Therapeutic Actionability of Circulating Cell-Free DNA Alterations in Carcinoma of Unknown Primary.

Abstract

Cancer of unknown primary (CUP) is a metastatic disease with unidentifiable primary tumor. Somatic alterations can be assessed noninvasively via liquid biopsies interrogating cell-free DNA (cfDNA). We evaluated 1,931 patients with CUP with a cfDNA next-generation sequencing panel (73-74 genes). Overall, 1,739 patients (90%) had ≥ 1 cfDNA alteration. We then explored alteration actionability (per the levels of evidence from the OncoKB database); 825 patients (47.4% of 1,739) had level 1, level 2, or resistance/R1 alterations. Among 40 clinically annotated patients with CUP who had cfDNA evaluated, higher degrees of matching treatment to alterations (Matching Score > 50% <i>v</i> ≤ 50%) was the only variable predicting improved outcome: longer median progression-free survival (10.4 <i>v</i> 2.5 months; <i>P</i> = .002), overall survival (13.4 <i>v</i> 5.7 months; <i>P</i> = .07, trend), and higher clinical benefit rate (stable disease ≥ 6 months/partial response/complete response; 83% <i>v</i> 25%; <i>P</i> = .003). In summary, cfDNA frequently reveals strong level-of-evidence actionable alterations in CUP, and high degrees of matching to therapy correlates with better outcomes.