Genetic characteristics of combined hepatocellular-cholangiocarcinoma tumors in a tertiary care center: A case series.

Abstract

e16215 Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare malignancy (1) with a 5-year OS as low as 10% (2-4). While cHCC-CC tumors demonstrate a spectrum of HCC or CC features (1,5-8), due to the rarity of this malignancy, pathological and clinical characterization has been challenging, compounded by the heterogeneity of the disease (5,8-10). In this case series, we review clinicopathologic factors from cases within our hospital system related to survival outcomes and review the genomic landscape to inform potential future therapeutic decision making. Methods: 1,392 cases from the Banner Health MDA system were reviewed. Of these, fifteen cases were confirmed as cHCC-CC. Six patients have evaluable records of their complete treatment course. NGS data was available for seven patients. Results: Of the six patients that had evaluable records, the average time from diagnosis to transition to hospice or last visit was 11.5 months (range of 2-44 months, median 6 months). Four of these patients were initially diagnosed with stage IV disease, and two were initially diagnosed with stage II disease. Two patients did undergo disease recurrence during their treatment course. Five patients transitioned to hospice less than one year after diagnosis, with an average of 4.6 months to this transition (range 2-8 months). One patient experienced prolonged survival of 44 months and is still alive at the time of analysis. All six patients had cHCC-CC that more closely resembled CC as opposed to HCC. Of the seven patients who underwent NGS sequencing of their tumors, 24 unique mutations of interest were detected, including 8 that have not been previously described in cHCC-CC. The most common alterations were in TP53 (present in five patients) and the TERT promoter region (present in four patients), which was consistent with previous studies. Multiple recurrent signaling pathway alterations were identified in the MAPK/RAS/ERK pathway (MAP2K2 (MEK2), non-V600 BRAF Class II, PTPN11), MHC Class 1 antigen presentation (B2M), glutathione metabolism/detoxification pathway (GSTP1), and TGF-B/BMP (BMPR1A). Copy number gain of Myc and Met are also described. This analysis demonstrates that cHCC-CC harbors alterations targetable by novel therapeutics in development including RAS inhibitors and BET inhibitors. In addition, approved drugs such as capmatinib that target MET amplification and tovorafenib that can inhibit Class II BRAF alterations are promising avenues of investigation. Conclusions: We describe a series of cHCC-CC that pathologically mostly resembles a cholangiocarcinoma phenotype, but harbor alterations not seen in either type of cancer that have strong potential for future therapeutic targeting.