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In Reply We read with interest the 3 Letters to the Editor in response to our study on the potential impact of using comprehensive genomic profiling early in the management of patients presenting with cancer of unknown primary source (CUP).1 We believe that the 3 letters, in different ways, enhance the discussion of our study as the transition from one-size-fits-all nontargeted chemotherapy to genomic-driven targeted therapy continues. The letter from Cobain et al from the Universities of Michigan and California at San Diego cites the importance of considering appropriate surgical procedures in some forms of cancers initially presenting as CUP. We agree completely that Mullerian tract–derived cancers such as serous carcinomas within the abdominal cavity should be surgically debulked whenever possible. In our study,1 we attempted to limit the criteria for CUP to exclude cases in which surgical treatment was immediately needed at the time of presentation, which, in most cases, included a broad nondiagnostic immunohistochemical (IHC) workup before the diagnosis of CUP was conferred. We also agree with Cobain et al that all targeted therapies are “off-label” for patients with a diagnosis of CUP and that genomically driven clinical trials for patients with CUP are needed. We thank Varghese and Saltz from Memorial Sloan Kettering Cancer Center for their comments concerning the definition of “actionability” in the setting of cancer presenting as CUP.
Also, in response to Varghese and Saltz, TTF1-positive tumors with EML4-ALK fusions characteristic of non–small-cell lung cancer were not included in our series. One case in our series did feature a TMPRSS-ERG fusion diagnostic of metastatic prostatic carcinoma. This case was listed as a CUP in that the tumor did not mark by IHC analysis as being of prostatic origin and the clinical workup did not suggest that the patient had prostate cancer. Although not a focus of our present study, we believe that hybrid capture–based comprehensive genomic profiling can definitively identify the site of origin in approximately 10% to 15% of CUP cases. The case example in our article of an EML4-ALK fusion cancer responding dramatically to crizotinib therapy cannot, in our opinion, be designated as a lung cancer by current diagnostic criteria because IHC analysis was negative for TTF1, positive for vimentin, and featured a poorly differentiated, nonmucinous, sarcomatoid morphologic appearance. Finally, we thank Whang and Hayes from the University of North Carolina for their letter describing the prolonged response of a patient to an anti-human epidermal growth factor receptor 2 plus chemotherapy regimen for an ERBB2-amplified CUP. Finally, our article1 and all 3 Letters to the Editor have in common the desire to see the development of mechanism-driven prospective clinical trials in which genomic profiling is used to search for “druggable” alterations in CUP cases to achieve a comparison of the results of the use of targeted therapies when possible with generic chemotherapy and testing whether this approach can improve the clinical outcomes for patients with this devastating form of cancer.
Corresponding Author: Jeffrey S. Ross, MD, Department of Pathology and Laboratory Medicine, Albany Medical College, 47 New Scotland Ave, Mail Code 81, Albany, NY 12208 (firstname.lastname@example.org).
Conflict of Interest Disclosures: All authors are employees of, hold leadership positions in, and own stock in Foundation Medicine, Inc. No other disclosures are reported.
Published Online: May 14, 2015. doi:10.1001/jamaoncol.2015.0945.
Ross JS, Miller VA, Stephens PJ. Genomic Profiling of Cancers of Unknown Primary Site—Reply. JAMA Oncol. 2015;1(4):542–543. doi:10.1001/jamaoncol.2015.0945
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