Prospective study for comprehensive genomic profiling (GP) in cancer of unknown primary (CUP): Feasibility, molecular landscape, and clinical utility in current era.

Abstract

834 Background: CUP presents a unique niche and challenge for application of GP. Absence of a primary limits consensus regarding site-directed and availability of tissue specific targeted therapy. We evaluated the real time feasibility and clinical utility of GP in CUP. Methods: Treatment eligible CUP pts were prospectively enrolled. A novel next-gen targeted sequencing (NGS) assay (ActionSeq/FusionSeq) was used to find genomic alterations (GAs) (somatic mutations in 212 and fusions in 53 cancer-associated genes). The primary objective was to determine prevalence of GAs and to assess the clinical impact via change in pre-test planned therapy (either referral to biomarker pertinent clinical trial (CT) or off label use of FDA approved drugs). With 54 pts we achieved 80% power (α 0.05) to a treatment change in 10% (5% to 15%) pts. Results: Between 9/2016 and 8/2019, 150 pts were consented. Tissue for GP was available in 59 (39%) pts (for 91 pts, samples had exhausted or insufficient tissue). Test was successfully performed on 54 (92%) pts. Cohort characteristics include: median age: 58 yr, male 43%, ECOG PS ≤1 96%, median IHC 8 (range 2-26), median survival 33 m (95% CI 18-47). Median reporting time was 23 days. Four (7%) pts had no identifiable GAs. A fusion ( PTRPK) was seen in 1 (2%) pt. Among 50 pts, total number of GAs were 487; 123 (26%) were “clinically relevant” (median 2.5/pt, range 1-11) while 364 (76%) were variants of unknown significance. Of the 123 GAs, 94 were mutations and 29 were amplifications. The 5 most common mutations were TP53, KRAS, PIK3CA, ARID1A, and NRAS and amplifications were CCND1, FGFR3, ERBB2, EGFR, and MYC. Planned therapy change post ActionSeq occurred in 13 pts (22%, 95% CI 13-34) (2 received an off-label drug; 9 were CT eligible [2 enrolled, 5 had PS decline, 2 pending]; 2 were lost to follow-up). Responses were seen in 2 of 4 pts who received GP based treatment. Conclusions: Comprehensive GP should be offered early to CUP pts. GP can help identify novel therapy and clinical trial options. Given the high rate of insufficient tissue cases, integrating a tissue sensitive algorithm involving IHC and GP in therapeutic management of CUP is merited.