How Can Genetic Testing and Tumor Biomarker Testing Inform Your Treatment When Newly Diagnosed with Ovarian Cancer?

Understanding the relationship between BRCA1/2, HRD, and PARP inhibitor drugs during first-line maintenance treatment.

 

Genetic testing and tumor biomarker testing are recommended for people newly diagnosed with ovarian, fallopian tube, or primary peritoneal cancer because they may help predict the degree of benefit a person may experience from PARP (Poly ADP-ribose polymerase) inhibitor maintenance therapy.

What is Maintenance Therapy?

After you finish chemotherapy for the first time, your doctor will most likely discuss the option to continue with maintenance therapy. Maintenance therapy may benefit people by keeping their cancer from coming back or growing after they have finished chemotherapy.

The PARP inhibitors olaparib (Lynparza) and niraparib (Zejula) are approved as maintenance therapy for all people with stage III or IV epithelial ovarian cancer following benefit from first-line chemotherapy treatment. First-line chemotherapy refers to the first time chemotherapy is used to treat a disease. 

BRCA1/2 Mutations and HRD

When a tumor’s ability to repair its DNA by a process called homologous recombination repair is broken, it is referred to as the tumor being homologous recombination deficient (HRD). BRCA1/2 mutations that have been either inherited (through the germline) or found only in the tumor (somatic) are known to cause HRD. Homologous recombination (HR) status can be detected with a test that determines the degree of genomic instability in a tumor - this may be referred to as HRD testing. A tumor is HRD positive when:

• a person has an inherited BRCA1/2 mutation
• a person’s tumor has a BRCA1/2 mutation
• a tumor is HRD despite non-mutated BRCA1/2 genes

Sometimes a tumor is “BRCA-like” even when the BRCA genes are not mutated. In those cases, we don't understand the mechanism of the defect in detail, but we know that the HRD test is positive. It is estimated that around half of all people diagnosed with ovarian cancer will have tumors that are HRD.

The Relationship Between PARP Inhibitor Drugs and HRD

Results from clinical trials studying PARP inhibitor maintenance treatment in ovarian cancer have shown that people with BRCA1/2 gene mutations in their blood (germline/hereditary) or tumor (somatic) receive the most benefit from PARP inhibitor maintenance therapy. Therefore, it is very important to determine if a BRCA1/2 mutation is present. If genetic testing is negative, tumor biomarker testing can be done to determine if a BRCA1/2 change is in the tumor or if the tumor is HRD. This is because clinical studies have also shown that people without BRCA1/2 mutations whose tumors are HRD may receive substantial benefit from PARP inhibitor maintenance therapy. People whose tumors are HRP (homologous recombination proficient - have a negative HRD test) are expected to receive a more modest benefit and should discuss the pros and cons of taking a PARP inhibitor with their doctor.

The Importance of Genetic Testing and Tumor Biomarker Testing

Doctors learn whether or not you have an inherited BRCA1/2 mutation by ordering genetic testing. If your results indicate that you have inherited a BRCA1/2 mutation, your tumor will be HRD. It is important to receive genetic testing even if you do not have a family history of cancer. 

Doctors learn the HR status of your tumor by ordering a biomarker test of your tumor.  A sample of your tumor, which is usually taken at the time of surgery or during a biopsy, is sent to a laboratory. The results of the tumor biomarker test will tell the doctor if your tumor is HRD (a positive HRD test) or is homologous recombination proficient (HRP) (a negative HRD test). 

Talk with your doctor about the results of your genetic and tumor biomarker testing to discuss the pros and cons of incorporating a PARP inhibitor as maintenance therapy.

 

 

 

 

 

 

 

Check Out These Additional Resources: 

Video: What is a PARP Inhibitor? Dana Farber Cancer Institute (3 minutes)

Video: AZ Precision Medicine – Homologous Recombination Deficiency and Cancer Care (5 minutes) 

MedlinePlus - Help Me Understand Genetics

 

 

 

Sources:

How, J. A., Jazaeri, A. A., Fellman, B., Daniels, M. S., Penn, S., Solimeno, C., Yuan, Y., Schmeler, K., Lanchbury, J. S., Timms, K., Lu, K. H., & Yates, M. S. (2021). Modification of homologous recombination deficiency score threshold and association with long-term survival in epithelial ovarian cancer. Cancers (Basel), 13(5), 946. doi: 10.3390/cancers13050946

Hockings, H., & Miller, R. E. (2023). The role of PARP inhibitor combination therapy in ovarian cancer. Therapeutic Advances in Medical Oncology, 15. doi: 10.1177/17588359231173183

Stewart, M. D., Merino Vega, D., Arend, R. C., Baden, J. F., Barbash, O., Beaubier, N., Collins, G., French, T., Ghahramani, N., Hinson, P., Jelinic, P., Marton, M. J., McGregor, K., Parsons, J., Ramamurthy, L., Sausen, M., Sokol, E. S., Stenzinger, A., Stires, H….Allen, J. (2022). Homologous recombination deficiency: Concepts, definitions, and assays. Oncologist, 27(3), 167-174. doi: 10.1093/oncolo/oyab053

 

 

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