Comprehensive genomic profiling to predict origin and direct site-specific personalized therapy for cancer of unknown primary in the molecular era

Abstract Background Comprehensive genomic profiling (CGP) holds the potential as a diagnostic tool to identify the primary tissue site of patients with cancer of unknown primary (CUP). This study aims to evaluate the effectiveness of patient-centered precision therapy (PCPT) directed by CGP, relative to conventional chemotherapy, in previously untreated patients with CUP. Methods Patients diagnosed with CUP between July 2017 and January 2022 were screened for analysis. A comprehensive 90-gene expression assay was utilized to identify tissue-of-origin, while CGP was performed on the Illumina NextSeq 500 system. Survival analysis was performed using Kaplan-Meier method. Significant OS variables were further investigated through multivariate analysis using the Cox proportional hazard model. A P-value of less than 0.05 was considered significant. Results 48 patients were identified for final analysis. The 90-gene assay was able to predict 11 different tumor types. The most common types of cancer were lung cancer (n = 10, 20.8%). The median OS was 19.2 months (95% CI, 13.6–24.7). CGP analyses were performed on 36 samples. The mean number of non-silent mutations detected per sample was 8.2 (range: 1 to 30). The most commonly mutated genes included TP53, KRAS, KMT2D, BRAF, CIC, SMAD4, KEAP1, SMARCA4, and STK11. PCPT for CUP was significantly associated with significant longer OS compared with empirical therapy (median OS: 23.8 vs. 9.7 months; HR, 0.39; 95% CI, 0.24–0.63; P < 0.001). Multivariate analysis identified PCPT as initial therapy (HR = 0.21, p = 0.02), female (HR = 0.33, p = 0.02), and favorable performance status (HR = 0.32, p < 0.001) as prognostic indicators that correlate with prolonged OS. Conclusion Comprehensive genomic profiling contributes to CUP origin prediction and patient-centered precision therapy, and the data support a significant association between PCPT and longer OS compared to empirical chemotherapy. This treatment strategy deserves further research.