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Comment & Response
July 2015

Genomic Profiling of Cancers of Unknown Primary Site: The Next Steps

Author Affiliations
  • 1Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
JAMA Oncol. 2015;1(4):541-542. doi:10.1001/jamaoncol.2015.0939

To the Editor In their February 2015 article on genomic profiling of cancers of unknown primary (CUP), Ross et al1 state that 169 of 200 CUPs harbored “clinically relevant genomic alterations” with the conclusion that “comprehensive genomic profiling shows promise to identify targeted therapeutic approaches to improve outcomes for this disease.” We respectfully suggest that their definition of “clinically relevant” may be overly inclusive and therefore impractical for oncologists caring for patients with CUP at this time.

The most common alterations that were reported to be clinically relevant were in KRAS, CDKN2A, and MCL1. Despite a few promising small studies of MEK inhibition in KRAS-mutant lung cancer, targeted therapies directed at mutant RAS have generally been unsuccessful, and there is little compelling evidence that CDKN2A and MCL1 are actionable targets.2,3 It is also unclear how the authors have confirmed a diagnosis of CUP given the lack of reported clinical information. Samples are included in the study with TMPRSS2-ERG and EML4-ALK fusions, samples that the authors themselves note should be excluded because they suggest likely primary prostate and lung cancers, respectively. We agree that the endless search for a primary is unlikely to change treatment for most patients. However, by including patients with a likely primary site of disease such as lung cancer in CUP reports such as this, the authors risk simply reporting the excellent responses to targeted therapies seen in appropriately selected patients with those cancers.

We agree with the authors on several points. Patients with CUP have been subjected to unnecessary diagnostic tests with medical, emotional, and financial costs. They have been underserved by clinical research in which trial eligibility typically requires a known primary site of disease and potentially have much to gain from “basket studies” in which patients receive targeted therapies based on the presence or absence of specific genomic alterations. Furthermore, knowledge in this field is changing rapidly, and mutations that are not clinically relevant today may be relevant tomorrow. We are leading a research effort to perform comprehensive genomic profiling for patients with CUP at our institution to determine whether these results can inform treatment decisions and, most importantly, to learn whether these informed decisions do or do not ultimately lead to improved clinical activity and improved patient outcomes. We are hopeful that comprehensive genomic profiling will improve outcomes for patients with CUP through precision use of targeted therapies; however, this is a hypothesis that needs to be tested.

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Article Information

Corresponding Author: Anna M. Varghese, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E 66th St, New York, NY 10065 (varghesa@mskcc.org).

Published Online: May 14, 2015. doi:10.1001/jamaoncol.2015.0939.

Conflict of Interest Disclosures: None reported.

Ross  JS, Wang  K, Gay  L,  et al.  Comprehensive genomic profiling of carcinoma of unknown primary site: new routes to targeted therapies [published online February 12, 2015].  JAMA Oncol. doi:10.1001/jamaoncol.2014.216.Google Scholar
Jänne  PA, Shaw  AT, Pereira  JR,  et al.  Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study.  Lancet Oncol. 2013;14(1):38-47.PubMedGoogle ScholarCrossref
Gandara  DR, Hiret  S, Blumenschein  GR,  et al.  Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): a phase I/Ib trial.  J Clin Oncol.2013;31(suppl):abstr 8028.Google Scholar