Feasibility and value of genomic profiling in cancer of unknown primary: real-world evidence from prospective profiling study

Abstract

Real-world evidence regarding the value of integrating genomic profiling (GP) in managing cancer of unknown primary (CUP) is limited. We assessed this clinical utility using a prospective trial of 158 patients with CUP (October 2016-September 2019) who underwent GP using next-generation sequencing designed to identify genomic alterations (GAs). Only 61 (38.6%) patients had sufficient tissue for successful profiling. GAs were seen in 55 (90.2%) patients of which GAs with US Food and Drug Administration-approved genomically matched therapy were seen in 25 (40.9%) patients. A change in therapy was recommended and implemented (primary endpoint of the study) in 16 (10.1%) and 4 (2.5%) patients of the entire study cohort, respectively. The most common reason for inability to implement the profiling-guided therapy was worsening of performance status (56.3%). Integrating GP in management of CUP is feasible but challenging because of paucity of tissue and aggressive natural history of the disease and requires innovative precision strategies.

Figure 1.

Study schema, genomic landscape, and clinical actionability of genomic alterations identified on profiling patients with cancer of unknown primary (CUP). A) Shows the study schema, describing flow of patients with CUP through current study and key study-specific milestones with timelines. Although genomic alterations are seen in a substantial subset of patients able to achieve successful profiling, only a minority can undergo profiling-guided therapy (PGT). B) Shows attrition of patients seen at each landmark stage of the study with the highest magnitude of breakdown in clinical profiling of CUP occurring in tissue procurement. Only 38.9% patients appear to have adequate tumor tissue for profiling. C) Shows the genomic landscape of CUP patients with oncoplot displaying genes altered in at least 10% of patients. Each column represents a patient and each row a gene. Alterations are grouped by pathway (left) and in descending order by frequency. Patients are arranged by immunohistochemical (IHC) grouping (top) (Supplementary Methods, available online): group A: strongly or diffusely positive for CDX2 and CK20 (lower gastrointestinal [GI] profile); group B: CDX2 positive and CK20 negative or weakly positive or CDX2 weakly positive (upper GI profile); group C: GATA3 positive; group D: PAX8 positive; group E: CK5/6, p63 or p16 positive; group F: CK7 positive but not included in any of the groups above. Colored squares show variant, and grey and white squares show no mutation and unsuccessful mutation testing. Fusions are shown along the bottom grid. Upper bars indicate total mutations identified in each patient. Horizontal bars (far right) indicate percentage of patients harboring a variant. D) Shows proportion of patients with genomic alterations classified for clinical actionability (Supplementary Methods, available online). Group 1 genomic alterations, those with biomarker-specific genomically matched US Food and Drug Administration–approved drugs in any solid tumor indication, were seen in 40% cases. CI = confidence interval; seq = sequence. PS = Performance Status; RTK = Receptor Tyrosine Kinase.