Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

作者：Kato Shumei^*; Krishnamurthy Nithya; Banks Kimberly C; De Pradip; Williams Kirstin; Williams Casey; Leyland Jones Brian; Lippman Scott M; Lanman Richard B; Kurzrock Razelle

来源：Cancer Research, 2017, 77(16): 4238-4246.

DOI：10.1158/0008-5472.CAN-17-0628

Carcinomaof unknown primary (CUP) is a rare and difficult-to-treat malignancy, themanagement of which might be improved by the identification of actionable driver mutations. We interrogated 54 to 70 genes in 442 patients with CUP using targeted clinicalgrade, next-generation sequencing of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66% (290/442) >= 1 characterized alteration(s), excluding variants of unknown significance. TP53-associated genes were most commonly altered [37.8% (167/442)], followed by genes involved in the MAPK pathway [31.2% (138/442)], PI3K signaling [18.1% (80/442)], and the cell-cyclemachinery [10.4%(46/442)]. Among 290 patients harboring characterized alterations, distinct genomic profiles were observed in 87.9% (255/290) of CUP cases, with 99.7% (289/290) exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor-based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of noninvasive liquid biopsies in next-generation clinical trials.