P8.07 - Novel mutational profiles in relapsed/refractory advanced cancer patients' pre- and post-targeted therapy

Abstract

ABSTRACT Background: Molecular profiling by next generation sequencing (NGS) delivers information on mutant gene sequences, copy number alterations and translocations, and with immunohistochemistry (IHC) is a valuable tool in clinical decision making for patients entering targeted therapy trials. We hypothesized that advanced cancer patients with specific mutational profiles may benefit from targeted therapy and on progression acquire novel mutations due to tumor evolution and loss of target. Methods: All phase I patients (N > 80) had relapsed/refractory advanced cancer were profiled by NGS, majority by Precipio-421 (includes FISH) and Caris Molecular Intelligence (IHC, FISH, NGS) and Foundation One (NGS, FISH). Samples were annotated by histology, primary and/or metastatic site, biopsy location, gene mutation (G-site/G-mutation; P-site/P-mutation), domain, topology, mutation count/gene, different mutations within each gene and mutations that associate with mutant TP53. An NGS molecular profile of each patient was categorized into common and unique mutations, signaling pathway-networks (Cytoscape) identified for each profile, mutations mapped to known 3D-structure (when available) if not in COSMIC and response to therapy. Results: Predominant histology was adenocarcinoma followed by squamous cell carcinoma, neuroendocrine tumors and lymphoma. Of 250 unique mutations, TP53 was the most common followed by PIK3CA, KRAS, PMS2, PTEN, NOTCH2, CSMD3, ATM, MAP2K4, PRKDC, ARID1A, NOTCH1 and LRP1B. Most patients had on average >5 unique gene mutations, their proteins localized to the membrane, cytoplasm and nucleus generating a network of interconnected pathways that dysregulate several hallmarks of cancer. Examples of acquired mutational profilies pre-/post- targeted therapy are highlighted including a patient with ALK translocated NSCLC treated with crizotinib plus AT13387 (HSP90 inhibitor) (Giri et al, NEJM 2014), rectal cancer (CDK4/6 inhibitor), uterine cancer (PI3K inhibitor), ovarian cancer (anti-PDL-1) and triple hit DLBCL (BTK inhibitor). Conclusion: Molecular profiling of advanced cancer patients participating in targeted therapy trials provide an opportunity to identify ‘mutational signatures’ that may predict for drug sensitivity and guide rational drug combinations.