When it comes to understanding cancer at a molecular level, we delve into the world of DNA, where single and double-strand breaks (DSBs) breaks can wreak havoc. Among various DNA repair pathways, homologous recombination (HR) stands out as the mechanism that faithfully repairs these breaks. Homologous recombination repair (HRR) is a complex DNA damage repair system that fixes DSBs and interstrand cross-links by using a second copy of the gene as a template to restore the DNA’s genome integrity. Homologous recombination deficiency (HRD) occurs when the body fails to repair DSBs in the DNA. This leads to an overreliance on more error-prone alternate DNA repair systems. For individuals with ovarian cancer and HRD, this deficiency poses a unique challenge to their cancer cells, making repair a difficult task.

PARP Inhibitors: A Game-Changer

Proliferating cells frequently encounter endogenous single-strand breaks caused by environmental exposure and endogenous toxins. The survival of cells is dependent upon the efficient repair of single-strand breaks by complex pathways to ensure genomic integrity and error-free replication. The repair of single-strand breaks in DNA is accomplished through the process of base excision repair, which is facilitated by Poly (ADP-ribose) polymerase (PARP) enzymes. PARP enzymes serve as cellular repair agents, mending damaged DNA by adding ADP-ribose molecules to specific proteins, a process known as poly (ADP-ribosylation) or pADPr. In response to DNA damage, such as nicks or double-strand breaks (DSBs), PARP1 becomes highly active, adding pADPr chains to proteins, including itself, acting like tags that signal which proteins need attention. Other PARP family members, like PARP2 and PARP3, also contribute to DNA repair, with PARP2 aiding PARP1 and PARP3 preventing error-prone DNA repair processes.

PARP inhibitors lead to inhibition of PARP or trapping of PARP on the DNA, thus inhibition of the repair of single-strand breaks. Unrepaired single-strand breaks can be converted into double-strand breaks, which are toxic to the cells. In normal cells that possess the homologous recombination repair mechanism, double strand breaks are effectively repaired by the help of the homologous recombination (HR) pathway, ultimately resulting in the cell’s survival. In cells with a HRD, such as those with mutations in breast cancer (BRCA) 1 and 2 genes, this repair mechanism is absent. Consequently, these cells experience an accumulation of double-strand breaks, which ultimately leads to apoptosis and subsequent cell death.

The introduction of PARP inhibitors has yielded significant advancements in the treatment of ovarian, breast, pancreatic, and prostate cancers. PARP inhibitors are crucially designed to specifically target cancer cells while safeguarding healthy ones, resulting in improved progression-free survival, and enhancing overall quality of life of the cancer patients. PARP inhibitors such as olaparib, niraparib, rucaparib, and talazoparib have been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of ovarian, breast, pancreatic, and/or prostate cancer. These have been approved as maintenance therapy, following completion of first-line platinum-based chemotherapy. Niraparib is found to be more effective than olaparib and rucaparib. Talazoparib is the most effective, trapping PARP1 100 times more efficiently than niraparib.

Exploring HRD Testing and its Status

As many as 50 percent of women with advanced ovarian cancer have HRD-positive cancer cells. Recent advancements in cancer research have highlighted the value of HRD status as a predictive and prognostic biomarker. International guidelines now recommend HRD testing alongside BRCA1/2 testing for individuals newly diagnosed with high-grade epithelial ovarian cancer. This combined testing approach provides vital insights into treatment decisions.

Healthcare providers determine whether a person’s tumor is HRD positive. It may be evaluated using two distinct categories of biomarkers. Ovarian tumors may exhibit specific mutations in breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2), as well as genomic instability. Genomic instability, characterized by significant structural alterations to chromosomes, leads to distinct quantifiable genomic abnormalities and damage within the genome due to HRD. The genomic scars characteristic for HRD encompass:

• Loss of heterozygosity (LOH): Loss of one of the two alleles originally present in a cell

• Large-scale state transitions (LST): Chromosomal breaks between adjacent regions of at least 10 mb

• Telomeric allelic imbalances (TAI): Presence of allelic imbalance located in the telomeric region of a chromosome

By evaluating these three distinct indicators of genomic instability, HRD score is calculated as the sum of LOH, TAI and LST scores.

Thus, the HRD status of the tumors can be given as:

• Positive HRD status (HRD deficiency): if they exhibit a high HRD score of ≥42 or if they test positive for tumor BRCA1/2.

• Negative HRD status (HRD proficiency): if they exhibit a high HRD score of <42 and test negative for tumor BRCA1/2.

Different tests have different ways of quantifying scar score and hence, have slightly different thresholds. The score above that threshold is indicative of potential therapeutic advantages associated with PARP inhibitor treatment, regardless of the individual’s BRCA 1/2 status. Myriad uses a simple sum of HRD components and has a threshold of 42. Strand Life Sciences uses a different scoring function and a threshold of 50.

In the sample set of over 750 patients, Strand Life Sciences has found that 32% of cases show HRD positivity (score> 50) despite the patients having a negative BRCA status.

Significance of HRD testing

The utilization of genomic scar tests in universal HRD testing holds potential for providing valuable insights into personalized maintenance treatment strategies for patients diagnosed with advanced ovarian cancer after a positive response to frontline platinum-based chemotherapy. The HRD tests and HRD indicators may be highly beneficial in predicting treatment response to PARP inhibitors.

References

1. Bruin, M.A.C., Sonke, G.S., Beijnen, J.H. et al. Pharmacokinetics and Pharmacodynamics of PARP Inhibitors in Oncology. Clin Pharmacokinet 61, 1649–1675 (2022). https://doi.org/10.1007/s40262-022-01167-6
2. Cortesi, L., Rugo, H.S. & Jackisch, C. An Overview of PARP Inhibitors for the Treatment of Breast Cancer. Targ Oncol 16, 255–282 (2021). https://doi.org/10.1007/s11523-021-00796-4
3. Miller RE, Elyashiv O, El-Shakankery KH, Ledermann JA. Ovarian Cancer Therapy: Homologous Recombination Deficiency as a Predictive Biomarker of Response to PARP Inhibitors. Onco Targets Ther. 2022 Oct 4;15:1105-1117. https://pubmed.ncbi.nlm.nih.gov/36217436/
4. Feiyue Zheng, Yi Zhang, Shuang Chen, Xiang Weng, Yuefeng Rao, Hongmei Fang, Mechanism and current progress of Poly ADP-ribose polymerase (PARP) inhibitors in the treatment of ovarian cancer, Biomedicine & Pharmacotherapy, Volume 123, 2020, 109661, https://doi.org/10.1016/j.biopha.2019.109661
5. Van Wilpe S, Tolmeijer SH, Koornstra RH, de Vries IJ, Gerritsen WR, Ligtenberg M, Mehra N. Homologous recombination repair deficiency and implications for tumor immunogenicity. Cancers. 2021 May 7;13(9):2249. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124836/