Recently the analysis of deficiencies in the homologous recombination repair (HRR) machinery has gained greater importance in precision medicine as it enables the identification of patients’ eligibility for PARP inhibitors. Cancers such as ovarian, pancreatic, breast, and prostate are currently at the forefront of development but other cancer types are likely to follow.

What is HRR?

Homologous recombination and DNA repair (HRR) are essential for genome maintenance. Homologous recombination DNA repair is a process by which double-stranded DNA breaks and inter strand crosslinks use sister chromatids as a template for repair, thereby removing DNA damage in an error-free fashion. The deficiency in the HRR pathway leads to Homologous recombination deficiency (HRD) that is associated with several tumor types like breast, ovarian, prostate, and pancreatic cancers.

PARP inhibitors

Poly (ADP-ribose) polymerases (PARPs) are members of related enzymes that catalyze the transfer of ADP-ribose to target proteins. PARP1 and PARP2 play an important role in maintaining genomic stability by mediating DNA repair processes. Among the PARP families, PARP1 shows abundant expression compared to the others and is responsible for most of the cellular PAR formation.

Research studies have proven that pathogenic germline variants and clinically significant somatic mutations of HRR genes turn cancer cells susceptible to PARP inhibitors (PARPi) and other evolving targeted therapies, paving the way for precision medicine. Testing for genetic variation in HRR genes has thus acquired greater importance in risk stratification and treatment decision-making.

PARP inhibitors are a type of targeted therapy cancer drugs, that interferes with PARP enzymes (PARP1/PARP2) in the cells, where it interacts with the NAD+ binding site and initiating enzymatic inactivation of PARPs and trapping of PARPs at damaged DNA thereby leading to tumor cell death. These targeted therapies are specific to tumor cells and therefore create less damage to normal cells compared to conventional chemotherapy.

There are four main US FDA-Approved PARP inhibitors available. They are;

Olaparib (Lynparza) – Olaparib was approved by European Medicines Agency (EMA) in the European Union and by the USA Food and Drug Administration (FDA) in 2014 for the treatment of patients with deleterious or suspected deleterious germline BRCA (gBRCA)-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

In 2017, olaparib was approved for maintaining the treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who had a complete or partial response to platinum-based chemotherapy.

In 2018, olaparib was approved by the FDA for gBRCA mutated Her2- negative metastatic breast cancer. Among the PARP inhibitors, olaparib was the first to be approved for breast cancer treatment.

Niraparib (Zejula) – In 2020, Niraparib is approved by the FDA for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy.

Rucaparib (Rubraca)- In 2018, Rucaparib is approved by the US FDA for the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.

In 2020, the US FDA granted accelerated approval to rucaparib for patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and taxane-based chemotherapy.

Talazoparib (Talzenna)- Talazoparib is the fourth PARP inhibitor approved by the FDA. It is approved by FDA in 2018 and is the second approved treatment for women with HER2-negative advanced breast cancer and germline BRCA mutations.

What is a Comprehensive HRR panel?

Germline, somatic mutations, and gene promoter methylation of the BRCA gene are well-known causes of HRD, but other genetic abnormalities of the HRR pathway can also lead to HRD. A comprehensive HRR panel is a multi-gene biomarker testing panel that detects the germline and somatic mutations associated with 15 different genes including BRCA1/2, that are associated with HRD. A comprehensive HRR gene panel also provides insights into whether a patient will be benefited from PARPi therapy.

How is the Comprehensive HRR panel useful for cancer patients and clinicians with respect to PARP inhibitors?

Around 450 proteins are assumed to be involved in DDR pathways, including PARP1 and PARP2. PARP enzymes are integral to the base excision repair pathway, where it repairs the single-strand breaks in DNA. The unrepaired single-strand breaks result in the formation of double-strand breaks, which are repaired through the HRR pathway as mentioned earlier.

Synthetic lethality is a mechanism through which the PARP inhibitors target the tumor cells. Here the PARP inhibitors bind to PARP, inhibiting PARylation (a process by which, ADP-ribose moieties from NAD+ are transferred to target proteins) and also trapping inactivated PARP on DNA resulting in the generation of double-strand breaks. The preferential targeting of tumor cells thereby spares the healthy cell, thus providing the patients with benefits that are not achievable through conventional chemotherapy. Therefore the comprehensive HRR panel enables the clinicians to identify whether the patient is eligible for PARP inhibitor therapy and increases the patient’s chance to fight cancer with FDA-approved PARP inhibitor therapies.

Comprehensive HRR panel in the detection of Ovarian, Pancreatic, and Prostate cancer?

HRD is higher in ovarian and breast cancers than in other cancer types such as Ovarian cancer, pancreatic cancer, and prostate cancer. HRD is not limited to BRCA1 and 2 and comprises many DNA repair genes. The fundamental vulnerability of HRD has led to the design of a wide range of HRD-directed therapies. DNA repair targeted therapies exploit DNA repair defects because HR-deficient tumors are intrinsically sensitive to PARP inhibitors. Since the comprehensive HRR panel covers BRCA1 and BRCA2 HRR genes along with 12 other genes, it is indeed the best choice for detecting Ovarian, Pancreatic, and Prostate cancer.

Comprehensive HRR Panel vs BRCA 1/2 testing

	Specificity	Sensitivity	Genes covered	FDA approved – PARPi therapies	Cancers detected
Comprehensive HRR Panel	>99%	>99%	ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK1, CHEK1, CHEK2, FANCL, PALB2, PP2R2A, RAD51B, RAD51C, RAD51D,RAD54L	Olaparib, Rucaparib, Niraparib, Talazoparib	Ovarian Cancer, Prostate Cancer, Colorectal cancer, pancreatic Cancer, Breast cancer
BRCA 1/2 Testing	>99%	>99%	BRCA1 & BRCA2	Olaparib, Rucaparib, Niraparib, Talazoparib	Breast cancer, Prostate cancer

Comprehensive HRR panel in the detection of Ovarian, Pancreatic, and Prostate cancer?

HRD is higher in ovarian and breast cancers than in other cancer types such as Ovarian cancer, pancreatic cancer, and prostate cancer. HRD is not limited to BRCA1 and 2 and comprises many DNA repair genes. The fundamental vulnerability of HRD has led to the design of a wide range of HRD-directed therapies. DNA repair targeted therapies exploit DNA repair defects because HR-deficient tumors are intrinsically sensitive to PARP inhibitors. Since the comprehensive HRR panel covers BRCA1 and BRCA2 HRR genes along with 12 other genes, it is indeed the best choice for detecting Ovarian, Pancreatic, and Prostate cancer.

Can a Comprehensive HRR panel be cost-effective?

4baseCare is a leading precision oncology company with a strong focus on personalized cancer treatment using NGS (Next Generation Sequencing). They provide comprehensive HRR panels that provide every patient the maximum access to identify chances for FDA-approved PARP inhibitor therapy for various HRR deficient cancers at the most affordable price.

How can the utilization of the Comprehensive HRR panel impact treatment outcomes?

Timely utilization of a Comprehensive HRR panel can inform patient management and enable patient care by potentially minimizing exposure to unnecessary therapies and intensifying PARP inhibitor treatment strategies for tumors. Genetic biomarkers, on the other hand, define subsets of patients who are more likely to benefit from PARP inhibitor therapies that may not be efficacious in other patients.

References

1. Scott, R. J., Mehta, A., Macedo, G. S., Borisov, P. S., Kanesvaran, R., & El Metnawy, W. (2021). Genetic testing for homologous recombination repair (HRR) in metastatic castration-resistant prostate cancer (mCRPC): challenges and solutions. Oncotarget, 12(16), 1600.
2. Takaya, H., Nakai, H., Takamatsu, S., Mandai, M., & Matsumura, N. (2020). Homologous recombination deficiency status-based classification of high-grade serous ovarian carcinoma. Scientific reports, 10(1), 1-8.
3. Cresta Morgado, P., & Mateo, J. (2022). Clinical implications of homologous recombination repair mutations in prostate cancer. The Prostate, 82, S45-S59.
4. Cortesi, L., Rugo, H. S., & Jackisch, C. (2021). An overview of PARP inhibitors for the treatment of breast cancer. Targeted oncology, 16(3), 255-282.
5. Mekonnen, N., Yang, H., & Shin, Y. K. (2022). Homologous Recombination Deficiency in Ovarian, Breast, Colorectal, Pancreatic, Non-Small Cell Lung and Prostate Cancers, and the Mechanisms of Resistance to PARP Inhibitors. Frontiers in oncology, 2747.
6. Kim, D., & Nam, H. J. (2022). PARP inhibitors: clinical limitations and recent attempts to overcome them. International Journal of Molecular Sciences, 23(15), 8412.