HRD Testing and Biomarker-Driven Maintenance Transform Advanced Ovarian Cancer Care

Molecular profiling and homologous recombination deficiency testing are reshaping maintenance therapy strategies for advanced ovarian cancer, with HRD and BRCA status guiding PARP inhibitor and bevacizumab treatment decisions in newly diagnosed patients. As of early 2026, the clinical landscape is defined by a shift toward targeted interventions designed to delay recurrence and improve long-term survival in high-risk populations.

Ovarian cancer remains a significant global cause of cancer morbidity and mortality, with approximately 324,398 new cases and 206,839 deaths in 2022, accounting for about 2.1% of all cancer deaths in women. Epithelial ovarian cancer comprises approximately 85% to 90% of cases, and approximately 75% present at International Federation of Gynecology and Obstetrics stage III or IV due to delayed detection and lack of screening. Overall 5-year survival is approximately 47% but decreases to 29% in stage IV disease.

High-grade serous ovarian carcinoma comprises approximately 75% of EOC and typically presents at advanced stage due to minimal early symptoms and absence of validated screening. Approximately 50% of HGSOC tumors harbor homologous recombination deficiency driven by germline or somatic BRCA1/2 mutations and other homologous recombination repair pathway alterations such as ATM, ATR, and RAD51C/D, with epigenetic events, such as BRCA1 promoter methylation contributing to genomic instability. The Cancer Genome Atlas estimates germline BRCA1/2 mutations in approximately 11% to 15% of women with HGSOC and somatic mutations in another 7%.

Hereditary predisposition accounts for approximately 25% of ovarian cancer cases, primarily due to germline BRCA1/2 variants. Approximately 95% of HGSOC tumors harbor clonal somatic TP53 mutations, serving as a molecular hallmark and internal quality control marker for molecular assays. Combined tumor-based BRCA1/2 and TP53 testing can verify tumor cellularity and assist interpretation of somatic BRCA variants in low tumor-content samples. HRD status functions as a prognostic and predictive biomarker relevant to poly (adenosine diphosphate-ribose) polymerase inhibitor eligibility and underscores the need for accurate diagnostic assessment.

Gynecologic oncologists emphasize that these biomarker-driven approaches are critical. By tailoring maintenance to a patient's specific molecular signatures, clinicians can bridge the gap between initial response and long-term remission in some of the most challenging gynecologic diagnoses.

Tumor-based BRCA testing has become a practical first-line approach in newly diagnosed HGSOC. In a single-center study, tumor BRCA1/2 testing showed high concordance with germline testing, detecting all known germline mutations and identifying additional somatic variants. Tumor-first workflows can shorten reporting intervals, with median turnaround times of approximately 37 days observed in practice.

Because approximately 95% of HGSOCs harbor TP53 mutations, combined tumor BRCA1/2 and TP53 testing provides internal quality control. TP53 status can confirm tumor DNA adequacy in samples with low tumor cellularity.

Timely diagnosis of HRD-positive advanced ovarian cancer is hindered by nonspecific symptoms, lack of screening, and patient- and system-level barriers, leading to late-stage presentation, especially in low- and middle-income contexts. After tissue acquisition, pre-analytic and analytic variables including fixation quality, DNA degradation, and insufficient tumor cellularity can compromise HRD testing, with post-neoadjuvant specimens frequently inconclusive. Technical variability across HRD platforms further complicates interpretation due to differences in algorithms and cutoffs relative to the reference MyChoice CDx.

Assay failure rates of up to 25% of tumors due to limited tissue, poor DNA quality, or technical errors delay biomarker-informed decision making, whereas genomic scar-based assays may yield false positives or negatives depending on HRR reversion or uncaptured HRD biology. Cost and reimbursement barriers restrict access to reference assays, contributing to global disparities and highlighting the need for locally validated platforms and sustainable funding mechanisms.

HRD testing in advanced ovarian cancer encompasses assessment of either the causes of HRD or its genomic consequences. Causes include germline or somatic pathogenic variants in BRCA1/2 and other HRR genes such as ATM, PALB2, RAD51 family genes, and CHEK2, as well as BRCA1 promoter methylation. Consequences are reflected in genomic scars, including loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions, which collectively inform composite HRD scores.

Ongoing research focuses on integrating HRR gene panels with genomic scar assays, optimizing testing sequence, and refining HRD cutoffs.