Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site

IMPORTANCE: For carcinoma of unknown primary site (CUP), determining the primary tumor site may be uninformative and often does not improve outcome. OBJECTIVE: To discover opportunities for targeted therapies in patients with CUP not currently searched for in routine practice. DESIGN, SETTING, AND PARTICIPANTS: Comprehensive genomic profiling on 200 CUP formalin-fixed paraffin-embedded specimens (mean, 756× coverage) using the hybrid-capture-based FoundationOne assay at academic and community oncology clinics. MAIN OUTCOMES AND MEASURES: Presence of targetable genomic alterations (GAs) in CUP and responses to targeted therapies. RESULTS: There were 125 adenocarcinomas of unknown primary site (ACUPs) and 75 carcinomas of unknown primary site without features of adenocarcinoma (non-ACUPs). At least 1 GA was found in 192 (96%) of CUP specimens, with a mean (SD) of 4.2 (2.8) GAs per tumor. The most frequent GAs were in TP53 (110 55%), KRAS (40 20%), CDKN2A (37 19%), MYC (23 12%), ARID1A (21 11%), MCL1 (19 10%), PIK3CA (17 9%), ERBB2 (16 8%), PTEN (14 7%), EGFR (12 6%), SMAD4 (13 7%), STK11 (13 7%), SMARCA4 (12 6%), RB1 (12 6%), RICTOR (12 6%), MLL2 (12 6%), BRAF (11 6%), and BRCA2 (11 6%). One or more potentially targetable GAs were identified in 169 of 200 (85%) CUP specimens. Mutations or amplifications of ERBB2 were more frequent in ACUPs (13 10%) than in non-ACUPs (3 4%). Alterations of EGFR (10 8% vs 2 3%) and BRAF (8 6% vs 3 4%) were more common in ACUPs than in non-ACUPs. Strikingly, clinically relevant alterations in the receptor tyrosine kinase (RTK)/Ras signaling pathway including alterations in ALK, ARAF, BRAF, EGFR, FGFR1, FGFR2, KIT, KRAS, MAP2K1, MET, NF1, NF2, NRAS, RAF1, RET, and ROS1 were found in 90 (72%) ACUPs but in only 29 (39%) non-ACUPs (P < .001). CONCLUSIONS AND RELEVANCE: Almost all CUP samples harbored at least 1 clinically relevant GA with potential to influence and personalize therapy. The ACUP tumors were more frequently driven by GAs in the highly druggable RTK/Ras/mitogen-activated protein kinase (MAPK) signaling pathway than the non-ACUP tumors. Comprehensive genomic profiling can identify novel treatment paradigms to address the limited options and poor prognoses of patients with CUP.