Multi-institutional, Prospective Clinical Utility Study Evaluating the Impact of the 92-Gene Assay (CancerTYPE ID) on Final Diagnosis and Treatment Planning in Patients With Metastatic Cancer With an Unknown or Unclear Diagnosis

Sachdev P. Thomas; Lauren E. Jacobson; Anthony R. Victorio; Theresa N. Operaña; Brock E. Schroeder; Catherine A. Schnabel; Fadi Braiteh


JCO Precis Oncol 

In This Article

Abstract and Introduction


Purpose: Metastatic cancers of unknown primary or with unclear diagnoses pose diagnostic and management challenges, often leading to poor outcomes. Studies of the 92-gene assay have demonstrated improved diagnostic accuracy compared with standard pathology techniques and improved survival in patients treated on the basis of assay results. The current study assessed the clinical impact of the 92-gene assay on diagnostic and treatment decisions for patients with unknown or uncertain diagnoses.

Methods: Patients in this prospective, multi-institutional, decision-impact study included those for whom the 92-gene assay was ordered as part of routine care. Participating physicians completed electronic case report forms that contained standardized, specialty-specific questionnaires. Data collection included patient and tumor characteristics and clinical history. The key study objective of clinical impact was calculated on the basis of changes in final diagnosis and treatment after testing.

Results: Data collection included 444 patients, 107 physicians (73 oncologists and 34 pathologists), and 28 sites. Molecular diagnoses from 22 different tumor types and subtypes across all cases were provided in 95.5% of patients with a reportable result (n = 397). Physicians reported that the 92-gene assay was used broadly for diagnostic dilemmas that ranged from single suspected tumor type (29%) to a differential diagnosis of two or more suspected tumor types (30%) or cancers of unknown primary (41%). Integration of 92-gene assay results led to a change in the recommended treatment in 47% of patients.

Conclusion: Findings from this clinical utility study demonstrate that the 92-gene assay led to a change in treatment decisions in every other patient case. These data additionally define the role of this assay in clinical practice and strongly support the consideration of molecular tumor typing in the diagnosis and treatment planning of patients with metastatic cancer with unknown or uncertain diagnosis.


Metastatic cancers that are initially characterized as unknown primary (CUP), or with other features that may lead to diagnostic uncertainty with respect to tumor type diagnosis, can prolong the clinicopathologic workup and result in delays in the initiation of treatment, additional costs, and relatively poor patient outcomes.[1–3] Novel technologies and therapeutic options to help improve patient outcomes are needed. Numerous diagnostic and treatment strategies, such as enhanced pathologic techniques, molecular classification of tumor type and subtype, comprehensive mutational profiling, and novel combination regimens of cytotoxics plus biologics, have been proposed without universal consensus.[4–10]

Investigational approaches to personalize the systemic treatment of metastatic cancer solely on the basis of the patient's somatic genomic alterations, disregarding histologic context, have had mixed and disappointing results.[11–14] Results from several recent phase II studies that evaluated targeted agents for specific genomic alterations across a variety of tumor types have provided evidence that mutations are not targetable in similar manners across tumor types.[11,12] Thus, the clinical utility of this approach is unclear. Whereas driver mutations matter, the integration of tumor type and subtype remains critical when considering the efficacy of a targeted therapy aimed at a putative driver mutation.[15] Given that empirical chemotherapy approaches are associated with poor prognosis in patients with CUP or uncertain diagnoses, it might be more effective to refocus on methods with which to identify patient tumor type and subtype to guide therapy.[1,16]

Gene expression profiling–based molecular classification of tumors might prove efficacious by helping to identify the primary tumor type and histologic subtype for patients with unknown or uncertain diagnoses. The 92-gene assay (CancerTYPE ID) is a real-time RT-PCR–based assay that utilizes differential gene expression to assign tumors to one of 50 tumor types and subtypes in its spectrum. In clinical studies, molecular tumor classification using the 92-gene assay demonstrated 87% accuracy (95% CI, 84% to 89%), improved diagnostic accuracy compared with standard pathology techniques in poorly and undifferentiated metastatic tumors, and increased overall survival in patients with CUP who were treated on the basis of assay-directed therapy.[16–18] A survey-based retrospective study assessed the clinical utility of the 92-gene assay in decision making in clinical practice, but there have been no large-scale prospective studies to assess its impact in the clinical setting.[19] The current study assessed the clinical utility of the 92-gene assay in patients with unknown or uncertain diagnoses that were submitted as part of routine clinical care in the community setting. The primary objective was to assess clinical impact on the basis of changes in diagnostic and treatment decisions after the incorporation of 92-gene assay results.