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SDIRSACR Oncology Insights

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The Importance of Homologous Recombination Repair Deficiency (HRD) in Ovarian Cancer

Marijana Milovic Kovacevic , Simonida Bobic , Slobodan Kutic 1,2
1,2
1,2
1 Institute of Oncology and Radiology of Serbia, Belgrade, Serbia
2 University of Belgrade, Faculty of Medicine, Belgrade, Serbia

Keywords: homologous recombination repair deficiency (HRD), genomic instability, HR proficiency

Homologous recombination repair deficiency (HRD) has emerged as a pivotal biomarker and therapeutic target in
the management of ovarian cancer, particularly high-grade serous ovarian carcinoma (HGSOC), which constitutes the
most common and lethal subtype. HRD reflects an impaired ability of tumor cells to accurately repair DNA double-
strand breaks via the homologous recombination (HR) pathway, leading to genomic instability and tumorigenesis.
This deficiency is frequently caused by deleterious mutations in key HR pathway genes, such as BRCA1 and BRCA2,
but can also result from epigenetic silencing or other genetic alterations affecting the broader HR repair machinery.
Understanding the role of HRD in ovarian cancer has significantly advanced the landscape of precision oncology. Tumors
exhibiting HRD demonstrate increased sensitivity to DNA-damaging agents, including platinum-based chemotherapies
and, more recently, PARP (poly ADP-ribose polymerase) inhibitors, which exploit synthetic lethality to selectively target
HR-deficient cancer cells. Consequently, HRD status has become an essential criterion in treatment stratification,
guiding therapeutic decisions and improving clinical outcomes.
The identification of HRD involves both direct genetic testing for BRCA mutations and comprehensive genomic assays
that detect loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST), which
are indicative of a broader "HRD phenotype." Despite its clinical utility, challenges remain in standardizing HRD testing,
interpreting results, and addressing resistance mechanisms that can emerge during PARP inhibitor therapy. This abstract
underscores the critical importance of HRD in ovarian cancer from both a biological and clinical perspective. It highlights
the need for continued research into refining HRD diagnostics, understanding tumor heterogeneity, and developing
novel therapeutic strategies that can extend the benefit of HR-directed therapies to a wider patient population. As our
knowledge deepens, HRD assessment is likely to become increasingly central to the personalized treatment paradigm
in ovarian cancer care.
Homologous recombination repair deficiency (HRD) is a critical molecular vulnerability in ovarian cancer, particularly
in high-grade serous ovarian carcinoma (HGSOC), the most prevalent and aggressive subtype. HRD impairs the ability
of cells to repair DNA double-strand breaks via the high-fidelity homologous recombination (HR) pathway. This leads
to genomic instability, accumulation of mutations, and accelerated tumor evolution. HRD can result from germline or
somatic mutations in BRCA1 and BRCA2, but also from epigenetic silencing or defects in other HR-related genes such
as RAD51C, RAD51D, or PALB2. As such, HRD is not only a hallmark of ovarian cancer biology but also a determinant of
therapeutic response.
The importance of HRD in ovarian cancer lies in its dual role as both a prognostic and predictive biomarker. Patients with
HRD-positive tumors—particularly those with BRCA1/2 mutations—tend to exhibit improved responses to platinum-
based chemotherapy, the mainstay of first-line treatment. More significantly, HRD status predicts profound benefit
from PARP inhibitor therapy, which has revolutionized the treatment paradigm. Agents such as olaparib, niraparib, and
rucaparib exploit synthetic lethality by selectively killing HRD-positive tumor cells while sparing normal tissue, thereby
improving progression-free survival and delaying disease recurrence.

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