NEW YORK (Reuters Health) - Most carcinomas of unknown primary site (CUPs) have genomic alterations that could be amenable to targeted therapies, researchers report.
"Currently, comprehensive genomic profiling is typically used for patients that have rare cancers, have failed treatment or their disease has recurred, or whose disease represents some complexity, but to some degree, any/all patients with solid tumors and hematologic cancers could potentially benefit from genomic profiling in order to help oncologists match their patients to targeted therapies," Dr. Jeffrey S. Ross from Albany Medical College in Albany, New York, told Reuters Health by email.
Dr. Ross and colleagues used comprehensive genomic profiling based on next-generation sequencing to evaluate a series of 200 consecutive CUP specimens to determine whether the genome-derived drug targets identified could be used to guide personalized, targeted treatment.
They found 841 alterations in 121 genes, for a mean of 4.2 genomic alterations per CUP, according to their report, published online February 12 in JAMA Oncology.
Eighty-five percent of the CUP cases had at least one clinically relevant genomic alteration that could potentially guide decisions for targeted treatment, including 90% of the adenocarcinomas and 75% of the non-adenocarcinomas.
The most common clinically relevant alterations potentially affecting treatment decisions included KRAS (20%), CDKN2A (19%), MCL1 (10%), PTEN (7%), ERBB2 (8%), RICTOR (6%), BRAF (6%), and NF1 (4%).
Twenty-six alterations identified in this study were associated with targeted therapies approved for use in patients with a known primary tumor type, and 14 additional cases harbored genomic alterations linked in multiple reports with targetable activity (e.g., MET amplification and ERBB2 activating substitutions).
Even the genomic alterations not considered specific targets for approved therapies were linked to hundreds of registered clinical trials and could direct patient entry into studies testing targeted agents in both early and later stages of clinical development, the researchers say.
The cost of a complete diagnostic workup for CUP commonly exceeds $10,000, and 25% or more of these will result in "unknown" primary sites and no "on-label" therapies. Genomic profiling could eventually change all that.
"We hope these data show oncologists that FoundationOne -- a singular comprehensive genomic profiling approach -- can provide an immediate opportunity to influence therapy decisions based on relevant genomic alterations and potentially improve outcomes for patients living with CUP," Dr. Ross said.
"Broadly, I believe these data point to the value of molecular information and its potential to transform cancer care," Dr. Ross added. "Mounting recent evidence suggests that determining the tissue of origin of an unknown primary cancer may be less relevant for treatment than delineating the driver of genomic alterations that are fueling disease progression. Comprehensive genomic profiling could potentially offer a new, immediate, and vitally important approach to the treatment and care management of individuals with cancer."
Dr. Ross and his co-authors are employees and equity holders of Foundation Medicine, Inc, which markets FoundationOne.
"One could envision using an algorithm that integrates immunohistochemistry, select tissue-of-origin profiling, and comprehensive genomic profiling in some combination to maximize clinically meaningful benefit and minimize costs, especially in patients with limited or difficult-to-access tumors and poorly or undifferentiated neoplasms," writes Dr. Gauri Varadhachary from University of Texas MD Anderson Cancer Center in Houston, Texas, in a related editorial.
"Just as we need to be selective in our diagnostic approach using an effective algorithm that leverages the proteomics and genomics techniques," Dr. Varadhachary concludes, "we need to be selective in our research efforts to deliver validated new approaches to our patients with CUP."
Dr. Frank A. Greco, director of Sarah Cannon Cancer Center, Nashville, Tennessee, noted that the technique used in the new study cannot diagnose the type of tumor or tissue of origin in CUP.
"This requires a different gene-expression assay generally referred to as a molecular cancer-classifier assay. These assays are mentioned in the article and are critical for some patients since the specific type of cancer they have may be very treatable once it is diagnosed," he told Reuters Health by email.
"A molecular cancer-classifier assay performed on the biopsy should be done first," advised Dr. Greco, who was not involved in the new work. "These assays are about 90% accurate in diagnosing the type of cancer the patient harbors even though in CUP the anatomical primary or site of origin cannot be clinically detected. In relatively rare cases the diagnosis is incorrect or unclassifiable."
"It is likely in the future that knowledge of the primary site of an advanced cancer will be less important than identification of the molecular drivers of the cancer and treatment will be directed at the important genetic lesions within the cancer cells," Dr. Greco said. "Next-generation sequencing can help provide knowledge of the genetic alterations in cancer cells, but for now the specific type of cancer remains the gold standard on which therapies are based and depending on the specific cancer may be very effective. We are now slowly evolving into an era when genomic understanding will eventually lead to more effective rational based therapies, but we are not there yet for most patients."
Dr. Daniel Shao-Weng Tan from National Cancer Center Singapore, Singapore recently reported on molecular profiling to identify druggable targets in CUP. He told Reuters Health in an email that, "At present, not all institutions have the infrastructure to provide genomic profiling, although the landscape will almost certainly change in the next few years. Further, current profiling is limited to approved agents, for which there currently remain a handful, although again this list is growing steadily. Thus the current scope should remain patients who have access to clinical trials of novel therapeutics in the form of phase I-III trials."
"There is a role for molecular profiling for CUP," Dr. Tan concluded, "with the caveat that not all alterations discovered will necessarily respond based on historical data on another tumor type, due to cell context-specific implications."
SOURCE: http://bit.ly/1zSRVLN and http://bit.ly/1zSS1TG
JAMA Oncol 2015.
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