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<p>PARP inhibitors (PARPi) are effective in tumors with homologous recombination repair (HRR) deficiency (HRD), typically identified by germline/tumor mutations. However, genetic testing may miss intrinsic PARPi sensitivity and resistance. We evaluated strategies to improve detection and longitudinal monitoring of HRD across &gt;500 tumor samples and &gt;20 paired liquid biopsies, integrating genetic, genomic, and functional readouts. HRD was more frequent in high-grade ovarian cancer (HGOC; 52%) than in metastatic breast (mBC; 12%) or prostate cancer (mPC; 20%). Assay concordance was low-to-moderate, underscoring complementarity. RAD51 testing and the genomic instability score identified HRD in tumors lacking pathogenic HRR mutations (6% and 30% in mBC, 38% and 46% in HGOC, 14% and 27% in mPC, respectively). Longitudinal ctDNA sequencing revealed <i>BRCA1/BRCA2</i> reversion mutations in &gt;30% of post-PARPi mBC samples, which were associated with poor response to subsequent platinum therapy. These findings support the use of complementary HRD biomarkers in tissue and liquid biopsy to guide PARPi use and monitor response.</p>

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Comprehensive clinical cancer analysis of homologous recombination deficiency biomarkers in an academic molecular profiling program

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月11日

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  • Heura Domènech,
  • Sara Simonetti,
  • Paula Romero-Lozano,
  • Stephen J. Pettitt,
  • Paula Proszek,
  • Cristina Viaplana,
  • Michaela Smalley,
  • Lorena Magraner-Pardo,
  • Eduardo García-Galea,
  • Carmen Garcia-Duran,
  • Adela Rodríguez-Hernández,
  • Joanna Domènech-Vivó,
  • Marcel Romey,
  • Sara Arce-Gallego,
  • Anna Suñol,
  • Flaminia Pedretti,
  • Andrea Herencia-Ropero,
  • Paolo Nuciforo,
  • Mafalda Oliveira,
  • Cristina Saura,
  • Isabel Pimentel,
  • Carsten Denkert,
  • Christopher J. Lord,
  • Andrew N. J. Tutt,
  • Aleix Prat,
  • Rodrigo Dientsmann,
  • Susana Aguilar,
  • Sara Gutiérrez-Enríquez,
  • Joaquin Mateo,
  • Ana Oaknin,
  • Judith Balmaña,
  • Alba Llop-Guevara,
  • Ana Vivancos,
  • Violeta Serra

摘要

PARP inhibitors (PARPi) are effective in tumors with homologous recombination repair (HRR) deficiency (HRD), typically identified by germline/tumor mutations. However, genetic testing may miss intrinsic PARPi sensitivity and resistance. We evaluated strategies to improve detection and longitudinal monitoring of HRD across >500 tumor samples and >20 paired liquid biopsies, integrating genetic, genomic, and functional readouts. HRD was more frequent in high-grade ovarian cancer (HGOC; 52%) than in metastatic breast (mBC; 12%) or prostate cancer (mPC; 20%). Assay concordance was low-to-moderate, underscoring complementarity. RAD51 testing and the genomic instability score identified HRD in tumors lacking pathogenic HRR mutations (6% and 30% in mBC, 38% and 46% in HGOC, 14% and 27% in mPC, respectively). Longitudinal ctDNA sequencing revealed BRCA1/BRCA2 reversion mutations in >30% of post-PARPi mBC samples, which were associated with poor response to subsequent platinum therapy. These findings support the use of complementary HRD biomarkers in tissue and liquid biopsy to guide PARPi use and monitor response.