Jain, Apurva

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.

Purpose FGFR genetic aberrations (GAs) occur in an estimated 10% to 16% of intrahepatic cholangiocarcinomas (CCAs). The natural history of CCA with FGFR GAs, the prognostic role of coexisting GAs, and the outcome with FGFR-targeted inhibitors are unknown. Patients and Methods Patients with CCA with FGFR GAs were identified using next-generation sequencing or fluorescence in situ hybridization from four tertiary cancer centers and compared with FGFR wild-type counterparts. Data reviewed included demographic, treatment, overall survival (OS), and GA data. Fisher’s exact test, Kaplan-Meier plots, and log-rank tests were used for statistical analysis. Results Three hundred seventy-seven patients with CCA were identified, and 95 had FGFR GAs. FGFR2 GA was most common (n = 74, with 63 fusions) and seen in intrahepatic CCA. In patients with CCA, FGFR GAs occurred more frequently in younger patients (≤ 40 years; 20%) compared with older patients (> 40 years; 6.7%; P < .001), presented at an earlier stage (TNM stage I/II v III/IV: 35.8% v 22%, respectively; P = .001), and were associated with a longer OS compared with patients without FGFR GAs (37 v 20 months, respectively; P < .001). This difference remained significant after excluding 36 patients treated with FGFR inhibitors. There was no OS difference ( P = .60) between CCA with FGFR2 fusions (n = 63) versus other FGFR GAs (n = 29). Patients with FGFR GAs had a better OS with FGFR-targeted therapy compared with standard treatment ( P = .01). BAP1 mutation was the most common coexisting mutation without prognostic impact, whereas TP53 ( P = .04) and CDKN2A/B ( P = .04) were correlated with a shorter OS. Conclusion CCA with FGFR GAs represents a unique subtype occurring in younger patients with an indolent disease course. FGFR-targeted therapy may have a positive impact on OS in this subgroup.

4086 Background: Mutations in DNA repair pathway were identified in 13% of Biliary Tract Cancers (BTC) [ Cancer2016;122:3838–3847]. High TMB tumors including melanoma, lung cancer and those with microsatellite instability (MSI-H) are associated with susceptibility to immune blockade using checkpoint inhibitors. TMB data in BTC is limited and its association with actionable somatic mutation (mut) profiles in BTC is unknown. Methods: Comprehensive genomic profiling (CGP) of 309 FFPE tissue blocks of BTC pts with a hybrid capture of all coding exons of 236 cancer-related genes and 47 introns of 19 genes rearranged in cancer was done using FoundationOne. Base substitutions, indels, gene fusion/rearrangements, TMB, and MSI status were assessed. TMB was calculated by counting mutations across a 1.25Mb region and classified into high (TMBH; ≥20 mut/Mb), intermediate (TMBI; 6 - 19mut/Mb) and low (TMBL; < 6mut/Mb). MSI high (MSIH) and Stable (MSS) status was assigned by a computational algorithm examining 114 intronic homopolymer loci. Patients with TMB ≥6 mut/Mb (N = 60) were included in the clinical correlative portion of this study. Results: Sixty patients with TMB ≥6 mut were identified out of 309 pts of which 9 (15%) were TMBH and 51 (85%) were TMBI. These included 3 (5%) MSIH and 18 (30 %) MSS. The median age was 59 years (range: 29-86), 35 (58%) were females, majority were intrahepatic cholangiocarcinoma (n = 31; 52%) and 28 (47%) presented with advanced disease at diagnosis. Twenty three (38%) pts had received radiation therapy, 28 (47%) surgery and 3 (5%) received immunotherapy. Most frequent co-existing mut seen was TP53 (N = 35; 58%). APC mut was seen in 7 (12%) pts. DNA repair pathway muts ( MSH6, BRCA1, BRCA2, ATM, MLH1, or MSH2 genes) were identified in 78% of TMBH versus 16% in TMBI cases (p < 0.0001). Frequency of PIK3CA mut differed significantly between TMBH and TMBI (44% vs 10%, p < 0.0001). Pts with TMBI had a significantly better median OS (110 weeks) as compared to TMBH (43 weeks) (p = 0.003). Conclusions: DNA repair pathway and PIK3CA mut maybe associated with TMBH in BTC. A better understanding of TMB and associated actionable mutations in BTC may be of value for the management of BTC patients with targeted agents and immunotherapy.

4076 Background: Gallbladder carcinoma (GBC) is commonly diagnosed at an advanced, unresectable disease stage and has a poor prognosis. Comprehensive genomic profiling (CGP) has a developing role in guiding systemic, precision anti-cancer therapy. Methods: We performed hybrid capture-based CGP on FFPE samples for 491 consecutive advanced GBCs. Mean coverage depth was >550X for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer. All 4 classes of genomic alterations (GA) were detected. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA. Results: Median age was 64 (range 25-88) and 69% (337/491) of patients were female. 96% (470), 2.9% (14), and 1.4% (7) of GBC patients had the diagnosis of adenocarcinoma, adenosquamous, or carcinoma not specified (NOS), respectively. Commonly altered genes were TP53 (62%), CDNK2A (31%), ARID1A (18%), and SMAD4 (15%), and most of the genetic aberrations (GA) were short variants. Potentially targetable SCNAs (including ERBB genes, MET, FGFRs, and the CCND1-FGF3/4/19 11q13 amplicon) were identified in 21% of cases (Table). Oncogenic BRAF, ALK, or FGFR2/3 rearrangements were found in 7 cases (1.4%). Moreover, 7.8% of cases had BRCA2 or ATM GA, and 0.8% had INI1loss suggesting benefit from PARP or EZH2 inhibitors, respectively. TMB was low; the 25th, 50th, and 75th percentiles were 2.5, 3.8 and 6.3 mutations/Mb, respectively. Less than 1% of cases had microsatellite instability. Radiological response to TKIs and immunotherapy was noted. Conclusions: In addition to the significant opportunity for anti-HER targeted therapies, other subsets of GBC cases harbored kinase GA (particularly SCNA), the 11q13 amplicon, or BRCA2/ ATM/ INI1mutations that are linked to therapeutic benefit. How the frequency of both driver SCNA and DNA repair alterations in GBC can be linked with inflammation awaits additional investigation. [Table: see text]

Abstract Background Biliary tract malignancies, in particular cholangiocarcinomas (CCA), are rare tumors that carry a poor prognosis. BRCA2 mutation carriers have an increased risk of developing CCA with a reported relative risk of ∼5 according to the Breast Cancer Linkage Consortium. In addition to this risk, there are potential therapeutic implications in those harboring somatic and/or germline (GL) BRCA mutations. Therefore, it is important to define the clinical characteristics of GL/somatic BRCA1/2 variants in CCA patients. Materials and Methods We performed a multicenter retrospective analysis of CCA patients diagnosed between January 2000 and December 2013 with GL or somatic variants in BRCA1/2 genes detected by GL mutations testing and/or by tumor next generation sequencing. Cases were identified from clinical databases at participating institutions. Data including demographics, clinical history, surgical procedures, and systemic chemotherapy or radiation were extracted from patients' records. Results Overall, 18 cases were identified: 5 carriers of GL BRCA1/2 mutations (4 BRCA2; 1 BRCA1) and 13 harboring somatic variations (7 BRCA1; 6 BRCA2). Mean age at diagnosis was 60, SD ± 10 years (range 36–75 years), with male and female prevalence rates of 61.2% and 38.8%, respectively. Stage at diagnosis was I (n = 4), II (n = 3), III (n = 3), and IV (n = 8). Six patients had extrahepatic CCA and the rest intrahepatic CCA. Thirteen patients received platinum-based therapy and four were treated with poly ADP ribose polymerase inhibitors, of whom one experienced sustained disease response with a progression-free survival of 42.6 months. Median overall survival from diagnosis for patients with stage I/II in this study was 40.3 months (95% confidence interval [CI], 6.73–108.15) and with stages III/IV was 25 months (95% CI, 15.23–40.57). Conclusion BRCA-associated CCA is uncommon. This multicenter retrospective study provides a thorough clinical analysis of a BRCA-associated CCA cohort, which can serve as a benchmark for future development and design of expanded analyses and clinical trials.

BACKGROUNDBiliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum–based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance.METHODSPretreatment, formalin‐fixed, paraffin‐embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression‐free survival (PFS), and overall survival (OS).RESULTSWhen genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first‐line therapy, the joint status of cyclin‐dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT‐rich interaction domain 1A (ARID1A) was associated with PFS (P = .0004) and OS (P ≤ .0001). Patients with mutations in CDKN2A and TP53 were identified as a poor‐prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single‐mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached.CONCLUSIONSIn the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657‐66. © 2016 American Cancer Society.