- Design
- Prospective real-world implementation study
- Population
- 295 consecutive patients with high-grade serous carcinoma, Italy
- Primary outcome
- Profiling success and actionable findings
- Effect
- Success 96.6%; BRCA1 14.4%, BRCA2 8.8%; high GIS 46.7%
The PROMETHEUS study describes 26 months of routine comprehensive genomic profiling, including a homologous recombination deficiency genomic instability score, for 295 consecutive patients with high-grade serous carcinoma at an Italian cancer institute and its referring public hospitals.
Profiling succeeded in 285 cases (96.6%) and the instability score was evaluable in 93.6%. BRCA1 mutations were found in 14.4% and BRCA2 in 8.8%; 46.7% had a high instability score, and 15.4% had other potentially actionable alterations, mostly amplifications including CCNE1. Of patients with follow-up, 47% received biomarker-based PARP inhibitor maintenance. A high instability score was associated with better event-free and overall survival. Of 46 patients referred for genetic counselling, 32 carried a germline pathogenic variant.
The practical lesson for laboratories is that in-house HRD testing with tumour board review is feasible from routine blocks, including referred cases, and that tumour testing is an effective route to germline diagnosis.
- Consider in-house or regional HRD testing at diagnosis for every high-grade serous carcinoma.
- Select blocks with good tumour content to keep failure rates near the 3% reported here.
- Flag tumour BRCA1/2 variants for germline confirmation and genetic counselling.
- Report CCNE1 amplification when found; it marks a different biology from HRD.
- Route results through a molecular tumour board where one exists.
Why it matters
It shows that a single tumour test can drive both maintenance therapy and family genetic diagnosis.
Don't overread it
A single-institution implementation study; it shows feasibility rather than a survival benefit from testing itself.
The statistics, in plain English
A 96.6% success rate means about 3 in 100 samples failed. The survival link with a high instability score is observational and partly reflects PARP inhibitor use in those patients.
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