- Design
- Single-centre real-world implementation cohort with referral network
- Population
- 295 consecutive patients with high-grade serous carcinoma
- Primary outcome
- Feasibility and yield of comprehensive genomic profiling with HRD assessment
- Effect
- 96.6% success; BRCA1 14.4%, BRCA2 8.8%; GIS ≥42 in 46.7%
The PROMETHEUS study at Istituto Nazionale Tumori ran comprehensive genomic profiling with an HRD-capable 500-gene assay on 295 consecutive high-grade serous carcinomas over 26 months, including 132 referred from regional public hospitals.
Profiling succeeded in 96.6%. Pathogenic BRCA1 variants were found in 14.4% and BRCA2 in 8.8%. The genomic instability score was evaluable in 93.6% and was 42 or higher in 46.7%. Further potentially actionable alterations, mainly amplifications such as CCNE1, appeared in 15.4%. Of 116 patients with follow-up, 47.4% received biomarker-guided PARP inhibitor maintenance, and a high genomic instability score was associated with better event-free and overall survival. Of 46 referred for genetic counselling, 32 carried pathogenic germline variants.
For laboratories, the useful numbers are the failure rates: about 3% of samples failed sequencing and about 6% had no evaluable instability score. Tissue selection and tumour content are where much of that is decided.
The study is single-centre and descriptive, but it shows that a referral network can deliver HRD results reliably.
- Select the block with the highest tumour content for HRD testing.
- Record tumour cellularity on the request so failures can be anticipated.
- Flag pathogenic BRCA variants for germline counselling, since many proved hereditary.
- Expect around one in twenty samples without an evaluable instability score.
Why it matters
The pathologist's block choice largely decides whether a patient gets an HRD result that opens PARP inhibitor maintenance.
Don't overread it
The survival difference by genomic instability is observational and does not compare testing strategies.
The statistics, in plain English
A 96.6% success rate means about 10 of 295 samples could not be sequenced. That 32 of 46 counselled patients carried germline variants reflects who was referred, not the rate across all patients.
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