Intergroup-statement: statement of the german ovarian cancer commission, the North-Eastern German Society of gynecological Oncology (NOGGO), AGO Austria and AGO Swiss regarding the use of homologous repair deficiency (HRD) assays in advanced ovarian cancer

Archives of Gynecology and Obstetrics https://doi.org/10.1007/s00404-025-07991-y POSITION STATEMENT Intergroup‑statement: statement of the german ovarian cancer commission, the North‑Eastern German Society of gynecological Oncology (NOGGO), AGO Austria and AGO Swiss regarding the use of homologous repair deficiency (HRD) assays in advanced ovarian cancer Lukas Chinczewski1 · Philipp Harter2 · Lukas Heukamp3 · Doris Mayr4 · Christoph Grimm5 · Viola Heinzelmann‑Schwarz6 · Pauline Wimberger7 · Sven Mahner8 · Ioana Elena Braicu1 · Wolfgang Schmitt9 · Carsten Denkert10 · Jalid Sehouli1 Received: 30 January 2025 / Accepted: 21 February 2025 © The Author(s) 2025 Abstract Introduction Homologous recombination deficiency (HRD) is a key biomarker in the management of high-grade serous ovarian cancer (HGSOC), guiding treatment decisions, particularly regarding the use of poly(ADP-ribose) polymerase inhibitors (PARPi). As multiple HRD assays are available, each with distinct methodologies and cutoff values, the interpretation and clinical application of HRD testing remain complex. This intergroup statement, endorsed by the German Ovarian Cancer Commission, NOGGO, AGO Austria, and AGO Swiss, aims to provide guidance on the indications, appropriate use, and limitations of HRD testing in ovarian cancer. Materials and methods The statement is based on an interdisciplinary review of available literature, clinical trial data, and expert consensus. The recommendations focus on the current landscape of HRD assays, their clinical applicability, and practical considerations regarding the optimal timing and indications for testing. Results and discussion Various HRD assays, including established commercial tests and emerging academic-clinical approaches, are reviewed in this statement. The document outlines key eligibility criteria for HRD testing in ovarian cancer, emphasizing its relevance in specific histological subtypes and clinical scenarios. Additionally, exclusion criteria are defined, highlighting cases where HRD testing may not be appropriate due to insufficient clinical validation or lack of therapeutic implications. Finally, the statement discusses the pathological minimum requirements for tissue samples used in HRD testing, ensuring adequate sample quality and tumor content for reliable results. Conclusion HRD testing is a valuable tool for personalizing ovarian cancer treatment, particularly in identifying patients who may benefit from PARPi therapy. However, assay selection, timing, and result interpretation require careful consideration. This statement provides a structured approach to optimize HRD testing, aiming to improve clinical decision-making and patient outcomes. Keywords Gynecological oncology · Ovarian cancer · Homologous recombination deficiency testing · Maintenance therapy · Intergroup statement Definition of HRD and HRD testing Genomic instability (GIS) is one of the most common causes of tumorigenesis [1]. There are several DNA repair systems that play a significant role in maintaining genomic stability. If there is an imbalance or malfunction in these systems, often due to mutations, the genome exhibits instability. One of these DNA repair systems is the homologous recombination repair (HRR) system. When double strand breaks and interstrand cross-links (ICL) occur during genomic replication, the HRR system respond to these mutations with its proteins for repair. Extended author information available on the last page of the article Vol.:(0123456789) Archives of Gynecology and Obstetrics Defects in HRR pathway due to (epi-) genetic events may result in the phenotype of homologous repair deficiency (HRD), indicating the inability to repair DNA double-strand breaks. If HRD occurs, GIS can be promoted. GIS may manifest as genomic loss of heterozygosity (gLOH), telomeric imbalance (TAI) and large-scale transitions (LST). Especially in the tumorigenesis of high-grade serous ovarian cancer (HGSOC), the HRR system plays a significant role. Germline and somatic mutations within the breast-cancer gene (BRCA) 1 and BRCA 2 are mainly responsible for HRR pathway defects. Approximately 13 to 15% of patients with HGSOC show a germline mutation in BRCA1/2, and up to 3–7% show somatic mutations [2, 3]. However, besides BRCA1 and 2, there are other genes involved that may lead to HRD, such as BRCA1-associated RING domain 1 (BARD1), BRCA-interacting protein 1 (BRIP1), checkpoint kinase 1 (CHEK1), checkpoint kinase 2 (CHEK2), family with sequence similarity 175, member A (FAM175A), nibrin (NBN), partner and localizer of BRCA2 (PALB2), RAD51 paralog C (RAD51C), RAD51 paralog D (RAD51D), and many more. The clinical impact of these malfunctions in the HRR pathway was demonstrated by the introduction of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors (PARPi). The PARPi block base excision repair, which leads to the accumulation of singlestrand breaks during DNA replication. This ultimately results in a collapse of the repair system and the formation of double-strand breaks. In cells with HRD, these breaks cannot be adequately repaired, leading to synthetic letality in the presence of PARPi. The efficacy of PARPi in maintenance therapy for HGSOC has been demonstrated in several studies, including those utilizing different drugs such as Olaparib monotherapy in the SOLO1 study, the combination of Olaparib and bevacizumab in the PAOLA1 study, and Niraparib monotherapy in the PRIMA trial, which led to EMA and FDA approval [4–7]. The BRCA germline mutations were the first to be understood as an indicator for the effective use of PARPi. The PAOLA1 trial showed that not only patients with pathogenic BRCA1/2 mutations but also those with genomic instability measured by the Myriad MyChoice assay benefited from maintenance therapy with Olaparib. Therefore, the importance of other HRD-related genes is emphasized, and their inclusion in regular testing for patients with ovarian cancer (OC) is warranted. This would enable clinicians to make well-grounded clinical decisions regarding the use of PARPi. The aim of this statement is to simplify clinicians’ decision-making regarding indications and correct conduct of HRD testing in patients with OC based on current knowledge. Landscape of tests and its choice There are different tests available for the determining of HRD status. Principally, there are three different categories for the determining HRD: (1) Next-generation sequencing (NGS) assays: These assays analyze genomic DNA to detect mutations in genes associated with HRD, such as BRCA1 and BRCA2, as well as other HRD-related genes. a. Genetic Testing: mutations in the BRCA1 and BRCA2 genes are well-established indicators of HRD, particularly in breast and ovarian cancers. Genetic testing can identify these mutations, and the presence of such mutations suggests HRD. This testing can be performed through various methods, including targeted sequencing, multiplex ligat (...truncated)