our results and combat this aggressive malignancy.”

Reference

Takada K, Kubo T, Kikuchi J, et al. Effect of comprehensive cancer genomic profiling on therapeutic strategies and clinical outcomes in patients with advanced biliary tract cancer: A prospective multicenter study. Front Oncol. Published online September 2, 2022. doi:10.3389/fonc.2022.988527