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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.

BACKGROUND & AIMS Despite the significant association between obesity and several cancers, it has been difficult to establish an association between obesity and hepatocellular carcinoma (HCC). Patients with HCC often have ascites, making it a challenge to accurately determine body mass index (BMI), and many factors contribute to the development of HCC. We performed a case–control study to investigate whether obesity early in adulthood affects risk, age of onset, or outcomes of patients with HCC. METHODS We interviewed 622 patients newly diagnosed with HCC from January 2004 through December 2013, along with 660 healthy controls (frequency-matched by age and sex) to determine weights, heights, and body sizes (self-reported) at various ages before HCC development or enrollment as controls. Multivariable logistic and Cox regression analyses were performed to determine the independent effects of early obesity on risk for HCC and patient outcomes, respectively. BMI was calculated, and patients with a BMI ≥30 kg/m2 were considered obese. RESULTS Obesity in early adulthood (age, mid-20s to mid-40s) is a significant risk factor for HCC. The estimated odds ratios (OR) and 95% confidence intervals (CI) were 2.6 (1.4–4.4), 2.3 (1.2–4.4), and 3.6 (1.5–8.9) for the entire population, men, and women, respectively. Each unit increase in BMI at early adulthood was associated with a 3.89-month decrease in age at HCC diagnosis (P<.001). Moreover, there is a synergistic interaction between obesity and hepatitis virus infection. However, we found no effect of obesity on the overall survival of patients with HCC. CONCLUSION Early adulthood obesity is associated with increased risk of developing HCC at a young age in the absence of major HCC risk factors, with no effect on outcomes of patients with HCC.

Background & Aims Environmental factors have been identified that affect risk of hepatocellular carcinoma (HCC), but little is known about the effects of sex hormones on liver cancer development or outcome. We investigated whether menopause hormone therapy (MHT) affects risk, age at onset, or outcome of HCC. Methods We performed a case–control study of 234 female patients treated for HCC at a tertiary medical center and with 282 healthy women (controls), from January 1, 2004 through May 31, 2015. We collected detailed information on environmental exposures, ages of menarche and menopause, hysterectomies, and uses of birth control and MHT. We performed multivariable logistic and Cox regression analyses to determine the independent effects of factors associated with women on risk and clinical outcome in HCC. The primary outcomes were effect of MHT on HCC risk, the relationship between MHT with hepatitis virus infection on HCC development, and effect of MHT on age at HCC onset or survival after diagnosis of HCC. Results The estimated adjusted odds ratio (AOR) for HCC in women who ever used estrogen was 0.53 (95% CI, 0.32–0.88). This association was supported by the older age of HCC onset among estrogen users (mean, 64.5±0.9 years) vs non-users (mean, 59.2±1.1 years) (P=.001) and the reduced risk of HCC among long-term users (more than 5 years) (AOR, 0.36; 95% CI, 0.20– 0.63). Users of estrogen also had a reduced risk for hepatitis-associated HCC: AOR for users, 4.37 (95% CI, 1.67–11.44) vs AOR for non-users, 17.60 (95% CI, 3.88–79.83). Estrogen use reduced risk of death from HCC (hazard ratio, 0.55; 95% CI, 0.40–0.77) (P=.01). Median overall survival times were 33.5 months for estrogen users (95% CI, 25.7–41.3 months) and 24.1 months for non-users (95% CI, 19.02–29.30 months) (P=.008). Conclusion In a case–control study of women with HCC vs female controls at a single center, we associated use of estrogen MHT with reduced risk of HCC and increased overall survival times of patients with HCC. Further studies are needed to determine the benefits of estrogen therapy for women and patients with HCC, and effects of tumor expression of estrogen receptor.

4087 Background: The management of CCA has evolved as targeted and immune checkpoint inhibitor (ICPI) therapies have emerged. We used comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) that have potential to personalize therapy for CCA. Methods: 3634 CCA underwent hybrid capture based CGP on 0.8-1.1 Mb of the coding genome to identify GAs in exons and select introns in up to 404 genes, TMB, microsatellite status (MSI) and % monoallelic genome (gLOH). PD-L1 expression was determined by IHC (Dako 22C3). Results: 52% of CCA were female with a median age of 62 years (range 16 - > 89). The most common biopsy sites were liver (74%), lymph node (4%), bile duct (3.3%), and lung (2%). MSI-high was rare (1%), 118 and 47 cases had TMB > 10 and > 20 mut/mb respectively. Of the latter, 51% (24/47) were MSI-H. PD-L1 amplification (AMP) was present in 0.27%. Of 490 CCA tested, 43 (9%) were positive for PD-L1 expression. 11% of cases had gLOH > 16%, only 2 cases had both TMB > 20 and gLOH > 16%. GA were most common in TP53 (31%), CDKN2A (29%), KRAS (20%) and ARID1A (17%). Potentially targetable GAs included FGFR2 (11%, 85% fusions), BRAF (5%, 50% V600E), ERBB2 (5%, 72% AMP), MET (2%, 90% AMP), EGFR (0.52%) and rarer ( < 0.5%) FGFR3, RET, FGFR1, ALK, and ROS1 fusions. The FGFR2 fusions had 128 unique 3’ partner genes including BICC1 (26%), CCDC6 (3.2%), AHCYL1 (2.6%) and KIAA1217 (2.6%). FGFR2 fusions occurred in a mutually exclusive fashion from high gLOH (p < 0.002), but not high TMB. GA in IDH1 (15%) were mutually exclusive of FGFR2 fusions (p < 1e-13), but co-occurred with PBRM1 GA (23%, p < 1e-21), ARID1A (26% p < 1e-10). IDH1 GA had gLOH similar to the overall CCA population but were enriched for low TMB (p < 1e-3). Conclusions: Nearly 20% of CCA cases harbor targetable kinase GA, half of which were FGFR2 fusions. Independently, an additional 10% (gLOH) and 1% (high TMB, MSI and/or PD-L1 AMP) may benefit from PARP inhibitors and ICPI respectively. Independently, co-mutation of IDH1 and PBRM1/ARID1A defines a class of CCA that warrants further investigation for sensitivity to PARP inhibitors and may serve as a paradigm for other tumors (ie. gliomas) with a similar co-occurrence landscape.

Purpose: Molecular profiling has been used to select patients for targeted therapy and determine prognosis. Noninvasive strategies are critical to hepatocellular carcinoma (HCC) given the challenge of obtaining liver tissue biopsies.Experimental Design: We analyzed blood samples from 206 patients with HCC using comprehensive genomic testing (Guardant Health) of circulating tumor DNA (ctDNA).Results: A total of 153/206 (74.3%) were men; median age, 62 years (range, 18-91 years). A total of 181/206 patients had 1 alteration. The total number of alterations was 680 (nonunique); median number of alterations/ patient was three (range, 1-13); median mutant allele frequency (% cfDNA), 0.49% (range, 0.06%-55.03%). TP53 was the common altered gene [>120 alterations (non-unique)] followed by EGFR, MET, ARID1A, MYC, NF1, BRAF, and ERBB2 [20-38 alterations (nonunique)/gene]. Of the patients with alterations, 56.9% (103/181) had 1 actionable alterations, most commonly in MYC, EGFR, ERBB2, BRAF, CCNE1, MET, PIK3CA, ARID1A, CDK6, and KRAS. In these genes, amplifications occurred more frequently than mutations. Hepatitis B (HBV)-positive patients were more likely to have ERBB2 alterations, 35.7% (5/14) versus 8.8% HBV-negative (P ¼ 0.04).Conclusions: This study represents the first large-scale analysis of blood-derived ctDNA in HCC in United States. The genomic distinction based on HCC risk factors and the high percentage of potentially actionable genomic alterations suggests potential clinical utility for this technology.Recent technological advances in molecular diagnostics have allowed for the study of solid malignancies through noninvasive blood sampling. Importantly, intact circulating tumor cells (CTCs) and cell-free DNA (cfDNA) [leukocyte-derived and tumor-derived (circulating tumor DNA; ctDNA)] can now be interrogated through advanced sequencing methods in order to identify somatic mutations that may be druggable targets for future therapies (1, 2). Although cfDNA and ctDNA are similar in that they both derive from cell lysis and apoptosis (3), ctDNA is the fraction of cfDNA, which can range from <0.1% to >10% (4), specifically derived from primary or metastatic tumors (5). Therefore, profiling the mutational landscape of ctDNA from solid tumors may represent a particularly attractive method for identifying tumor-associated somatic mutations. Applications that can be envisioned to be of clinical utility for hepatocellular carcinoma (HCC) include detection of genomic changes, mutational analysis, prognostication, oncogenic

Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide. In patients with HCC, histopathogical differentiation is an important indicator of prognosis; however, because determination of HCC differentiation is difficult, the recently described immunohistochemical (IHC) marker glypican3 (GPC3) might assist in HCC prognostication.The goal of our study was to investigate GPC3's IHC staining pattern and define the relationship between its expression and patients' clinicopathologic features and overall survival. We retrieved clinical parameters from 101 pathologically diagnosed HCC patients' medical records and classified these patients into 4 clinical score categories (0–3) based on increasing GPC3 staining intensity and the percentage of stained tumor cells in their resection and biopsy specimens. Histopathological samples were well, moderately, and poorly differentiated in 33, 22, and 12 patients, respectively, and the GPC3 expression rate was 63%, 86%, and 92%,respectively. The median overall survival was 49.9 months (confidence interval (CI): 35.3–64.6 months) for clinical scores 0–1 and 30.7 months (CI: 19.4–41.9 months) for clinical scores 2–3. This difference was not statistically significant (P = .06) but showed a strong trend. In conclusion, a greater GPC3 expression is associated with a worse HCC prognosis and may be a promising prognostic marker.

PURPOSE Intrahepatic cholangiocarcinoma (IHCCA), a global health problem, is increasing in incidence and has differing etiologies worldwide. Next-generation sequencing (NGS) is rapidly being incorporated into the clinical management of biliary cancers. IHCCA is enriched with actionable mutations, and there are several promising targeted therapies under development. NGS data from Asia, where IHCCA is most prevalent, are limited. METHODS Comprehensive genomic profiling of formalin-fixed paraffin-embedded tumor tissue from 164 Asian and 283 Western patients with IHCCA was performed using NGS. We measured the distribution of DNA repair genetic aberrations (GAs) in IHCCA, along with actionable mutations. Also, we evaluated the association between DNA repair GAs and tumor mutation burden (TMB). Based on the TMB status, patients were distinguished into 3 levels: low (< 6 mut/Mb), intermediate (6-10 mut/Mb), and high (TMB-H; ≥ 10 mut/Mb). RESULTS Seventy-two percent of Asian patients had ≥ 1 actionable GA, with a significantly higher frequency in KMT2C , BRCA1/2, and DDR2 compared with Western patients ( P = .02, .003, and .003, respectively); 60.9% of Western patients had ≥ 1 actionable GA and higher frequency of CDKN2A/B and IDH1/2 GAs ( P = .0004 and < .001, respectively). GAs in nuclear factor kappa B pathway regulators and DNA repair genes occurred more frequently in Asian patients ( P = .006 and .001, respectively). There was a higher frequency of TMB-H in Asian compared with the Western cohort (12.2% v 5.9%; P = .07). CONCLUSION A higher burden of DNA repair mutations and frequency of patients with TMB-H in the Asian IHCCA cohort compared with the Western patients suggests a potential role for DNA repair and immune checkpoint inhibitors in the Asian population. Future clinical trials should account for this genetic heterogeneity.