The clinical deployment of immune checkpoint inhibitors (ICIs) has created a tandem drive for the identification of biomarkers linked to benefit. Comprehensive genomic profiling was performed to evaluate the frequency of genomic biomarkers of ICI response in 755 patients with advanced hepatocellular carcinoma (HCC). Median age was 62 years' old, 73% were male, 46% had extrahepatic disease, 107 had documented hepatitis C, 96 had hepatitis B and 4 patients were coinfected. Median tumor mutation burden (TMB) was 4 mutations/Mb and only 6 tumors (0.8%) were TMB-high. Out of 542 cases assessed for microsatellite instability (MSI), one (0.2%) was MSI-high and TMB-high. Twenty-seven (4%) patients had POLE/D alterations. One patient had a pathogenic POLE R762W mutation but TMB was 4 mutations/Mb. Forty percent had DNA damage response gene alterations. In a small case series (N=17) exploring the relationship between biomarkers and ICI response, one patient (TMB 15 mutations/Mb, MSI-low) had a sustained complete response to nivolumab lasting > 2 years. Otherwise there were no significant genomic or TMB differences between responders, progressors, and those with stable disease. Overall, markers of genomic instability were infrequent in this cohort. Larger clinically annotated datasets are needed to explore genomic and non-genomic determinants of ICI response in HCC.

PURPOSE: Appendiceal neoplasms are heterogeneous and are often treated with chemotherapy similarly to colorectal cancer (CRC). Genomic profiling was performed on 703 appendiceal cancer specimens to compare the mutation profiles of appendiceal subtypes to CRC and other cancers, with the ultimate aim to identify potential biomarkers and novel therapeutic targets. METHODS: Tumor specimens were submitted to a Clinical Laboratory Improvement Amendments-certified laboratory (Foundation Medicine, Cambridge, MA) for hybrid-capture-based sequencing of 3,769 exons from 315 cancer-related genes and 47 introns of 28 genes commonly rearranged in cancer. Interactions between genotype, histologic subtype, treatment, and overall survival (OS) were analyzed in a clinically annotated subset of 76 cases. RESULTS: There were five major histopathologic subtypes: mucinous adenocarcinomas (46%), adenocarcinomas (30%), goblet cell carcinoids (12%), pseudomyxoma peritonei (7.7%), and signet ring cell carcinomas (5.2%). KRAS (35% to 81%) and GNAS (8% to 72%) were the most frequent alterations in epithelial cancers; APC and TP53 mutations were significantly less frequent in appendiceal cancers relative to CRC. Low-grade and high-grade tumors were enriched for GNAS and TP53 mutations, respectively (both χ2 P < .001). GNAS and TP53 were mutually exclusive (Bonferroni corrected P < .001). Tumor grade and TP53 mutation status independently predicted OS. The mutation status of GNAS and TP53 strongly predicted OS (median, 37.1 months for TP53 mutant v 75.8 GNAS-TP53 wild type v 115.5 GNAS mutant; log-rank P = .0031) and performed as well as grade in risk stratifying patients. CONCLUSION: Epithelial appendiceal cancers and goblet cell carcinoids show differences in KRAS and GNAS mutation frequencies and have mutation profiles distinct from CRC. This study highlights the benefit of performing molecular profiling on rare tumors to identify prognostic and predictive biomarkers and new therapeutic targets.

Background

Fibrolamellar carcinoma is a rare and poorly understood malignancy that affects the young in the absence of underlying liver disease. Despite reported small review series, the literature lacks large retrospective studies that may help in understanding this disease.

Methods

Medical record review was undertaken for all patients histopathologically diagnosed with fibrolamellar carcinoma, seen at Memorial Sloan-Kettering Cancer Center, the University of California San Francisco, and Johns Hopkins Hospital from 1986 to 2011. Demographic, clinical, pathologic, and treatment data were recorded. Overall survival was estimated by using Kaplan-Meier methods. The impact of different clinicopathologic variables on survival was assessed with Cox regression models.

Results

Ninety-five patients were identified. Median age was 22 years, 86% were Caucasian, and 50% presented with stage IV disease. There were more females than males (58% vs. 42%). Seventy-seven percent of the patients underwent surgical resection and/or liver transplantation; of these 31.5% received perioperative therapy. Patients with unresectable disease, including 8 patients treated in clinical trials, were treated with chemotherapy, occasionally given with interferon or biologic agents. Ten patients received sorafenib, and 7 received best supportive care. Median survival was 6.7 years. Factors significantly associated with poor survival were female sex, advanced stage, lymph node metastases, macrovascular invasion, and unresectable disease.

Conclusions

The clinicopathologic characteristics and survival outcomes from this dataset are consistent with those reported in the literature. Surgical resection and disease extent were confirmed as important predictors of survival. The possibility of a negative association between female sex and prognosis could represent a clue as to future therapeutic strategies.