From Personalized Medicine

Potential Clinical Utility of Gene-expression Profiling in Identifying Tumors of Uncertain Origin

Marianne Laouri; Meredith Halks-Miller; W David Henner; J Scott Nystrom

Authors and Disclosures

Abstract and Introduction
Methods & Materials
Results
Discussion
Conclusion

References

Abstract and Introduction

Abstract

Aim: To evaluate the potential impact of a gene-expression-based test on the diagnosis of primary tumors in difficult-to-diagnose cases.
Materials & methods: The Tissue of Origin Test uses 2000 gene measurements to classify the most likely primary tumor. We categorized 284 consecutive samples by pretest diagnosis, then recategorized the samples using test results to identify cases with changes in diagnosis.
Results: A total of 64% of incoming diagnoses were nonspecific. A leading diagnosis for the primary site was provided for remaining cases, indicating an unresolved differential. Overall, the test predicted a change in the most likely primary site, either a change from nonspecific to specific site or a change from one specific primary site to another in 81% of the cases and confirmed the suspected primary site for 15% of cases.
Conclusion: A new molecular diagnostic has the potential to change both primary site identification and therapy selection for the majority of patients tested.

Introduction

In approximately 3–5% of all new cancer cases, the primary site is difficult to diagnose.^[1] These cases manifest in a wide variety of clinical presentations, and pathologists and oncologists often cannot reach consensus on the primary site even after an exhaustive evaluation involving a complete review of clinical history, physician examination, complete blood count, urinalysis, serum chemistries, chest radiograph and computed tomography or MRI.^[2,3] Pathological evaluation usually involves an extensive use of immunohistochemistry (IHC) stains. However, IHC stains often lack the range, sensitivity and specificity required for selection of a primary site, particularly if a range of possible sites exists.^[4–7] As a result, the success rate of identifying the tissue of origin in patients who present with an unresolved diagnosis can be less than 30%.^[8]
While rapid advances are being made in characterizing tumors for the presence or absence of targets for drug treatments, the studies that determine the effectiveness of a cancer treatment are uniformly conducted in cohorts of patients with particular tissues of origin whether it is breast, prostate, colorectal or other types of cancer. In addition, the presence of a particular target in a tumor does not necessarily predict activity unless that information is linked to knowledge of the primary site. For example, both breast carcinoma and ovarian cancer are frequently estrogen receptor positive (ER⁺) but antiestrogen therapy is only effective in treatment of ER⁺ breast cancers. Where it is not self evident from clinical, surgical or imaging findings, determination of the tissue of origin remains a key diagnostic element in the treatment decisions of medical oncologists and radiation therapists.
Gene-expression profiling has been used in recent years to assist in the diagnosis of the primary site in conjunction with standard clinical and pathological evaluations. Several gene-expression molecular diagnostic assays are available and have been validated in clinical trials to identify the primary site in 75–90% of cancers of uncertain primary site.^[9–14,101] These tests may be used as a way to support one diagnosis over the other when the histological and clinical evidence points to different primary sites, or if there is simply insufficient evidence to make a diagnosis of the primary site. The Tissue of Origin Test (Pathwork® Diagnostics, CA, USA) is a molecular diagnostic test developed as an aid to diagnosis for difficult-to-diagnose malignancies. This study used data collected by a central laboratory (Pathwork Diagnostics Laboratory, CA, USA) on a series of consecutive cases to address the following questions: whether the use of a gene-expression profiling test such as the Tissue of Origin Test results in a change of primary site diagnosis (tissue of origin), and whether the test contributes to the diagnostic precision of cases where the primary site is uncertain. The study also explored whether a change in diagnosis could result in a change in the patient's treatment using the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of tumors of specific primary sites. The purpose of the study was to explore and describe the clinical utility of molecular diagnostic tests in the diagnosis and management of this patient population.

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