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. 2015 Apr;1(1):40-49.
doi: 10.1001/jamaoncol.2014.216.

Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site: New Routes to Targeted Therapies

Jeffrey S Ross  1   2 , Kai Wang  1 , Laurie Gay  1 , Geoff A Otto  1 , Emily White  1 , Kiel Iwanik  1 , Gary Palmer  1 , Roman Yelensky  1 , Doron M Lipson  1 , Juliann Chmielecki  1 , Rachel L Erlich  1 , Andrew N Rankin  1 , Siraj M Ali  1 , Julia A Elvin  1 , Deborah Morosini  1 , Vincent A Miller  1 , Philip J Stephens  1
Affiliations

Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site: New Routes to Targeted Therapies

Jeffrey S Ross et al. JAMA Oncol. 2015 Apr.

Erratum in

  • Error in a Data Point in Table 3.
    [No authors listed] [No authors listed] JAMA Oncol. 2019 Aug 1;5(8):1232. doi: 10.1001/jamaoncol.2019.2894. JAMA Oncol. 2019. PMID: 31393522 Free PMC article. No abstract available.

Abstract

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.

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