title: Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site: New Routes to Targeted Therapies.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.|Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Laurie
authors.initials: L
authors.lastname: Gay
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Geoff A
authors.initials: GA
authors.lastname: Otto
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Emily
authors.initials: E
authors.lastname: White
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Kiel
authors.initials: K
authors.lastname: Iwanik
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Gary
authors.initials: G
authors.lastname: Palmer
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Doron M
authors.initials: DM
authors.lastname: Lipson
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Erlich
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Rankin
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Elvin
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morosini
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine Inc, Cambridge, Massachusetts.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D064847:Multimodal Imaging / Q000379:methods; D009154:Mutation; D009382:Neoplasms, Unknown Primary / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D049268:Positron-Emission Tomography; D057285:Precision Medicine; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor