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Background <p>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.</p> Methods <p>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.</p> Results <p>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; <i>p</i> = 0.002). Similarly, in the HRR cohort, both MUT (104 months) and VUS (128 months) showed inferior OS compared to WT (144 months; <i>p</i> = 0.012). The secondary cohort confirmed a consistent prognostic gradient, with VUS demonstrating intermediate outcomes between WT and MUT groups (<i>p</i> &lt; 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; <i>p</i> = 0.067), whereas BRCA1/2 VUS were not independently associated with OS after adjustment for major clinicopathological factors.</p> Conclusions <p>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.</p>

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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

  • 期刊论文

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  • 发表日期：

    2026年8月4日

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  • Marianna Garofoli,
  • Maria Iole Natalicchio,
  • Giuseppina Bruno,
  • Aldo Rosano,
  • Brigida Anna Maiorano,
  • Sabrina Rossetti,
  • Sarah Scagliarini,
  • Lorena Incorvaia,
  • Luigi Formisano,
  • Ilaria Toma,
  • Guido Giordano,
  • Giovanna Pecoraro,
  • Francesco Grillone,
  • Laura Palumbo,
  • Marco Pisino,
  • Marta Palladino,
  • Concetta Rita Di Pippo,
  • Valeria Bafunno,
  • Nicole Brighi,
  • Chiara Casadei,
  • Cristian Lolli,
  • Maria Concetta Cursano,
  • Vincenzo Emanuele Chiuri,
  • Pasquale Rescigno,
  • Emiliano Tamburini,
  • Francesca Sanguedolce,
  • Fabio Calabrò,
  • Ugo De Giorgi,
  • Matteo Landriscina,
  • Vincenza Conteduca

摘要

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.