Of the 289 patients enrolled in the study, 252 had successful assays performed; of these, 247 (98%) had a tissue of origin predicted. “Sites most commonly predicted were biliary tract (18%), urothelium (11%), colorectal (10%), and non–small-cell lung (7%),” the authors observed. Of the 223 patients who were candidates for treatment, 194 received assay-directed site-specific treatment.

Median survival for the 194 patients was 12.5 months (95% CI: 9.1 to 15.4 months), which was significantly improved when the assay predicted tumor types clinically more responsive compared with predictions of more resistant tumors (13.4 vs 7.6 months, respectively; P=0.04).

In conclusion, these results demonstrate that “molecular tumor profiling contributes to the management of patients with CUP and should be a part of their standard evaluation,” as stated by the authors.4

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Not so fast, noted two separate letters to the Journal of Clinical Oncology in response to the article.

“I respectfully suggest, with regret, that their trial is insufficient to support this claim,” wrote Leonard B. Saltz, MD, of Memorial Sloan-Kettering Cancer Center, New York, NY. “[T]he design of the trial presented is insufficient to establish (or refute) the claim that molecular profiling should be regarded as standard practice in CUP. Such a claim would require a trial that directly demonstrates that use of expression profiling improves outcome, and such a trial has yet to be performed.

“Overstatement of the accomplishments of the current trial risks fostering the dual misperceptions that a truly definitive trial is either not needed or is unfeasible, neither of which is the case. A trial in which patients with CUP are randomly assigned to best empiric therapy versus expression profile–directed therapy, or some similar design, remains needed, appropriate, and what our patients deserve.”5

Added Mary-Elizabeth Percival, MD, and A. Dimitrios Colevas, MD, of Stanford University School of Medicine, Stanford Cancer Center, Stanford, CA, “Although we applaud the authors’ attempts to apply novel technology to the prospective treatment of patients in a difficult clinical situation, we believe that there are problems with their methodology. The authors did not perform an intention-to-treat analysis, which introduces multiple layers of bias… Therefore, we conclude that this study does not provide meaningful evidence to support claims of clinical benefit for the 92-gene assay.”6

Where Do We Stand?

In response to the opposition, Hainsworth et al wrote that “none of the US National Cancer Institute cooperative groups has performed a CUP trial (randomized or otherwise) in the last 25 years… [O]ncologists who see and treat patients with CUP will need to consider the increasing evidence that supports the use of molecular profiling for tissue of origin diagnosis and decide when it is time to make a change in practice.”4

Dr. Ettinger added, “Over the next decade, as therapies become more effective in treating solid tumors, the use of GEP will become more important and commercially available tests will be used. At present, GEP for tissue of origin is not recommended for standard management by the NCCN.”

“I do believe patients diagnosed with CUP might be better served at large academic cancer centers where treatment including clinical trials may be more greatly individualized,” Dr. Ettinger concluded. “However, good communication between the oncologist in private practice and the academic centers has allowed patients with CUP to be treated in the community setting.”


1. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Occult Primary (Cancer of Unknown Primary [CUP]. Version 1. 2013. Available at: http://www.nccn.org/professionals/physician_gls/pdf/occult.pdf. Accessed August 26, 2013.

2. Greco FA. Cancer of unknown primary site: evolving understanding and management of patients. Clin Advances Hematol Oncol. 2012;10(8);518-524.

3. Varadhachary G. New strategies for carcinoma of unknown primary: the role of tissue-of-origin molecular profiling. Clin Cancer Res. 2013;19(15):4027-4033.

4. Hainsworth JD, Rubin MS, Spigel DR, et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon Research Institute. J Clin Oncol. 2013;31(2):217-223. Epub 2012 Oct 1.

5. Saltz LB. Role of expression profiling in carcinoma of unknown primary remains unknown. J Clin Oncol. 2013;31(19):2513-2514.