Prognostic impact of variants of uncertain significance (VUS) in BRCA genes and homologous recombination repair (HRR) genes in prostate cancer: a real-world multicenter study.
20 affiliations
- 1Unit of Medical Oncology and Biomolecular Therapy and CREATE Center for Research and Innovation Medicine, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, Foggia, Italy.
- 2Molecular Pathology and Oncological Genetics Unit, Policlinico Riuniti, Foggia, Italy.
- 3Sovrintendenza Sanitaria Centrale, INAIL, Roma, Italy.
- 4Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy.
- 5Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy.
- 6UOC di Oncologia, Azienda Ospedaliera di Rilievo Nazionale Cardarelli di Napoli, Naples, Italy.
- 7Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), Section of Medical Oncology, University of Palermo, Palermo, Italy.
- 8Department of Medical Oncology, Università degli Studi di Napoli Federico II, Naples, Italy.
- 9Department of Oncology and Palliative Care, Cardinale G Panico, Tricase City Hospital, Tricase, Italy.
- 10Oncology Unit, Oncology Department, "Azienda Ospedaliero Universitaria (AOU) Dulbecco" Hospital, Catanzaro, Italy.
- 11University Oncology Unit, University of Salento Fazzi Hospital, Lecce, Italy.
- 12Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
- 13Medical Oncology, Ospedale Ca' Foncello di Treviso, AULSS2 Marca Trevigiana, Treviso, Italy.
- 14Unit of Medical Oncology, "Sacro Cuore di Gesù" Hospital, Gallipoli, Italy.
- 15Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
- 16Newcastle Hospitals and NHS Trust, Newcastle upon Tyne, UK.
- 17Pathology Unit, Department of Clinical and Experimental Medicine, University of Foggia, Policlinico Riuniti, Foggia, Italy.
- 18IRCCS National Cancer Institute Regina Elena, Rome, Italy.
- 19Unit of Medical Oncology and Biomolecular Therapy and CREATE Center for Research and Innovation Medicine, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, Foggia, Italy. [email protected].
- 20Unit of Medical Oncology and Biomolecular Therapy and CREATE Center for Research and Innovation Medicine, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, Foggia, Italy. [email protected].
Abstract
Background
Variants of uncertain significance (VUS) in BRCA1/2 and other homologous recombination repair (HRR) genes represent a major interpretative challenge in prostate cancer, particularly in the next-generation sequencing era. While pathogenic alterations are associated with poor prognosis and therapeutic implications, the clinical impact of VUS remains unclear.Methods
We conducted a retrospective, real-world multicenter study including 1402 patients with metastatic castration-resistant prostate cancer (mCRPC) from 11 Italian academic centers (702 in the primary cohort; 700 in the validation cohort). Patients were stratified as wild-type (WT), pathogenic/likely pathogenic mutated (MUT), or VUS carriers in BRCA1/2 and other HRR genes. Overall survival (OS) was assessed using Kaplan-Meier estimates and Cox regression models. VUS were reclassified according to updated ENIGMA guidelines.Results
In the primary cohort, BRCA MUT and VUS were detected in 4.7 and 1.8% of patients, respectively, while other HRR MUT and VUS were observed in 14.1 and 14.0%. After re-evaluation, 7.7% of VUS changed classification, including three reclassified as clinically significant. For clinical outcome analyses, we restricted evaluation to patients harboring VUS located within functional domains. In the BRCA cohort, median OS from tumor diagnosis was significantly shorter in MUT (72 months) and VUS (74 months) compared with WT (144 months; p = 0.002). Similarly, in the HRR cohort, both MUT (104 months) and VUS (128 months) showed inferior OS compared to WT (144 months; p = 0.012). The secondary cohort confirmed a consistent prognostic gradient, with VUS demonstrating intermediate outcomes between WT and MUT groups (p < 0.001). No significant association was observed between VUS and response to first-line therapy in mCRPC. In multivariable analysis, BRCA1/2 pathogenic alterations retained a trend toward worse OS compared with WT patients (HR 1.78, 95% CI 0.96-3.30; p = 0.067), whereas BRCA1/2 VUS were not independently associated with OS after adjustment for major clinicopathological factors.Conclusions
In this large real-world study, VUS in BRCA/HRR genes were associated with intermediate but clinically relevant prognostic outcomes, suggesting potential biological significance. Although current guidelines do not support treatment decisions based on VUS, systematic re-evaluation and integration of functional data may refine risk stratification and improve precision oncology strategies in prostate cancer.
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BibTeX
@article{garofoli2026prognostic,
title = {{Prognostic impact of variants of uncertain significance (VUS) in BRCA genes and homologous recombination repair (HRR) genes in prostate cancer: a real-world multicenter study.}},
author = {Marianna Garofoli and Maria Iole Natalicchio and Giuseppina Bruno and Aldo Rosano and Brigida Anna Maiorano and Sabrina Rossetti and Sarah Scagliarini and Lorena Incorvaia and Luigi Formisano and Ilaria Toma and Guido Giordano and Giovanna Pecoraro and Francesco Grillone and Laura Palumbo and Marco Pisino and Marta Palladino and Concetta Rita Di Pippo and Valeria Bafunno and Nicole Brighi and Chiara Casadei and Cristian Lolli and Maria Concetta Cursano and Vincenzo Emanuele Chiuri and Pasquale Rescigno and Emiliano Tamburini and Francesca Sanguedolce and Fabio Calabrò and Ugo De Giorgi and Matteo Landriscina and Vincenza Conteduca},
journal = {BMC medicine},
year = {2026},
month = aug,
doi = {10.1186/s12916-026-05086-2},
url = {https://europepmc.org/article/MED/42972372},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Prognostic impact of variants of uncertain significance (VUS) in BRCA genes and homologous recombination repair (HRR) genes in prostate cancer: a real-world multicenter study.
AU - Marianna Garofoli
AU - Maria Iole Natalicchio
AU - Giuseppina Bruno
AU - Aldo Rosano
AU - Brigida Anna Maiorano
AU - Sabrina Rossetti
AU - Sarah Scagliarini
AU - Lorena Incorvaia
AU - Luigi Formisano
AU - Ilaria Toma
AU - Guido Giordano
AU - Giovanna Pecoraro
AU - Francesco Grillone
AU - Laura Palumbo
AU - Marco Pisino
AU - Marta Palladino
AU - Concetta Rita Di Pippo
AU - Valeria Bafunno
AU - Nicole Brighi
AU - Chiara Casadei
AU - Cristian Lolli
AU - Maria Concetta Cursano
AU - Vincenzo Emanuele Chiuri
AU - Pasquale Rescigno
AU - Emiliano Tamburini
AU - Francesca Sanguedolce
AU - Fabio Calabrò
AU - Ugo De Giorgi
AU - Matteo Landriscina
AU - Vincenza Conteduca
PY - 2026
DA - 2026/08/04
JO - BMC medicine
DO - 10.1186/s12916-026-05086-2
UR - https://europepmc.org/article/MED/42972372
AB - Background Variants of uncertain significance (VUS) in BRCA1/2 and other homologous recombination repair (HRR) genes represent a major interpretative challenge in prostate cancer, particularly in the next-generation sequencing era. While pathogenic alterations are associated with poor prognosis and therapeutic implications, the clinical impact of VUS remains unclear.Methods We conducted a retrospective, real-world multicenter study including 1402 patients with metastatic castration-resistant prostate cancer (mCRPC) from 11 Italian academic centers (702 in the primary cohort; 700 in the validation cohort). Patients were stratified as wild-type (WT), pathogenic/likely pathogenic mutated (MUT), or VUS carriers in BRCA1/2 and other HRR genes. Overall survival (OS) was assessed using Kaplan-Meier estimates and Cox regression models. VUS were reclassified according to updated ENIGMA guidelines.Results In the primary cohort, BRCA MUT and VUS were detected in 4.7 and 1.8% of patients, respectively, while other HRR MUT and VUS were observed in 14.1 and 14.0%. After re-evaluation, 7.7% of VUS changed classification, including three reclassified as clinically significant. For clinical outcome analyses, we restricted evaluation to patients harboring VUS located within functional domains. In the BRCA cohort, median OS from tumor diagnosis was significantly shorter in MUT (72 months) and VUS (74 months) compared with WT (144 months; p = 0.002). Similarly, in the HRR cohort, both MUT (104 months) and VUS (128 months) showed inferior OS compared to WT (144 months; p = 0.012). The secondary cohort confirmed a consistent prognostic gradient, with VUS demonstrating intermediate outcomes between WT and MUT groups (p < 0.001). No significant association was observed between VUS and response to first-line therapy in mCRPC. In multivariable analysis, BRCA1/2 pathogenic alterations retained a trend toward worse OS compared with WT patients (HR 1.78, 95% CI 0.96-3.30; p = 0.067), whereas BRCA1/2 VUS were not independently associated with OS after adjustment for major clinicopathological factors.Conclusions In this large real-world study, VUS in BRCA/HRR genes were associated with intermediate but clinically relevant prognostic outcomes, suggesting potential biological significance. Although current guidelines do not support treatment decisions based on VUS, systematic re-evaluation and integration of functional data may refine risk stratification and improve precision oncology strategies in prostate cancer.
SN - 1741-7015
ER -