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Originally published as JCO Early Release 10.1200/JCO.2009.23.7982 on July 27 2009 © 2009 American Society of Clinical Oncology.
Reply to G.R. Varadhachary et alDepartment of Pathology, The Methodist Hospital and The Methodist Hospital Research Institute, Houston, TX
Pathwork Diagnostics LLC, Redwood City, CA
5 Degrees Biosciences, San Jose, CA
Pathwork Diagnostics, LLC, Redwood City, CA We appreciate the positive comments on our work1 from Drs Varadhachary and Raber.2 We have followed their group's work in this field and also want to acknowledge their important contributions. It is clear that we all share enthusiasm for the recent advances in tissue of origin determination by gene expression analysis and the promise that these approaches may lead to better outcomes for patients with tumors of unknown origin. As mentioned in Varadhachary and Raber,2 we did not use the term carcinoma of unknown primary (CUP) in our article.1 In part, this was because of the fact that the validation study was performed with tumor tissues for which the origin was known (by necessity to allow comparison to a reference diagnosis). Furthermore, we believe that the potential application of this approach includes other tumors which might not be strictly classified as CUPs, but for which features of the pathology, clinical history, or response to therapy result in uncertainty as to the tissue of origin. Although many cases of uncertain primary cancer can be adequately resolved by consultations with expert pathologists, radiologists, and oncologists, other cases will remain uncertain even after a full evaluation. The new National Comprehensive Cancer Network guidelines for Occult Primary tumors indicate, "immunochemistry markers for unknown primary cancers...are not 100% specific or sensitive,"3 and thus uncertainty can remain even after some studies suggest a specific tissue of origin. For such cases, we believe that gene expression profiling can provide independent and complementary evidence for the primary tissue. Another issue raised by Varadhachary and Raber2 is the availability of sufficient sample for a test that requires 1 µg of RNA from frozen tissue. In our experience, we routinely obtain more than 5 µg of RNA from approximately 100 mg of tissue, and thus, if frozen tissue is available, it is likely that adequate amounts of RNA would be obtained. In this study, only 2% (six of 351) of samples failed processing from sample to successful microarray data file. The remaining 84 samples referred to were excluded because they did not meet predefined criteria for entry into the study. We concur that in clinical practice, procurement of frozen tissue is a significant limitation for widespread use of gene expression profiling tests such as the Pathwork Tissue of Origin Test (Pathwork Diagnostics, Redwood City, CA). However, recent advances in RNA amplification technologies allow for lower RNA input into gene expression–based tests. Further development of the Pathwork Tissue of Origin Test has been performed and a new version of the test, for use with formalin-fixed paraffin-embedded samples, achieves equivalent performance. Data from a multicenter validation study with formalin-fixed paraffin-embedded samples will be published in the American Society of Clinical Oncology 2009 Annual Meeting proceedings. We agree that the choice of tissues for training and validation sets is critical for developing a test with adequate clinical performance. However, we disagree with the impression that inclusion of tissues such as prostate, lymphoma, breast, and colon represent a limitation. While some tissue types are represented more frequently than others among uncertain primary cancers, it is important to include a wide range of possible tumor morphologies (even within the same site of origin) and tissue sites in the classification to make it most useful in narrowing down the differential diagnosis. The 15 tissues included in the Pathwork Tissue of Origin Test represent 58 morphologies that are often included in the differential diagnosis of a patient who presents with a metastatic tumor of unknown origin. The over-representation of some tissue types in the training set (n = 2,039) was accounted for in the algorithm design. With regards to the question whether CUPs are fundamentally different tumors from those that are classifiable with current approaches, we believe that the vast majority of these tumors retain molecular profiles of their site of origin. It has recently been shown that gene expression assays can identify a putative site of origin in 62% to 86% of samples previously diagnosed as CUP.4–7 This evidence suggests that, for the majority of cases currently classified as CUP, there is significant molecular similarity with their tissue of origin. It is not an unreasonable hypothesis to suggest that, given that they share molecular characteristics, they are more likely to respond to treatments that are appropriate for their suspected origin. In fact, evidence from Dr Varadhachary's8 own work in patients with tumors showing molecular profiles of colon cancer supports this hypothesis. The development of molecular classification tools for patients with CUP is an attempt to answer an important clinical question: how do we best treat these patients and improve their outcomes? We agree with Varadhachary and Raber2 that our results and those of others are encouraging and that the best measure of success will be the demonstration of improvement in patient outcomes and cost effectiveness. Certainly, the availability of a reliable test that has been well validated in cases with a known diagnosis is a prerequisite for the design and performance of such studies. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: David W. Henner, Pathwork Diagnostics (C); C. Ted Rigl, Pathwork Diagnostics (C); Ljubomir Buturovic, Pathwork Diagnostics (C); Raji Pillai, Pathwork Diagnostics (C) Consultant or Advisory Role: None Stock Ownership: David W. Henner, Pathwork Diagnostics; C. Ted Rigl, Pathwork Diagnostics; Glenda G. Anderson, Pathwork Diagnostics; Ljubomir Buturovic, Pathwork Diagnostics; Raji Pillai, Pathwork Diagnostics Honoraria: Federico A. Monzon, Pathwork Diagnostics Research Funding: Federico A. Monzon, Pathwork Diagnostics Expert Testimony: None Other Remuneration: Federico A. Monzon, Pathwork Diagnostics REFERENCES
1. Monzon FA, Lyons-Weiler M, Buturovic LJ, et al: Multicenter validation of a 1,550 gene expression profile for identification of tumor tissue of origin. J Clin Oncol 27:2503–2508, 2009. 2. Varadhachary GR, Raber MN: Gene expression profiling in cancers of unknown primary. J Clin Oncol 27:e85–e86, 2009. 3. NCCN Occult Primary Panel Members. NCCN Clinical Practice Guidelines in Oncology: Occult Primary. Fort Washington, PA: National Comprehensive Cancer Network, 2009. 4. Varadhachary GR, Talantov D, Raber MN, et al: Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J Clin Oncol 26:4442–4428, 2008. 5. Horlings HM, van Laar RK, Kerst JM, et al: Gene expression profiling to identify the histogenetic origin of metastatic adenocarcinomas of unknown primary. J Clin Oncol 26:4435–4441, 2008. 6. Bridgewater J, van Laar R, Floore A, Van'T Veer L: Gene expression profiling may improve diagnosis in patients with carcinoma of unknown primary. Br J Cancer 98:1425–1430, 2008.[CrossRef][Medline] 7. Monzon FA, Henner WD, Medeiros F. Use of a microrarray-based 1,550-gene expression profile in the diagnosis of carcinoma of unknown primary (CUP) Proceedings of the 2009 ASCO Gastrointestinal Cancers Symposium, abstr 313. 8. Varadhachary GR, Raber MN, Matamoros A, Abbruzzese JL: Carcinoma of unknown primary with a colon-cancer profile-changing paradigm and emerging definitions. Lancet Oncol 9:596–599, 2008.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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