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.

FIG 1.

Baseline characteristics of the study population. (A) CONSORT diagram of the study depicting eligibility and exclusion criteria, the frequency of patients with ICC and ECC, and the frequency of molecular profiling among patients with advanced disease. (B) Histogram of patients stratified by age of initial diagnosis. The 847-patient cohort was subdivided into groups on the basis of age of initial CCA diagnosis, in increments of 5 years. Patients 50 years and younger represented 15% of the cohort. CCA, cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma; HCC, hepatocellular carcinoma; ICC, intrahepatic cholangiocarcinoma.

FIG 2.

Genomic profiling of young (50 years and younger) versus older (older than 50 years old) patients with CCA. In an analysis of 459 patients who underwent genomic profiling for CCA, FGFR2 fusions, ATM mutations, and BRAF mutations were more commonly seen in younger patients. Starred columns highlight genes with statistically significant differences in rates of alterations present between young and older patients (all P < .05). All gene labels indicate point mutations at the gene with the following exceptions, which include copy number alterations: ATM, CDKN2A, cMET, PIK3CA/PIK3R1, ARID1A, PIK3CA, and SMAD4. CCA, cholangiocarcinoma.

FIG 3.

Spectrum of gene alterations targeted with targeted therapies in (A) young (50 years and younger) and (B) older (older than 50 years) patients in our cohort. Among patients who received targeted therapy, the majority in both age groups received targeted therapy directed at FGFR2 fusions or IDH1 mutations. Gene names without the type of alteration indicated refer to mutations of those genes. ALK, anaplastic lymphoma kinase; Amp, amplification; HER2, human epidermal growth factor receptor 2; MET, mesenchymal-epithelial transition factor.

FIG 4.

Differences in median overall survival between young (50 years and younger) and older (older than 50 years) patients who presented with advanced disease. Compared with older patients, young patients who presented with advanced disease had higher median OS. OS, overall survival.