Homologous recombination deficiency (HRD) is the loss of one of the DNA repair systems on which our cells rely. Its study, together with testing for mutations in the BRCA gene, is recommended by the main guidelines to prescribe therapies targeting these molecular alterations, which constitutes a milestone in the treatment of ovarian cancer.
Madrid, August 20th, 2024
Cancer therapy has experienced a considerable progression in recent years, enabling both the introduction of targeted therapies and significant advances in traditional chemotherapy.
Targeted therapies are based on a selective approach to the molecular alterations that cause cancer, therefore minimizing adverse effects on healthy cells. These therapies, for instance, may target DNA repair mechanisms or hormonal regulation. In the case of urogenital cancers, particularly ovarian and prostate cancers, DNA damage response inhibitors, such as poly-ADP ribose polymerase (PARP) inhibitors, constitute promising therapeutic pathways.
Specifically in the case of ovarian cancer, PARP inhibitors such as olaparib and niraparib have demonstrated their efficacy in the presence of BRCA mutations or homologous recombination deficiency (HRD), leading to their approval for specific indications. Likewise, prostate cancer patients with mutations affecting DNA damage response have been shown to be responsive to these agents, ushering in a new milestone in the treatment of this disease.
These PARP inhibitors selectively act on cells whose DNA repair system is damaged. One of the particularities of human DNA lies in the fact that it is continuously damaged and repaired during replication. To repair these errors, one of the mechanisms on which our cells rely is homologous recombination. When cells are incapable of repairing DNA breaks, this situation is known as homologous recombination deficiency (HRD). This characteristic has been used to develop drugs that specifically attack tumor cells that show this alteration, such as PARP inhibitors.
PARP inhibitors selectively act on cells whose DNA repair system is damaged, such as HRD-positive cancer cells.
HRD can be due to defects in several genes and is a common occurrence, with approximately half of high-grade serous ovarian cancer patients showing HRD, which implies a high degree of genomic instability. In these cases, PARP inhibitors have revolutionized this area, providing major benefits for ovarian cancer patients with BRCA mutations and/or HRD. This therapy acts by blocking the PARP function in cancer cells, which renders them incapable of repairing certain types of damage to DNA. This means that in an HRD-positive tumor, in which cancer cells already have difficulties for self-repair, PARP inhibitors further impede this mechanism, leading to the death of these cells, which is known as synthetic lethality. Thus, expansion of these cancer cells can be stopped.
Moreover, several clinical trials have shown that BRCA mutation status and HRD affect the response to first-line chemotherapy and to maintenance therapy with PARP inhibitors, therefore affecting progression-free survival and overall survival.
To date, the main clinical guidelines both in Europe and in America (ESMO, NCCN) recommend testing genes BRCA1/2 in all patients diagnosed with high-grade ovarian cancer to detect somatic and germline mutations, as well as testing for HRD, in order to identify those patients who would benefit the most from PARP inhibitor therapy. Consequently, there is an urgent need to develop increasingly reliable HRD tests, overcoming their current limitations, since they play a critical role in the diagnostic and therapeutic process, in addition to their prognostic and predictive value for patients.
Approximately half of high-grade serous ovarian cancer patients show HRD.
In the USA, only FDA-marked diagnostic tests (CDx) are recommended for HRD molecular diagnosis. However, in Europe, each laboratory is allowed to select its preferred test. Selection criteria for these tests may take into account the existence of a clinical validation supporting their HRD algorithm, as well as their easy integration into the laboratory’s diagnostic routine.
Specifically in Spain, the “Common Catalog of Genetic and Genomic Tests” was published in January this year; this document incorporates the obligation to perform different genetic diagnostic tests, including HRD testing for ovarian cancer patients. Thus, not only is there clinical evidence, but its integration in clinical management has also been proposed. The challenge lies in providing hospitals with an easy way to integrate HRD testing into their diagnostic routine so that patients can really benefit from it. This is our current goal.
This article has been written by Inés Calabria and Marcia Ajenjo and was originally published in the Farmabiotec magazine on June 28, 2024.
