Abstract 4700: One size does not fit all: Fingerprinting advanced carcinoma of unknown primary through comprehensive profiling identifies aberrant activation of the PI3K and MAPK signaling cascades in concert with impaired cell cycle arrest

Abstract

Abstract Background: Carcinoma of unknown primary (CUP) represents a heterogeneous group of cancers without an identifiable primary disease site where staining for a vast array of immunohistochemical markers is undertaken to identify tumor lineage. Given rapid advances in characterizing cancer genomes, we sought to describe the molecular profiles of patients with advanced CUP treated with novel targeted therapies on phase I clinical trials to identify pathways of interest to drive future therapeutic strategies. Methods: Of patients with advanced malignancies seen in the Phase I clinic, we identified 16 CUP patients on whom adequate tissue was available to perform next-generation sequencing (NGS) from FFPE sections using a targeted NGS assay in a CLIA laboratory (Foundation One, MA). 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: Of 16 tumor specimen, 14 demonstrated genomic alterations with a median of 4 aberrations within each specimen (range 0 - 10, total of 69 alterations); two patients did not demonstrate any tested changes. All patients with detected mutations possessed an exclusive unique molecular profile of aberrations with no two patients demonstrating an identical panel of mutations. A total of 69 alterations were identified of which 18 (26%) led to aberrant cell signaling within the PI3K/AKT/MTOR (including 4 with PIK3CA mutations) or the MAPK signaling cascades, primarily KRAS mutations in 3 patients. Also noted were 13 (19%) alterations impairing cell cycle arrest most commonly affecting cyclin dependent kinases, 10 (14%) impacting epigenetic regulation and DNA methylation, 10 (14%) affecting known tumor suppressor genes including TP53 in 8 patients, and 10 (14%) unique alternations in transcriptional regulators. Conclusion: With thorough molecular profiling, we can identify the unique fingerprint of potential actionable aberrations in a subset of advanced CUP patients. Herein we identified activation of the PI3K/AKT/MTOR and RAS/RAF/MEK signaling pathways combined with impaired cell cycle arrest in 8 of 16 (50%) tested patients, suggesting that a combination of PI3K and MAPK cascade inhibitors in combination with a cell cycle inhibitor may be of therapeutic value to these patients. Further matching patients to these actionable aberrations is underway, thereby translating these therapeutic targets to the bedside with the development of novel targeted therapies. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Gauri Varadhachary, Apostolia M. Tsimberidou, Jennifer J. Wheler, Vivek Subbiah, Filip Janku, Sinchita Roy Chowdhury, Ralph Zinner, Funda Meric-Bernstam, David S. Hong. One size does not fit all: Fingerprinting advanced carcinoma of unknown primary through comprehensive profiling identifies aberrant activation of the PI3K and MAPK signaling cascades in concert with impaired cell cycle arrest. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4700. doi:10.1158/1538-7445.AM2014-4700