Genomic Analysis Could Influence Unknown Primary Site Tumour Treatments

Next-generation sequencing could identify treatment targets for patients with carcinoma of unknown primary site

medwireNews: The majority of patients with carcinoma of unknown primary site (CUP) harbour at least one clinically relevant genomic alteration (GA) that could help guide treatment decision-making, US researchers say.

Comprehensive genomic profiling of tumour specimens from 125 patients with adenocarcinoma (A)CUP and 75 patients with non-ACUP revealed an average of 4.2. GAs per sample, with 96% of patients having at least one GA detected.

Moreover, 85% of CUP specimens had at least one GA that could potentially be targeted by specific therapies, report lead author Jeffrey Ross, from Albany Medical College in New York, and team in JAMA Oncology.

“Given the poor prognosis of CUP 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”, they write.

Over half (55%) of the GAs identified were found to affect TP53, while 20% were detected in KRAS, 37% in CDKN2A, 12% in MYC and 11% in ARID1A. Other genes with GAs included PIK3CA (9%), ERBB2 (8%), EGFR (6%), BRAF (6%) and BRCA2 (6%).

Further analysis revealed that ACUP samples had a different GA profile to non-ACUPs, with a higher rate of ERBB2 Mutations or amplifications (10 vs 4%), as well as changes to EGFR (8 vs 3%) and BRAF (6 vs 4%).

And clinically relevant mutations in the treatment targetedreceptor tyrosine kinase/Ras/mitogen-activated Protein kinase signalling pathways were “strikingly” more common in ACUP than non-ACUP specimens, at 72% versus 39%, a significant difference.

These included alterations in KRAS, BRAF, ALK, KIT, RET and ROS1, the team notes.

“[G]iven that with a single assay [next-generation sequencing] can discover unanticipated therapeutic targets for patients presenting with CUP, clinical trials are needed to compare the front line use of comprehensive genomic profiling to identify targeted regimens with the conventional use of generic cytotoxic chemotherapy”, the researchers conclude.

“The value of this approach is bolstered by recent evidence suggesting that determining the tissue of origin of an unknown primary cancer may be less relevant than delineating the driver GAs that are fueling disease progression.”

Reference

Ross J, Wang K, Gay L, et al. Comprehensive genomic profiling of carcinoma of unknown primary site. New routes to targeted therapies. JAMA Oncol 2015; Advance online publication 12 February. doi:10.1001/jamaoncol.2014.216

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