CUP Syndrome

Cancer of unknown primary (CUP) is a class of metastatic malignancy detected when the site of primary origin could not be determined precisely after a complete assessment that includes patient history, physical examination, imaging, serum markers, and pathologic evaluation of tumor samples. It constitutes 3% to 5% of all newly diagnosed cancers per year worldwide. Including cancers of uncertain primary origin, the total number increases to 12% to 15% of all newly diagnosed malignancies. Recommended treatments involve empirical chemotherapy and have shown modest clinical benefits. The prognosis is unfavorable in 80% to 85% of CUP cases, with current overall survival of 2.7 to 11 months after diagnosis and a 1-year survival rate of 15%~20%. The identification of the tissue of origin based on molecular profiling by gene expression analysis has been expected to allow more effective and specific treatment for patients with CUP, thereby prolonging their survival time. Indeed, a large prospective trial of site-specific therapy based on gene expression profiling showed promising efficacy for patients with CUP, yielding a median OS of 12.5 months.

Canhelp-Origin Test

Canhelp Origin Test is a molecular test based on real time quantitative RT-PCR technology and is validated with an overall accuracy of 90% for identifying the primary site of metastatic cancer, especially in poorly differentiated or undifferentiated tumors. The qPCR based assay measures the expression pattern of 90 specific markers of tissue samples and classifies 21 major tumor types covering more than 95% of solid tumor by incidence.

Recent studies showed Canhelp Origin Test an excellent accuracy for classifying metastatic triple negative breast cancer and identifying the primary site of metastatic brain tumors and Liver Metastases. A Phase III study CUP001 (NCT03278600) is ongoing to evaluate the clinical utility of Canhelp Origin Test in predicting primary site and directing therapy in patients with cancer of unknown primary. CUP001 is the world's first prospective randomized controlled phase III clinical trial of cancer of unknown primary initiated by Chinese investigators, has proved for the first time that site-specific treatment guided by 90-gene expression assay can significantly improve PFS and OS compared with empirical chemotherapy in CUP patients. This finding provides high-level evidence-based medical evidence for gene expression profile testing to guide organ-specific treatment for CUP patients, which is expected to change the current treatment status of CUP.

Test & Methodology

The expression profile of 90 tumor specific genes is obtained by extracting RNA from tumor enriched sections of formalin fixed paraffin embedded (FFPE) tissue and performing real time quantitative RT-PCR using Taqman™ technology. 

The test identifies the most likely tissue origin and histological type based on the degree of similarity of the sample’s 90-gene expression profile to a reference database of gene expression profiles from tumors of known primary site and histological subtype.

Figure: Test Sample Result. The top 5 tumor types with the highest similarity score values are:
breast cancer (90.3), cervix cancer (1.7), ovary cancer(1.6), germ cell tumor (1.1) and neuroendocrine cancer (1), thus suggesting the sample is most likely breast cancer.

The test result is reported as a series of similarity scores for each of the tumor types. The similarity score was estimated as a measure of the similarity of the gene expression pattern of the specimen to the gene expression pattern of the indicated tumor type. The similarity score ranges from 0 to 100, and adds to 100 across all tumor types. The tumor type with the highest similarity score was considered as the likely tumor origin and compared with the reference diagnosis.

Intended Use

Pathologist:

- Tumor is poorly differentiated or undifferentiated.
- Specimen is small, constraining the diagnostic workup.
- IHC results are inconclusive or contradict with previous results.
- Unable to differentially diagnose two or more cancer types.

Oncologist:

- Patient has a history of multiple cancers.
- Atypical metastatic site.
- Inconsistent clinical and pathological diagnoses.
- Doubt about initial diagnosis when the patient fails initial therapy.