FROM JAMA ONCOLOGY
A genomic analysis of 200 carcinoma of unknown primary site, or CUP samples found that nearly all (96%) contained at least one genetic alteration, and most (85%) had one or more clinically relevant mutation. Adenocarcinomas of unknown primary site, or ACUPs accounted for 63% of the total and non-ACUP cases comprised 38%.
Investigators analyzed tumor samples that had no confirmed primary site, based on analyses by diagnostic imaging, immunohistochemical (IHC) staining, fluorescence in situ hybridization (FISH), serum biomarkers, mRNA transcriptional profiles, and/or prior surgery.
“Some oncologists have hypothesized that a test that can guide targeted therapy selection for patients with CUP ‘up front’ would have utility in clinical management and could help avert the expensive and potentially futile search for the primary lesion that is often pursued,” Dr. Jeffrey Ross and his colleagues wrote (JAMA Oncol. 2015 Feb. 12 [ doi:10.1001/jamaoncol.2014.216 ]).
Clinically relevant genetic alterations (GAs) were defined as those genes targeted by drugs currently on the market or in clinical trials. Out of 169 CUP samples that contained relevant GAs, 113 were in the ACUP group, and 90 (72%) of these were in the receptor tyrosine kinase (RTK)/Ras signaling pathway. Non-ACUP samples had a much smaller proportion in this pathway, 39% of the relevant GAs.
The most common clinically relevant GAs that could potentially affect treatment decisions included KRAS (20%), CDKN2A (19%), MCL1 (10%), PTEN (7%), PIK3CA (9%), ERBB2 (8%), RICTOR (6%), BRAF (6%), and NF1 (4%).
The authors suggest that comprehensive genomic profiling (CGP) analysis may offer cost savings. A CUP diagnostic work-up might include imaging procedures, IHC panels, serum tumor marker panels, and mRNA profiling, and often costs over $10,000. In about one-quarter of cases, the primary site remains unknown, and therapies considered are off label.
The need to locate the primary tumor site when a patient presents with metastatic disease is called into question by a clinical outcome study that reports the impact of therapy selection based on knowledge of the primary site is estimated to be at most several months. Dr. Ross and his associates did not seek to identify the primary site, but rather to identify a treatment option specific to the tumor. Use of CGP at time of diagnosis may enable identification of targeted treatment options to improve response rates, progression-free survival, and overall survival without searching for the primary site.
Clinical trials are needed to compare front-line use of CGP to identify targeted regimens with conventional use of nonspecific cytotoxic chemotherapy in patients with CUP.
“Only by routinely investigating the genomic landscape of a tumor can we realize the full clinical impact of refocusing diagnostic testing away from costly laboratory and imaging studies,” wrote Dr. Ross and associates.
