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

To the Editor We would like to commend Ross et al¹ for undertaking this important work because carcinoma of unknown primary (CUP) represents a fertile ground for the implementation of molecular therapeutics. Because no standard therapy exists, CUP presents a unique opportunity to use comprehensive genomic profiling to guide targeted therapy as an initial treatment. However, we would like to comment on 2 specific concerns.

First, the authors suggest that we should abandon the practice of identifying primary tumor site, on the basis of the premise that this diagnostic evaluation is expensive and often uninformative.¹ We believe that a focused evaluation to find the tumor origin, potentially incorporating genomic profiling, remains important for a select group of patients and should not be disregarded. An illustrative example from our CUP clinic at the University of Michigan demonstrates this concept: we elected to pursue a repeat biopsy for a woman in her 70s who presented with abdominal carcinomatosis. Her initial diagnosis was adenocarcinoma of unknown origin on the basis of peritoneal fluid cytologic analysis; however, an omental biopsy revealed that the tumor was likely of Mullerian origin via immunohistochemical analysis. Because optimal surgical debulking has been demonstrated to confer survival benefit in this setting,² we referred the patient for operative intervention. Although we concur that tumor origin diagnostics are usually not informative, we must be careful not to neglect information that may alter therapy for a small number of patients. Our challenge is thus to identify creative, cost-effective methods to select patients for whom this information matters. We must also not forget that patients often wish to know the origin of their cancer given that lack of a definitive diagnosis can be disconcerting.

Second, whereas this study provides evidence that targetable genomic alterations can be identified in the CUP population, trials are warranted to determine whether delivery of targeted therapy will indeed improve outcomes. In addition, we advocate for a study that incorporates genomic profiling at diagnosis, such that patients might receive biomarker-driven therapy as the initial treatment for their cancer. In addition, a recent study of more than 400 patients with diverse cancers who underwent next-generation sequencing highlighted that increasingly, many of the actionable mutations may be targetable with an already approved drug (albeit usually off label).³ No targeted therapies are currently approved for use in CUP, and the off-label prescribing of these medications poses numerous challenges. Therefore, a multicenter trial incorporating access to targeted therapeutics already approved for use in other malignant neoplasms (ie, BRAF, EGFR, ALK inhibitors) for patients with CUP is imperative.

Corresponding Author: Erin F. Cobain, MD, Comprehensive Cancer Center, University of Michigan Health Systems, 1500 E Medical Center Dr, C369 Med Inn, SPC 5848, Ann Arbor, MI 48109 (ecobain@med.umich.edu).

Published Online: May 14, 2015. doi:10.1001/jamaoncol.2015.0942.

Conflict of Interest Disclosures: Dr Chinnaiyan serves on the scientific advisory boards of Paradigm Diagnostics and Oncofusion Therapeutics and is a cofounder of Oncofusion Therapeutics. Dr Kurzrock serves as a consultant for Sequenom and has ownership interest in RScueRx Inc. No other disclosures are reported.