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Genomic profiling provides actionable information for carcinomas of unknown primary site
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Comprehensive genomic profiling identified at least one clinically relevant genomic alteration in most carcinomas of unknown primary site, according to study results.
These findings may help identify targeted treatments for this patient population, researchers said.
Jeffrey S. Ross, MD, of the department of pathology at Albany Medical College and medical director of Foundation Medicine, and colleagues used the FoundationOne assay (Foundation Medicine) to conduct comprehensive genomic profiling of 200 formalin-fixed paraffin-embedded specimens from patients with adenocarcinomas (n = 125) or carcinomas (n = 75) of unknown primary site. The median age of the population was 58.5 years (range, 27-88) and 54% were women.
Researchers identified a total of 841 alternations in 121 genes. Ninety-six percent of tumor samples harbored at least one genomic alteration and 85% harbored a clinically relevant genomic alteration, or one that could be targeted by a currently approved therapy. Researchers noted 26 of the identified alterations are associated with approved targeted therapies.
A greater proportion of adenocarcinomas than carcinomas of unknown primary site harbored a targetable genomic alteration (90% vs. 75%); however, the frequency of clinically relevant genomic alterations per tumor was comparable between patients in each cohort (1.9 vs. 2.1).
The most common genomic alternations that could inform treatment decisions were KRAS (20%), CDKN2A (19%), MCL1 (10%), PTEN (7%), PIK3CA (9%), ERBB2 (8%), RICTOR (6%), BRAF (6%) and NF1 (4%).
Alterations that occurred more frequently in adenocarcinoma of unknown primary site samples included ERBB2 (10% vs. 4%), EGFR (8% vs. 3%), BRAF (6% vs. 4%) and those in the (RTK)/Ras signaling pathway (72% vs. 39%; P ˂ .001). However, MLL2 (10% vs. 3%) occurred more frequently in carcinoma samples.
Researchers also identified biologically relevant alterations that could not be linked to targeted treatment options, the most common of which were TP53 (55%), MYC (12%), ARID1A (11%), SMAD4 (6%), SMARCA4 (6%), RB1 (6%) and PBRM1 (4%).
“Carcinoma of unknown primary site accounts for 3% of adult malignant neoplasms in the United States, and evaluation for a primary anatomic site of origin is often unrevealing and may involve invasive studies,” Ross and colleagues concluded. “Given the poor prognosis of carcinoma of unknown primary site treated by nontargeted conventional therapies, comprehensive genomic profiling shows promise to identify targeted therapeutic approaches to improve outcomes for this disease while potentially reducing the often costly and time-consuming search for the tumor’s anatomic site of origin.”
The opportunities to provide personalized medicine to patients with carcinomas of unknown primary site should be reflected in clinical trials, Gauri Varadhachary, MD, of the department of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, wrote in an accompanying editorial.
“We will require creative approaches to clinical studies and learning from current trends,” Varadhachary wrote. “These trends can then perhaps help in establishment of an international carcinoma of unknown primary site mutation consortium that groups carcinomas of unknown primary site subtypes (eg, liver, osseous, nodal, carcinomatosis dominant presentations) and mutations to plan innovative smaller trials. Just as we need to be selective in our diagnostic approach using an effective algorithm that leverages the proteomics and genomics techniques, we need to be selective in our research efforts to deliver validated new approaches to our patients with carcinomas of unknown primary site.” – by Alexandra Todak
Disclosure: Varadhachary reports no relevant disclosures. The researchers report employment with and equity ownership in Foundation Medicine, Inc.
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