Biliary tract cancers (BTCs) are a histologically and molecularly diverse group of malignancies arising from the gallbladder and the ductal epithelium of the biliary tree. Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver malignancy in the United States. Surgical resection with negative margins is the only recognized curative treatment option for iCCA; however, most patients will present with advanced or unresectable disease. The clinical presentation is largely non-specific, with the characteristic symptoms of biliary malignancies being less frequent than extrahepatic cholangiocarcinoma. Clinical management in iCCA is heavily influenced by the molecular profile of individual tumors. Hence, pathologists must exercise caution to prevent tissue exhaustion during the diagnostic workup of iCCA and ensure the availability of tissue samples for molecular testing. Establishing standardized procedures for obtaining adequate tissue and using molecular testing is vital. Circulating tumor DNA (ctDNA) offers a potential alternative to tissue-based analysis, especially in cases with insufficient tissue samples. Drugs targeting alterations in NTRK, IDH1, BRAF, FGFR2, and HER2 are commonly utilized. Targeting the MDM2–p53 pathway represents an avenue for future investigations in advanced BTCs. Liver transplantation and locoregional therapies are treatment modalities that may represent curative intent treatments for patients with unresectable disease, and larger explorations are warranted. Akin to HCC, a multidisciplinary team–based approach is essential for patients with BTCs. Through this narrative review of literature, we provide an overview of the current management of iCCA with perspectives regarding future directions in the clinical management of iCCA. We also present patient perspectives regarding the importance of patient advocacy and access to advances in clinical research for patients with BTCs.

Pre-clinical data suggest that mutations in the MEN1, DAXX, and/or ATRX genes may potentially increase radiation efficacy in cancer cells. Herein, we explore the association between response to peptide receptor radionuclide therapy (PRRT) and those mutations in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We analyzed tissue-based next generation sequencing (NGS) assay results and clinicopathologic data from 28 patients with GEP-NETs treated with PRRT. Findings were correlated with progression-free survival (PFS) and objective response rate (ORR). Patients with mutations in MEN1, DAXX, and/or ATRX (n = 13) had a longer median PFS (26.47 vs 12.13 months; P = 0.014) than wild-type (n = 15) patients when adjusted for surgery prior to PRRT, tumor grade, and presence of TP53 mutation. Alterations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended toward longer PFS compared to patients without concurrent mutations (31.53 vs 17.97 months; P = 0.09). ORR was higher in patients with a mutation in MEN1, DAXX, or ATRX (41.67% vs 15.38%). In pancreatic NET patients, these target mutations also showed a longer PFS (28.43 vs 9.83 months; P = 0.04). TP53 alterations showed a shorter PFS than wild-type cases (11.17 vs 20.47 months; P = 0.009). Mutations in MEN1/DAXX/ATRX are associated with improved PFS in patients with GEP-NETs receiving PRRT and might be used as a biomarker for treatment response.

Background: Peptide Receptor Radionuclide Therapy (PRRT), a form of Radioligand Therapy (RLT), and Capecitabine/Temozolomide (CAPTEM) are cornerstones of systemic therapy for metastatic pancreatic neuroendocrine tumors (PNETs). Data regarding comparative efficacy are lacking. Herein, we compare the efficacy of PRRT vs. CAPTEM as second-line/beyond regimens and treatment sequencing. Methods: Clinicopathologic, radiographic, and genomic data were captured for metastatic PNETs seen in our multi-disciplinary NET clinic between 2013 and 2023. The primary outcome was progression-free survival (PFS) after progression on a previous line of systemic therapy. The secondary outcomes were objective response rate (ORR), time to response (TTR), and overall survival (OS). Results: Fifty-nine cases were included. PFS was similar in the PRRT (n = 29) and CAPTEM (n = 30) groups (PRRT = 21.90 months vs. CAPTEM = 20.03 months; HR 0.99; p = 0.97). On subgroup analysis, PRRT had longer PFS in cases without extrahepatic metastases (26.47 months vs. 17.67 months; p = 0.03) and cases with a mutation in the MEN1, DAXX, and/or ATRX genes (28.43 months vs. 18.67 months; p = 0.03). PRRT had reduced PFS in patients with grade 3 disease (7.83 months vs. 16.33 months; p = 0.02). ORR did not vary significantly (34.78% vs. 40.91%; p = 0.67). CAPTEM responders showed shorter TTR (6.03 months vs. 11.15 months; p = 0.03). In patients who received both, OS did not vary based on the sequence (HR 1.20; p = 0.75). Conclusions: PFS, ORR, and OS are similar when using PRRT vs. CAPTEM as second-line-and-beyond therapy for patients with metastatic PNETs. However, patients with MEN1, DAXX, and/or ATRX mutations or without extrahepatic metastases might better benefit from PRRT and patients with grade 3 disease from CAPTEM. Candidates for surgical debulking or with tumor-induced symptoms may benefit from initial treatment with CAPTEM due to shorter TTR.

PURPOSE: Approximately one in three patients with appendiceal cancer (AC) is diagnosed before age 50 years. Early-onset appendiceal cancer (EOAC) exhibits distinct clinicopathologic and demographic features compared with late-onset disease, suggesting potential biological differences. However, the molecular differences remain poorly understood. This study aims to compare EOAC and late-onset AC (LOAC, ≥50 years) mutational profiles and evaluate their impact on overall survival (OS). METHODS: A retrospective analysis was conducted using the Memorial Sloan Kettering—Metastatic Events and Tropisms database. Patients were stratified by age at the time of surgery into EOAC and LOAC groups. Logistic regression was used to assess differences in mutational profiles between these two groups. Findings were validated using data from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange project. Kaplan-Meier survival analysis and multivariable Cox proportional hazard models were used to evaluate associations with survival. RESULTS: The study included 200 patients with appendiceal adenocarcinoma (median age: 55 years, IQR, 47-68), of whom 70 (35%) had EOAC and 130 (65%) had LOAC. Patients with EOAC had higher odds of harboring PIK3CA mutations compared with LOAC (17.1% v 7.7%; odd ratio, 2.65; P = .04), which was consistent when combined with the GENIE data set (12.3% v 5.9%; P < .01). PIK3CA mutations were exclusively observed in patients with metastatic disease (11.8%) and were more common in adenocarcinoma not otherwise specified (NOS) than mucinous tumors (63.6% v 36.4%; P = .04). In multivariable analysis, PIK3CA mutations were independently associated with worse OS (hazard ratio, 2.62 [95% CI, 1.32 to 5.20]; P < .01). CONCLUSION: PIK3CA mutations are more common in EOAC and independently associated with worse OS. These findings suggest incorporating PIK3C A mutation status into prognostic assessments and warrant further investigation of PIK3CA inhibitors as a potential therapeutic strategy for appendiceal adenocarcinoma.

Background: Gastroenteropancreatic poorly differentiated neuroendocrine carcinomas (GEP‐NECs) are aggressive cancers where cytotoxic chemotherapy is the backbone of treatment. While the addition of immunotherapy with immune checkpoint inhibitors (IOs) to chemotherapy is recommended for lung NECs, evidence regarding IO efficacy in GEP‐NECs is limited. We explore outcomes with systemic therapies in patients with metastatic GEP‐NECs using the National Cancer Database (NCDB). Methods: Cases of metastatic GEP‐NECs with years of diagnosis between 2018 and 2022 were identified within the NCDB. Overall survival (OS) was analyzed using Kaplan–Meier estimations and Cox proportional hazards regression. Results: Four thousand one hundred twenty‐seven cases were included. 1209 (29.29%) patients did not receive any systemic therapy (chemotherapy/immunotherapy/both). Among the 2918 patients that received systemic therapy, 758 (25.98%) patients received immunotherapy (immunotherapy alone = 21; chemotherapy plus immunotherapy [chemoIO] = 737). The percentage of patients receiving immunotherapy alongside chemotherapy increased from 12.27% in 2018 to 34.18% in 2022. Two thousand two hundred eighty cases were included for survival analysis. Patients treated with chemoIO ( N = 532) had prolonged OS versus chemotherapy alone ( N = 1748), with median OS of 10.51 months vs. 8.31 months (HR, 0.77; 95% CI, 0.69–0.85; p < 0.001). The association was significant in all histological subgroups (small‐cell, p < 0.001; large‐cell, p = 0.04; others/not specified, p = 0.01). Conclusions: Combination chemoIO may improve survival in metastatic GEP‐NECs as compared to chemotherapy alone. Results of currently ongoing clinical trials exploring the role of immunotherapy in extrapulmonary NECs may help guide clinical practice in GEP‐NECs.