Therapeutic Actionability of Circulating Cell-Free DNA Alterations in Carcinoma of Unknown Primary
Shumei Kato, Caroline Weipert, Sophia Gumas, Ryosuke Okamura, Suzanna Lee, Jason K. Sicklick, Jennifer Saam, Razelle Kurzrock
Abstract
PURPOSE 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). METHODS We evaluated 1,931 patients with CUP with a cfDNA next-generation sequencing panel (73-74 genes). RESULTS 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% v ≤ 50%) was the only variable predicting improved outcome: longer median progression-free survival (10.4 v 2.5 months; P = .002), overall survival (13.4 v 5.7 months; P = .07, trend), and higher clinical benefit rate (stable disease ≥ 6 months/partial response/complete response; 83% v 25%; P = .003). CONCLUSION In summary, cfDNA frequently reveals strong level-of-evidence actionable alterations in CUP, and high degrees of matching to therapy correlates with better outcomes.