Personalized Therapy Selection by Integration of Molecular Cancer Classification by the 92-Gene Assay and Tumor Proﬁling in Patients With Cancer of Unknown Primary

Sep 21, 2026

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Cancer of unknown primary (CUP) describes metastatic cancers lacking a clinically identified primary site, leading to poor prognosis and limited treatment options. Site-specific therapy guided by clinical features, standard pathology, and molecular assays can improve overall survival. In MOSAIC, the 92-gene CancerTYPE ID assay was used with tumor profiling to quantify molecular aberrations, including KRAS, IDH1/2, BRCA1/2, and BRAF, and to identify tissue-of-origin signals. Results support integrating CancerTYPE ID to find actionable genetic alterations and enable FDA-approved targeted therapy or clinical trial enrollment.

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Original Reports | Diagnostics Personalized Therapy Selection by Integration of Molecular Cancer Classiﬁcation by the 92-Gene Assay and Tumor Proﬁling in Patients With Cancer of Unknown Primary Harry E. Fuentes Bayne, MD1 ; Pashtoon M. Kasi, MD2 ; Li Ma, PhD3; Lowell L. Hart, MD4; Jenna Wong, MS3; David R. Spigel, MD5 ; Catherine A. Schnabel, PhD3; James A. Reeves, MD4; Thorvardur R. Halfdanarson, MD1 ; Kai Treuner, PhD3 ; and F. Anthony Greco, MD5 DOI [https://doi.org/10.1200/PO.24.00191](https://doi.org/10.1200/PO.24.00191) | ABSTRACT | | | --- | --- | | PURPOSE | Cancer of unknown primary (CUP) is a syndrome comprising metastatic cancers without a clinically identiﬁed primary site. Although patients with CUP have an unfavorable prognosis, treatment with site-speciﬁc therapies guided by clinical features, standard pathology, and molecular assays can improve overall survival. The 92-gene assay (CancerTYPE ID) is a gene expression–based classiﬁer that helps identify the tissue of origin for metastatic cancers with unknown or uncertain diagnoses. This study reports the frequency of selected molecular aberrations of oncogenes, including KRAS, IDH1/2 , BRCA1/2, and BRAF, in patients with CUP in the MOSAIC database to highlight potential treatment options. | | METHODS | MOSAIC is a database of patients with CUP submitted for CancerTYPE ID testing and NeoTYPE biomarker testing. Tumor biopsy samples were analyzed by CancerTYPE ID for tumor type identiﬁcation and further tested for molecular aberrations of oncogenes, including KRAS, IDH1/2 , BRCA1/2, and BRAF. | | RESULTS | CancerTYPE ID identiﬁed a speciﬁc tumor type in 92.5%(2,929 of 3,168) of CUP cases in the MOSAIC database. The most commonly identiﬁed histological type was adenocarcinoma (75.4%), with pancreaticobiliary being the most common molecularly diagnosed cancer (24.9%). Aberrations in KRAS, IDH1/2 , BRCA, and BRAF genes were identiﬁed in 18.8%(n 5 597) of biopsies. A cancer-speciﬁc US Food and Drug Administration (FDA)–approved or investigational targeted therapy was potentially available for 24.6%(n 5 147) of these patients. | | CONCLUSION | This retrospective analysis supports incorporating CancerTYPE ID into the evaluation for patients with CUP to help determine the tissue of origin and identify actionable genetic alterations. This approach may allow more patients with CUP to beneﬁt from site-speciﬁc FDA-approved targeted therapies or enrollment into clinical trials. | ACCOMPANYING CONTENT Appendix Accepted August 7, 2024 Published September 4, 2024 JCO Precis Oncol 8:e2400191 © 2024 by American Society of Clinical Oncology Creative Commons Attribution Non-Commercial No Derivatives 4.0 License INTRODUCTION Cancer of unknown primary (CUP) is a syndrome characterized by metastatic cancers with an unidentiﬁable primary site after a thorough diagnostic workup.1-3 Despite advancesin diagnostic techniques, CUP remains a signiﬁcant clinical challenge due toitspoor prognosis. It accounts for 2%-5% of metastatic cancers and ranks as the fourth leading cause of cancer-related deaths globally.1-3 The heterogeneity of CUP arises from concealed primary sites, which create diagnostic and therapeutic challenges due to inconclusive pathological evaluations.4 ,5 Although site-speciﬁc therapy improves outcomes in 15%-20% of cases, 80%-85% of patients with CUP face uncertain tumor origins, leading to empiric chemotherapy and a median survival of just 3-10 months.2,3,6 Identifying the tissue of origin is crucial for optimal therapy selection.1 ,7 CancerTYPE ID, a molecular classiﬁer, helps identify CUP origins by matching gene expression results with a comprehensive reference database.1 The MOSAIC database includes thousands of CUP cases that underwent CancerTYPE ID testing and tumor type–guided biomarker analysis to identify the tissue of origin and actionable biomarkers. The advent of precision medicine has introduced several new cancer therapies targetin

FAQs

What is the main goal of combining molecular cancer classification with tumor profiling for CUP?

To assess whether molecular cancer classiﬁcation plus tumor profiling identifies additional treatment options for patients with cancer of unknown primary or unclear diagnoses.

How often did the 92-gene CancerTYPE ID assay identify a tumor type in CUP cases?

CancerTYPE ID identiﬁed a specific tumor type in 92.5% of CUP cases in the MOSAIC database.

Which types of genetic alterations and treatment opportunities were highlighted in the study?

Alterations in KRAS, IDH1/2, BRCA, and BRAF were detected in about 20% of patients, and a cancer-specific FDA-approved or investigational targeted therapy was potentially available for 24.6% of patients with a molecularly diagnosed cancer type.

Sep 21, 2026

Uploaded by Theodore