Genetic Testing Helps Guide Treatment in Prostate Cancer

Veda Giri, MD

Genetic testing has created an impact in breast, ovarian, and prostate cancers, in terms of screening and therapeutic decisions for patients, explains Veda Giri, MD. The importance of genetics cannot only determine molecular mutations that can be targeted, but also who might be at risk for prostate cancer.

There are several mutations that have been identified and associated with prostate cancer in various studies, such as BRCA1/2, mismatch repair deficient (dMMR) genes, and HOXB13. A discovered mutation could lead to additional treatment options or enrollment on clinical trials that were previously not available for a patient.¹

For example, if a BRCA1/2 or ATM mutation is discovered for a patient with metastatic castration-resistant prostate cancer (mCRPC), they now have the option of PARP inhibition, which has demonstrated increased survival for these patients. In 2016, the FDA granted olaparib (Lynparza) a breakthrough therapy designation for this patient population who previously received taxane-based chemotherapy and either enzalutamide (Xtandi) or abiraterone acetate (Zytiga). The phase II TOPARP-A trial demonstrated that olaparib had a nearly 90% overall response rate in a subgroup of patients who had DNA-repair defects.²

Additional PARP inhibitors are being investigated for these patients following the results demonstrated with olaparib. For instance, rucaparib (Rubraca) is being explored in the ongoing phase III TRITON3 trial versus physician’s choice of abiraterone acetate, enzalutamide, or docetaxel for patients with BRCA1/2 or ATM mutations (NCT02975934). “The development of new agents further increases the importance of genetic testing for patients with prostate cancer,” said Giri.

OncLive: Please provide an overview of your presentation on genetic testing for patients with prostate cancer.

In an interview during the 2018 OncLive^® State of the Science Summit™ on Prostate Cancer, Giri, an associate professor at Thomas Jefferson University Hospital, discussed the developing role of genetic testing for the screening and management of patients with prostate cancer.Giri: It is an exciting time for genetic testing and evaluation for patients with prostate cancer. The role of genetic testing for the management of screening and treatment for men is rising. In my talk, I discussed what the current management recommendations are based on genetic test results—whether it is screening, active surveillance, or emerging clinical trials for patients with metastatic prostate cancer.

It is also important to understand what it means to have genetic testing. In my discussion, I dived deeper into the current guidelines for the genes to test and which individuals might want to consider genetic testing, whether it is to help guide their treatment or to better understand their risk for prostate cancer.

I also discussed the considerations to have in mind before proceeding with genetic testing, the current implications for men and their families, and other thoughts to give to this field when proceeding with genetic testing. When is the best time for a patient to receive genetic testing and how do you know if it is appropriate? There are a few scenarios for men to consider genetic testing for inherited prostate cancer. One scenario is in the setting of a man who has had metastatic disease and has gone through the standard lines of treatment, but their disease is progressing. In that case, precision oncology is where genetics is taking off to help guide targeted therapies. Genetics can help inform additional options for treatment, such as PARP inhibitors, or help put the patient on a clinical trial for agents such as pembrolizumab (Keytruda) to target the dMMR cancers.

There are some increasing FDA indications that are emerging for PARP inhibitors and immune checkpoint inhibitors for patients with different kinds of dMMR tumors. The clinical trials that are studying PARP inhibitors and other agents, such as pembrolizumab, are growing exponentially in the space of mCRPC. That is another patient scenario where we are seeing a rise for the consideration of genetic testing.

What are some of the genes that we are looking for in these patients?

The other group of men who we would want to consider genetic testing are those who have a family history of specific cancers. It is important for men to consider not only a history of prostate cancer in the family, but also breast, ovarian, pancreatic, and colon cancer. These cancers can be linked to inherited risk for prostate cancer based upon the genes that could have an inherited mutation. It is important for men to consider cancers in men and women in their families and on the maternal and paternal sides of the family. Men should keep a broad view of the family history and bring that to the genetic evaluation appointment.The genes that have had the greatest association with risk for prostate cancer are BRCA1/2. BRCA2 has been associated with aggressive prostate cancer. HOXB13 is a hereditary prostate cancer gene that does not have a role in guiding the management for advanced or metastatic disease, but does confer some of the highest risks for prostate cancer. Incorporating that in screening is still being studied.

The dMMR genes, such as MLH1, MSH2, PMS2, and MSH6, are linked with Lynch syndrome, which is a hereditary colon cancer that can be important in terms of considering clinical trials for men with advanced prostate cancer.

Can you speak to the use of PARP inhibitors for patients with BRCA1/2 mutations?

Additional genes in the DNA repair pathways are also important for men with metastatic disease in terms of guiding their treatment. The current NCCN guidelines have expanded beyond BRCA1/2. They also recommend testing for PALB2. It could be an option to do multigene testing for the evaluation of men with prostate cancer risk. A PARP inhibitor could be considered for a man who has his tumor tested for tumor-derived mutations. In this space, if a mutation is found in BRCA1/2, ATM, or other DNA-repair genes, that man could be considered for PARP inhibitors either on or off clinical trial. Usually a man has gone through previous lines of therapy and had progression of disease.

Are there any ongoing genomic-based clinical trials that you would like to share?

How can the prostate cancer community better utilize genetic testing?

However, we are finding that a certain percentage of men with tumor testing could have inherited that mutation. That is where it becomes important to consider germline genetic testing to determine if the mutation is inherited, what that means for treatment, and additional considerations, such as cancer risks for themselves and their families.There are several clinical trials that are incorporating genetic information into the stratification of patients and in terms of the study of agents, such as PARP inhibitors. They are mostly in the mCRPC setting, but we are going to be seeing more trials in the earlier-stage setting because of the information that is coming forth regarding inherited mutations.One way is for oncologists, urologists, or radiation oncologists to start thinking about the field of genetic counseling and genetic testing. Classically, it was not thought of nor was it on the forefront in terms of data that might be used for the management of prostate cancer, but that is increasingly changing. Having providers start thinking about identifying men who might be candidates for genetic evaluation, where to refer those patients, or how to engage those patients in genetic counseling is a step forward. Whether that is to refer a patient to a cancer genetic center or to a genetic counselor in the community, it is important to have the discussion of what it means to have genetic testing for their families.

Is there anything else you would like to add?

The providers themselves want to deliver this information and give the genetic education to patients to streamline the flow of receiving the genetic information. Providers then need to have proper training and experience in providing the genetic information to patients. Patients can then make informed decisions about genetic testing. Something that we discuss in the genetics community are the federal laws around genetic discrimination. This is particularly important for individuals who are otherwise healthy and do not have a cancer diagnosis but could also be important for individuals who also have a cancer diagnosis.

There is a federal law called GINA [Genetic Information Nondiscrimination Act] that provides protection from health insurance discrimination if a person is found to carry a genetic mutation for most health insurance plans. It also provides protection for employment discrimination for most employments; however, small businesses do not fall under the federal law. The federal law does not cover life insurance, long-term care, disability insurance, or several of the federal health insurance plans. It is important for a person to know this upfront before going forward with genetic testing, so they can look at their individual situation and determine if their financial plans are in place prior to receiving genetic testing. This is another facet to understand before launching forward with genetic testing.

References

1. National Cancer Institute. Genetics of Prostate Cancer. cancer.gov/types/prostate/hp/prostate-genetics-pdq. Updated March 16, 2018. Accessed March 26, 2018.
2. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Eng J Med. 2015;373:1697-1708. doi: 10.1056/NEJMoa1506859.