The Cholangiocarcinoma in the Young (CITY) Study: Tumor Biology, Treatment Patterns, and Survival Outcomes in Adolescent Young Adults With Cholangiocarcinoma

Abstract

PURPOSE Increased awareness of the distinct tumor biology for adolescents and young adults (AYAs) with cancer has led to improvement in outcomes for this population. However, in cholangiocarcinoma (CCA), a paucity of data exist on the AYA population. To our knowledge, we present the largest study to date on AYA disease biology, treatment patterns, and survival outcomes in CCA. METHODS A multi-institutional cohort of patients with CCA diagnosed with intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC) was used for analysis. Retrospective chart review was conducted on patients who were 50 years old and younger (young; n = 124) and older than 50 years (older; n = 723). RESULTS Among 1,039 patients screened, 847 patients met eligibility (72% ICC, 28% ECC). Young patients had a larger median tumor size at resection compared with older patients (4.2 v 3.6 cm; P = .048), more commonly had N1 disease (65% v 43%; P = .040), and were more likely to receive adjuvant therapy (odds ratio, 4.0; 95% CI, 1.64 to 9.74). Tumors of young patients were more likely to harbor an FGFR2 fusion, BRAF mutation, or ATM mutation ( P < .05 for each). Young patients were more likely to receive palliative systemic therapy (96% v 69%; P < .001), targeted therapy (23% v 8%; P < .001), and treatment on a clinical trial (31% v 19%; P = .004). Among patients who presented with advanced disease, young patients had a higher median overall survival compared with their older counterparts (17.7 v 13.5 months; 95% CI, 12.6 to 22.6 v 11.4 to 14.8; P = .049). CONCLUSION Young patients with CCA had more advanced disease at resection, more commonly received both adjuvant and palliative therapies, and demonstrated improved survival compared with older patients. Given the low clinical trial enrollment and poor outcomes among some AYA cancer populations, data to the contrary in CCA are highly encouraging.

An assessment of risk factors for recurrence and survival for patients undergoing liver resection for intrahepatic cholangiocarcinoma

“…One study using age 45 years as a cutoff, also including adolescent patients ≥15 age, reported that younger patients had worse overall survival but the difference was not statistically significant, however, stage IV CCA patients undergoing chemotherapy had significantly worse overall survival [16]. Another multicenter study using age 50 years as a cutoff reported that younger patients were more likely to harbor FGFR2 fusion, BRAF mutation and ATM mutation, having a larger median tumor size at resection, have lymph node positivity and receive adjuvant therapy [17]. Similar to the previous study, this study also reported similar median overall survival in younger and older patients; however, younger patients with advanced disease had a higher median overall survival compared with older patients, (12.7 vs 13.5 months, P = 0.49) [17].…”

“…Another multicenter study using age 50 years as a cutoff reported that younger patients were more likely to harbor FGFR2 fusion, BRAF mutation and ATM mutation, having a larger median tumor size at resection, have lymph node positivity and receive adjuvant therapy [17]. Similar to the previous study, this study also reported similar median overall survival in younger and older patients; however, younger patients with advanced disease had a higher median overall survival compared with older patients, (12.7 vs 13.5 months, P = 0.49) [17]. Nevertheless, it is important to note that these studies included all CCA subtypes and not only iCCA.…”

Molecular Differences With Therapeutic Implications in Early-Onset Compared With Average-Onset Biliary Tract Cancers

“…Several reports from smaller data sets have previously suggested this clinical phenotype-enrichment of FGFR2 fusions in younger patients with BTC, particularly women. 13,22,[26][27][28] Fusion Differences in the prevalence of targetable molecular alterations in eoBTC versus aoBTC. aoBTC, average-onset biliary tract cancer; BRAF, B-Raf proto-oncogene; BRCA1, breast cancer gene 1; BRCA2, breast cancer gene 2; eoBTC, early-onset BTC; ERBB2, Erb-B2 receptor tyrosine kinase 2; FGFR2, fibroblast growth factor receptor 2; IDH1, isocitrate dehydrogenase 1; IDH2, isocitrate dehydrogenase 2; KRAS, Kirsten rat sarcoma viral oncogene; NGS, next-generation sequencing.…”

“…The finding of better survival outcomes for eoBTC compared with aoBTC is consistent with the previous literature on early-onset GI cancers. 6,13 Several reasons have been suggested including better comorbidity profile of patients with eoBTC. 6,13 Interestingly, we observed several favorable immune oncology-relevant biomarkers, namely, the IFG score, TIS, and angiogenesis for patients with aoBTC.…”

“…6,13 Several reasons have been suggested including better comorbidity profile of patients with eoBTC. 6,13 Interestingly, we observed several favorable immune oncology-relevant biomarkers, namely, the IFG score, TIS, and angiogenesis for patients with aoBTC. However, as previously stated, no differences were identified concerning the distribution of inflamed tumors or immune cell infiltration, which likely explains the lack of difference in survival outcomes.…”