CANCER OF UNKNOWN PRIMARY( CUP )

UPDATE

Bui Dac Chi,MD

Medic Center

People with a Cancer of Unknown Primary (CUP) have been diagnosed with some form of metastatic cancer, but the primary cancer cannot be located

• Cancer of unknown primary means that the original site, the primary, is either too small to find or has died. The aggressive remaining cancer spreads throughout the body. Though occasionally there are remarkable improvements, and even the rare cure with chemotherapy, it generally has a grim prognosis. CUP is often advanced when discovered and resistant to treatment. Occasionally, this illness responds to medicine, which at times can extend life, but even then it is often not curable

When a person is diagnosed with cancer that has spread within the body (metastatic cancer) the primary site – the place in the body where the cancer started – is not always obvious. Finding the genetic origin of the cancer is important to define the best treatment. When the origin of the cancer is not identified with confidence, after initial tests, this is described as Cancer of Unknown Primary or CUP

For some CUP patients the primary cancer will remain unknown and will never be identified

Cancers of unknown primary or occult primary malignancies are tumors that have metastasized from an unknown primary source, and make up approximately 2% - 6% of all cancer cases.

Conventional methods used to aid in the identification of the origin of a cancer of unknown primary malignancy include a thorough history and physical examination, computed tomography (CT) scans of the chest, abdomen, and pelvis, routine laboratory studies; and targeted evaluated of specific signs and symptoms. Identifying the primary origin of a tumor can dictate cancer specific treatment, expected outcome, and prognosis

Median survival ranges from 4 to 11o/o.1.3 and 5-year survival are 23o/o, 11o/o and

6o/o respectively.Most do not benefit from chemo.

Molecular profiling of cancers of unknown primary (CUP): paradigm shift in management of CUP.

Molecular profiling aimed at detection of biomarkers.Multiplatform approach…

IHC,sequencing(Sanger,NGS),qPCR,FISH,dISHPredictive biomarker molecular profiling of CUP

identifies actionable targets in ~ 80% of all cases.

Microarray-based gene expression testing (e.g., the Pathwork® Tissue of Origin Test), also known as gene expression profiling, is being offered by the manufacturer as being possibly useful in identifying the origin of cancers of unknown primary malignancy. The test measures the expression of more than 1,500 genes and compares the similarity of the gene expression profile of a cancer of unknown primary to a database of known profiles from 15 tissues with more than 60 histologic morphologies. The test uses a proprietary Pathchip® microarray and runs on the Affymetrix GeneChip® system. The report generated for each tumor consists of a similarity score, which is a measure of similarity of the gene expression profile of the specimen to the profile of the 15 known tumors in the database. Scores range from 0 (very low similarity) to 100 (very high similarity), and sum to 100 across all 15 tissues on the panel. If a single similarity score is greater than or equal to 30, it indicates that this is likely the tissue of origin. If every similarity score is between 5 and 30, the test result is considered indeterminate, and a similarity score of less than 5 rules out that tissue type as the likely origin.

The Pathwork Tissue of Origin test (Pathwork Diagnostics) uses measurements of the levels of 2,000 different mRNAs to determine the most likely tissue of origin for an unknown sample from among a panel of 15 different tumors. The similarity score test result is considered diagnostic if the highest similarity score is greater than 20, and this report confirms the cell of origin with99% certainty.

WHAT ABOUT DEALING WITH PATIENTS WHO REQUIRE ADMISSION?

Admit patient under an appropriate team (Cancer center, General Medicine hospital, General Surgery hospital…ie. Each area would have a responsible team).

CGP can identify novel treatment paradigms and suggested that early testing may have utility in CUP management. This study illustrates some important considerations in the diagnostic workup and management of patients with CUP.

FROM IMMUNOHISTOCHEMISTRY TO GENE EXPRESSION PROFILING.

Immunohistochemistry analysis is a vital component in the investigation of CUP cancers. However, the analysis has limitations because markers for CUP are not uniformly site specific or sensitive.

When the initial evaluation remains ambiguous as to theprimary cell of origin, the IHC analysis did not appear toprovide clarity for the primary site.

Several commercial molecular gene expression–based assays (Tissue of Origin test [Pathwork Diagnostics], CancerType ID [BioTheranostics, San Diego,CA], and MiRview Mets test [Rosetta Genomics, Philadelphia,PA; Rehovot, Israel]) for CUP are available with prediction accuracies in known primary cancers of 80% to 90%.

Genomic testing is becoming an integral tool used in directing future therapeutic decisions in patients with cancers of unknown origins.

Cancer of unknown primary site (CUP) is a well recognised clinical disorder, accounting for 3–5% of all malignant epithelial tumours. CUP is clinically characterised as an aggressive disease with early dissemination. Diagnostic approaches to identify the primary site include detailed histopathological examination with specific immunohistochemistry and radiological assessment. Gene-profiling microarray diagnosis has high sensitivity, and patients' outcomes are improved by its clinical use. Metastatic adenocarcinoma is the most common CUP histopathology (80%). CUP patients are divided into subsets of favourable (20%) and unfavourable (80%) prognosis. Favourable subsets are mostly given locoregional treatment or systemic platinum-based chemotherapy. Responses and survival are similar to those of patients with relevant known primary tumours. Patients in unfavourable subsets are treated with empirical chemotherapy based on combination regimens of platinum or taxane, but responses and survival are generally poor