Role for Somatic, Inherited Genetic Testing in Prostate Cancer Continues to Grow

Leonard G. Gomella, MD

The recommendations for genetic testing in prostate cancer continue to evolve, with the role for somatic testing and inherited testing becoming more pronounced, according to Leonard G. Gomella, MD, who added that the information yielded from these tests could inform personalized treatment approaches.

“We should not only ask about the family history of prostate cancer. Rather, we should seek out all cases of cancer in the family. We may find other hereditary genes that are associated with the patient’s risk of developing prostate cancer,” Gomella explained. “While we’re starting to do more genetic testing based on buccal swabs and blood tests, [we] need to start thinking about somatic testing, where we evaluate a very large panel of genes based on the primary tumor and the metastasis. Ultimately, this could hold the key to an optimal course of therapy for a patient.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Prostate Cancer, Gomella, chair of the Department of Urology at Sidney Kimmel Cancer Center, director of the Kimmel Cancer Center Network, and co-chair of the 2019 Prostate Cancer Consensus Conference, discussed the growing importance of genetic testing in prostate cancer.

OncLive®: Could you speak to the importance of molecular testing in prostate cancer? What are the different approaches available and how are they being used to personalize care?

Gomella: Molecular testing, in all areas of oncology, has become a very important component of precision medicine where we try to determine an optimal therapy for a patient, at any point in time. In urology, we have been working in 3 specific areas of molecular medicine in this disease: proprietary tumor molecular testing; testing the tumor or metastasis for a broad range of mutated genes; and testing patients, and possibly their families, for inherited genetic mutations.

Notably, we've been doing proprietary tumor molecular testing in urology for at least 5-6 years now. Proprietary companies are out there with their own unique molecular sequences, not mutated genes, but in certain over- or underexpressed genes, that are common in some cancers. For example, there are the Decipher and Polaris assays, which provide important information on patient outcomes. You send a tissue biopsy to a laboratory for one of these assays, and they provide you with information about the likelihood that a patient will develop metastasis or that they are going to die from their disease. This information helps direct different treatment approaches, such as active surveillance.

A new area in urology, but something that medical oncologists have become familiar with over the past few years, is somatic genetic testing. With this testing, you biopsy the tumor or the metastasis, which is sometimes more preferable. You then evaluate a wide panel, which could be [comprised of] 300-350 different genes, and you look for mutations. Traditionally, this [testing] has been used in medical oncology to identify candidates for clinical trials; this has been widely used across several tumor types.

In prostate cancer, one of the biggest advancements has been [the emergence of] immunotherapy, such as pembrolizumab (Keytruda), along with the development of PARP inhibitors. The identification of certain genetic alterations, certain mutated genes, tell us that a patient is eligible for PARP inhibitors. We must remember that drugs such as pembrolizumab are agnostic for tumor type. However, if you do one of these somatic biopsies, and you find high tumor mutational burden or high microsatellite instability, then patients are eligible for those medications.

Lastly, there is inherited genetic testing, which has been a big focus of the Philadelphia consensus meetings. This is where you do a buccal swab or a blood test, and you identify whether there is an inherited mutated gene in that individual; that gene may affect how you screen that patient for other cancers or may lead you to recommend other members of the family to be screened. However, if a patient has one of these mutated DNA repair pathway genes, such as BRCA1/2, and metastatic disease, they are now eligible to be treated with PARP inhibitors, based on that molecular genetic analysis. Patients can be treated with a PARP inhibitor if a somatic alteration is present, if they have metastatic castration-resistant disease, and have failed all therapies.

How do you approach genetic testing in your own practice? What is your process?

We have a unique situation here at the Sidney Kimmel Cancer Center because we actually have been doing a Multidisciplinary Prostate Cancer Clinic since 1996. In 2014, Veda N. Giri, MD, of Thomas Jefferson University Hospital, joined the faculty at Jefferson. For the first time ever, we incorporated a prostate cancer genetic clinic. Now, when patients come in for their first visit, we introduce them to the concept of genetic testing; however, we don't conduct the testing at that point because they are there for their primary treatment. We will usually bring them back for counseling and testing, once the treatment is underway. Most people don't want to hear about genes and inheritance when they're walking in with a new diagnosis of prostate cancer.

Normally, we screen the patients. Although we spend a lot of time talking about inherited genetic alterations that are associated with prostate cancer, there are 2 important concepts to remember. First, these mutated genes do not cause the cancer. If a patient has a BRCA1/2 mutation, or whatever the gene might be, it just increases their risk of developing an aggressive form of prostate cancer. In addition, today, 80% of patients have sporadic prostate cancer, with no identified family history and no identified genetic component. Moreover, 20% to 25% of patients, have some suggestion of a hereditary component. In only about 10% to 15% patients, can we actually put a finger on each person in a particular family that has had cancer; that’s a small number of patients but we can do a lot for subset.

Upon receiving test results, how do you choose among the available approaches?

To date, very few papers have connected mutated genes with active surveillance. One paper, which was published by Johns Hopkins University a couple of years ago, suggested that a patient who had a BRCA1/2 mutation was more likely to fall off the active surveillance pathway. However, we don't have a lot of guidelines on that yet, so, that's one of the areas that needs more work.

This is, however, integrated into screening decisions. In fact, if [a patient has] one of these common hereditary breast and ovarian cancer syndromes, [this is] usually discovered when a sister, mother, aunt, or grandmother went through screening. Breast cancer, as we all know, is about 15 years ahead [of prostate cancer]. It’s actually a double-edged sword because these genetic alterations are much more significant in women who develop breast or ovarian cancer than they are in men who develop prostate cancer. However, if a patient does have a family history of hereditary breast and ovarian cancer, they should consider early prostate cancer screening.

At the other end of the spectrum, when it comes to treatment of localized disease, we're not there yet. I have an inkling that in the next 5 to 6 years, we're going to identify the men at early stages, who need an aggressive treatment, something that no other test could pick up. However, we are not there yet.