Abstract 48: Theranostic profiling of adolescents and young adults (AYA) with advanced fibrolamellar hepatocellular carcinoma identifies aberrant activation of the PI3K/AKT/MTOR signaling cascade

Background: Fibrolamellar hepatocellular carcinoma (FLHCC) is an extremely rare malignancy predominantly affecting adolescents and young adults without underlying chronic liver disease. Its molecular profile is poorly defined. Given limited effective therapeutic options, we characterized the molecular profiles of patients with advanced FLHCC treated with novel targeted therapies on phase I clinical trials. Methods: Of over 3400 pts with advanced malignancies seen in the Phase I clinic, we identified 12 FLHCC pts (0.4 %). We performed single gene-PCR based testing for oncogenic mutations in KRAS, NRAS, BRAF, CKIT, EGFR, PIK3CA, MET, GNAQ, TP53, IHC for PTEN loss, ALK-1, estrogen receptor (ER) and FISH for her2/neu, cMET amplification and ALK-1 rearrangement on patients with adequate available tissue in the MD Anderson CLIA-certified lab. Additionally next-generation sequencing from FFPE sections using a targeted NGS assay in a CLIA laboratory (Foundation One, MA) was completed on two patients. Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Abnormal expression of the tumor suppressor gene PTEN was shown in 2 of 4 (50%) tested pt's tumors. The first patient's tumor shows overt PTEN loss on IHC while the second pt's tumor showed very weak cytoplasmic staining for PTEN. Interruptions of PTEN functions result in loss of negative regulation of AKT and its downstream components including mTOR. Single gene-based PCR sequencing for oncogenic mutations and the remainder of the tests using IHC and FISH were negative. Next generation sequencing of two pts revealed a missense mutation in FBXW7-E192A in one pt. The second pt's NGS profile did not reveal any actionable mutations. E192A is a missense mutation that occurs prior to the F-box domain and the highly conserved WD40 repeat region, which plays a role in substrate recognition. Mao et al (Science 2008) have reported that FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression and tumor cell lines harboring mutations in FBXW7 demonstrated particular sensitivity to rapamycin. . Conclusion: With thorough comprehensive molecular profiling, we can identify potential actionable aberrations in a subset of advanced FL-HCC patients. Herein we identified activation of the PI3K/AKT/MTOR pathway by PTEN loss and missen