Comparable Germline Variant Rates Seen Across Racial Groups in Metastatic Prostate Cancer

Kara N. Maxwell, MD, PhD

Among patients with metastatic prostate cancer in 3 prospectively ascertained, diverse cohorts, the real-world rates of DNA repair pathologic germline variants were found to be lower than previously reported, and did not significantly differ according to racial characteristics, according to Kara N. Maxwell, MD, PhD. Maxwell added that these population-level data not only provide better insight into real-world mutation prevalence among diverse patient groups but affirm the importance of genetic testing in guiding personalized treatment.

​​Maxwell and colleagues analyzed the prevalence of pathogenic germline variants in 3 cohorts of patients with metastatic prostate cancer who underwent genetic testing through a point-of-care model at the Basser Center of Penn Medicine, or a cancer genetics practice at either the VA Philadelphia health care or VA Greater Los Angeles health care.

Prospective data presented at the 2024 AACR Annual Meeting revealed consistent rates of pathogenic germline variants associated with prostate cancer across these cohorts, regardless of racial differences. However, differences in variants of uncertain significance were noted across cohorts, correlating with the racial diversity of each group. Additionally, the incidence of DNA repair pathologic germline variants in this study was 7.2% in the Penn Medicine cohort and 7.4% in the VAMC cohort.

“There’s been a lot of work trying to figure out if there are differences [in gene expression] between different racial groups, but we saw [comparable] mutation rates in this very diverse cohort across these different sites,” said Maxwell, who is an assistant professor of medicine (hematology-oncology) in the Department of Medicine at the University of Pennsylvania’s Perelman School of Medicine.

In an interview with OncLive®, Maxwell elaborated on the importance of understanding real-world germline mutation rates in a broader population of patients with metastatic prostate cancer, highlighted key findings from this prospective study and their implications, and underscored how these data support the use of streamlined point-of-care and nurse-embedded models to optimize genetic testing in clinical practice.

OncLive: What inspired your assessment of real-world clinical genetic testing rates in patients with metastatic prostate cancer?

Maxwell: Genetic testing has increased in recent years. At this point, all men with metastatic prostate cancer are indicated to have genetic testing. To tackle this large increase in the number of men who need genetic testing, many institutions have implemented point-of-care models where the medical oncologist sends patients for testing. We have done that at the University of Pennsylvania. In another model at the Philadelphia Veterans Affairs [VA] Medical Center, we embedded a nurse into our oncology program to facilitate genetic testing. We wanted to combine data from these 2 different clinical settings in addition to another VA site in Los Angeles where they also had an embedded nurse and look at the rates of mutations in men with metastatic prostate cancer across the 3 sites. We looked at an overall cohort of 1,000 individuals with metastatic prostate cancer to get a more population-based [understanding] of genetic testing rates, given that so much of our data is from more highly ascertained, high-risk populations.

With the increasing need for genetic testing in prostate cancer, what is the value of having this large dataset to validate the expected incidence of genetic mutations across racial and ethnic groups?

A lot of our early data came out of different academic institutions, where a lot of individuals are at high risk. [Based on this sampling, it was approximated that 10%] to 20% of men with metastatic prostate cancer may have alterations in DNA repair genes. [However], we weren’t seeing that at a clinical level. We wanted to take a step back and [determine] what the alteration rate actually is, because it is important for pre-test counseling so that individuals understand what they might be at risk for. It also [informs] clinical trial planning as well as therapeutic planning, and how we’re going to incorporate that into our counseling. Lastly, because resources are limited, knowing how many individuals are expected to be germline [mutation] positive [based on] real-world data is helpful.

What key data and observations were reported from this study at the 2024 AACR Annual Meeting?

This [study included] different practice settings, and we had a variety of patient makeups. The University of Pennsylvania cohort had more Caucasian individuals, our Philadelphia VA cohort was approximately 50% African American, and then our greater LA cohort had a higher percentage of Hispanic patients.

Despite those differences in racial diversity, when we look at genes that are known to be related to prostate cancer, the pathogenic variant rate was 7% across all 3 populations. There were differences in the rates of variants of uncertain significance, as we might expect, because of the different racial diversity of the populations. However, from a pathogenic variant rate, they were strikingly similar. That [finding] was informative to us.

How might these findings optimize the use of genetic testing and inform subsequent treatment decision-making in both clinical practice and clinical trials?

In other research, we found that genetic testing rates are still low among individuals with a National Comprehensive Cancer Network indication, namely metastatic prostate, pancreatic, and male breast cancers. [This is in addition to] the cancers that we see in women, as this particular study focused on men. One thing to take from this study is that genetic testing positivity rates are not particularly high in individuals with metastatic prostate cancer, so it makes sense to incorporate these lower-cost, lower-impact genetic testing strategies. For example, using a point-of-care model [such as] the one at the University of Pennsylvania, or a nurse-embedded model [as featured in] the VA system, [could be used] to streamline testing approaches. Future trials need to make sure that patients and providers are comfortable with that strategy. A lot of work is being done within the Basser Center at Penn Medicine to push this forward so that all individuals with metastatic prostate cancer could get tested.

How can the implementation and accessibility of genetic testing be improved, particularly in the community setting?

Awareness is out there; I think we’ve gotten to that point. The VA setting shows that it’s a lot of work for our individual nurses. However, having one person whose job it is to help [patients] navigate [genetic testing] can make a huge impact within an oncology practice, [especially] because cost has come down. [Additionally], the Basser Center has a video for pre-test genetic counseling, and we made one for the VA in collaboration with the Prostate Cancer Foundation. There are a lot of online resources that can help prepare patients for testing. We get prostate-specific maturation antigen scans when a man is diagnosed with localized prostate cancer and we get a bone scan when a man is diagnosed with metastatic prostate cancer, so we should look at genetic testing as one of those things that we get when a patient is diagnosed.

What is your take-home message for colleagues regarding this research?

Increasingly, radiation oncologists and urologists are seeing more patients with metastatic [prostate cancer], particularly in the oligometastatic setting. [Any] providers who are seeing patients with metastatic prostate cancer [need to] bring up genetic testing with their patients. It is more likely than not that your patients are not going to have a genetic alteration, but [we should consider] the impact [this knowledge could have] for potential treatment down the road with PARP inhibitor therapy, and its implications for the patient’s family. Figuring out how you can easily implement testing in your practice is important.

This research was supported by the Basser Center for BRCA at University of Pennsylvania. I am the director of the Men & BRCA Program, and we are excited for research like this to improve genetic testing rates and knowledge for all men with cancer. So much of our research focus in the genetic space has been in female cancers, so we’re thrilled to share our work.

Editor’s Note: Dr Maxwell did not report any disclosures.

Reference

1. Crawford T, Barrett E,Al-Saleem T, et al. Clinical genetic testing results in metastatic prostate cancer patients. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract 3372.