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Multi-omic analysis in carcinoma of unknown primary (CUP): therapeutic impact of knowing the unknown
Shumei Kato1, Sophia Gumas1, Jacob J Adashek2
1Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA.
Abstract:
Carcinoma of unknown primary (CUP) is a difficult-to-manage malignancy. Multi-omic profiles and treatment outcome vs. degree of precision matching were assessed. Tumours underwent next-generation sequencing (NGS) [tissue and/or blood-derived cell-free DNA (cfDNA)]. Selected patients had transcriptome-based immune profiling and/or programmed cell death 1 ligand 1 (PD-L1) immunohistochemistry analysis. Patients could be reviewed by a Molecular Tumor Board, but physicians chose the therapy. Of 6497 patients in the precision database, 97 had CUP. The median number of pathogenic tissue genomic alterations was 4 (range, 0-25), and for cfDNA, was 2 (range, 0-9). Each patient had a distinct molecular landscape. Food and Drug Administration (FDA)-approved biomarkers included the following: PD-L1+ ≥ 1%, 30.9% of CUPs tested; microsatellite instability, 3.6%; tumour mutational burden ≥ 10 mutations·Mb-1, 23%; and neurotrophic receptor tyrosine kinase (NTRK) fusions, 0%. RNA-based immunograms showed theoretically druggable targets: lymphocyte activation gene 3 protein (LAG-3), macrophage colony-stimulating factor 1 receptor (CSF1R), adenosine receptor A2 (ADORA2) and indoleamine 2,3-dioxygenase 1 (IDO1). Overall, 56% of patients had ≥ 1 actionable biomarker (OncoKB database). To quantify the degree of matching (tumours to drugs), a Matching Score (MS; roughly equivalent to number of alterations targeted/total number of deleterious alterations) was calculated post hoc. Comparing evaluable treated patients [MS high, > 50% (N = 15) vs. low ≤ 50% (N = 47)], median progression-free survival was 10.4 vs. 2.8 months (95% CI 0.11-0.64; HR 0.27; P = 0.002); survival, 15.8 vs. 6.9 months (95% CI 0.17-1.16; HR 0.45; P = 0.09); and clinical benefit rate (stable disease ≥ 6 months/partial/complete response), 71% vs. 24% (P = 0.003). Higher MS was the only factor that predicted improvement in outcome variables after multivariate analysis. In conclusion, CUPs are molecularly complex. Treatments with high degrees of matching to molecular alterations (generally achieved by individualized combinations) correlated with improved outcomes.
Insights
Molecularly complex carcinoma of unknown primary (CUP) shows improved outcomes with high-precision matching of treatments to genomic alterations. Higher matching scores correlate with better progression-free survival and clinical benefit rates in difficult-to-manage cancers.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Carcinoma of unknown primary (CUP) presents significant management challenges due to its heterogeneous nature.
- Understanding the molecular landscape of CUP is crucial for developing targeted therapeutic strategies.
- Previous approaches often lack the precision needed to effectively treat these complex malignancies.
Purpose of the Study:
- To assess multi-omic profiles in CUP patients.
- To evaluate the correlation between the degree of precision matching (tumor molecular alterations to targeted therapies) and treatment outcomes.
- To identify actionable biomarkers and druggable targets in CUP.
Main Methods:
- Tumor samples underwent next-generation sequencing (NGS) of tissue and/or cell-free DNA (cfDNA).
- Selected patients received transcriptome-based immune profiling and/or programmed cell death 1 ligand 1 (PD-L1) immunohistochemistry.
- A post-hoc Matching Score (MS) was calculated to quantify the precision of treatment-to-alteration matching.
Main Results:
- CUPs exhibit distinct and complex molecular landscapes, with a median of 4 pathogenic tissue genomic alterations.
- 56% of patients had at least one actionable biomarker, including PD-L1 expression, microsatellite instability, tumor mutational burden, and NTRK fusions.
- Higher Matching Scores (>50%) were significantly associated with improved progression-free survival (10.4 vs. 2.8 months), overall survival (15.8 vs. 6.9 months), and clinical benefit rates (71% vs. 24%) compared to lower scores.
Conclusions:
- Carcinoma of unknown primary is characterized by significant molecular complexity.
- Treatments demonstrating a high degree of matching to identified molecular alterations correlate with improved patient outcomes.
- Individualized combination therapies based on comprehensive molecular profiling represent a promising strategy for managing CUP.
