Blinded comparator study of immunohistochemistry (IHC) versus a 92-gene cancer classifier in the diagnosis of primary site in metastatic tumors.

Abstract

e21019 Background: Metastatic tumors of uncertain or unknown origin pose diagnostic and therapeutic challenges. Accurate tumor classification is fundamental to inform predictive biomarker testing and optimize therapy. Standard of care employs IHC analysis for tumor classification that is varied in approach and interpretation. More recently, gene expression-based tests have been proposed as diagnostic aids. This study directly compared the diagnostic accuracy of IHC vs molecular classification with a 92-gene RT-PCR assay (CancerTYPE ID) for determination of primary tumor site. Methods: In this prospectively-defined, blinded study, 132 high grade, metastatic cases were selected by City of Hope (COH). Cases were reviewed and reference diagnoses established by clinical correlation (eg, patient history, imaging). Blinded FFPE sections were evaluated by either IHC or the 92-gene RT-PCR assay. Results were scored within a clinically-relevant categorization system designated by COH for main tumor type and subtype. The primary endpoint was concordance with the reference diagnosis. Study unblinding and data analysis were conducted by an independent third party. Results: Final analysis included 123 cases (mean age±SD: 61.2±14.4y, 52% female; grades 3/4; 90% metastatic); 9 cases were excluded (8: RNA quality; 1: insufficient tumor tissue). The 92-gene assay demonstrated an overall accuracy of 78% for tumor classification vs 68% for IHC (P = 0.017). For tumor subclassification, the 92-gene assay correctly identified 72% of tumors compared to 61% with IHC (P=0.029). Sensitivities were similar for GI (77%) and kidney (77%). The 92-gene assay demonstrated higher sensitivities for lung (75% vs 67%), urinary bladder (75% vs 42%), and breast (73% vs 55%). Mean IHC use was 7.8 stains per case (median: 8, range: 2-15). Conclusions: This is the first study to directly compare the diagnostic accuracy of IHC vs molecular classification. Results from this blinded series of high grade metastatic cases demonstrate superior accuracy with the 92-gene assay vs standard of care IHC, and strongly support the diagnostic utility of molecular classification in difficult to diagnose metastatic cancer.