Retrospective analysis highlights differences in germline testing in prostate cancer

Carrie Horton, MS, CGC, discusses how the findings of a retrospective analysis of germline testing rates in racially diverse groups of men with prostate cancer will guide future research and influence the steps community oncologists can take to increase testing rates.

Increasing differences in genetically informed cancer care led researchers to conduct a study of germline testing (GT) in racially diverse groups of men with prostate cancer, highlighting the importance of GT in prostate cancer treatment.

A retrospective analysis of patients used the 14-gene prostate cancer panel to evaluate 427 men: African American (n = 237; 56%) and Caucasian (n = 190; 44%). The overall percentage of pathogenic/probably pathogenic (P/LP) variants was 8.2%.

Lower percentages of P/PL variants were reported in African American males (5.91%) versus Caucasian males (11.05%; p = .05). Furthermore, the percentages of variants of uncertain significance (VUS) were 25.32% versus 16.32%, respectively. (P = .02). Multiple VUSs were reported in 5.1% and 0.53% individuals, respectively (p =.008).1

“The idea is not to shy away from the differences. I think there has been a stigma in the past, but we can’t solve the problem by not looking at it,” said Carrie Horton, MS, CGC. “It was exciting to see Ambry [Genetics] are behind a lot of research into health inequalities and I hope it can motivate other groups to do the same.”

In an interview with OncologyLive®Horton, a senior clinical research specialist who designs and conducts studies at Ambry Genetics, discussed how the findings of the retrospective analysis of genetic testing in prostate cancer care will guide future research and influence the steps community oncologists can take to increase the testing rate. increase.

What was the impetus for this investigation?

This particular study came about when the lead researcher approached Veda Giri, MD, a medical oncologist at Thomas Jefferson University Hospital. [Ambry Genetics]. She’d seen an article we’d done before that looked at the results of genetic testing in individuals with prostate cancer, but it hadn’t been selected for any particular race or ethnicity. Since African Americans are more likely to develop and die from prostate cancer, there is a real opportunity for targeted therapies in that group. Therefore, the need for accurate genetic testing is even more important.

[Giri] came to us and wanted to see if we could use our existing dataset and design a protocol with the intention of evaluating the differences between African American men with prostate cancer and white men. By doing that, we enriched our cohort for African Americans so that our sample was roughly equal. In most previous studies of genetic testing in prostate cancer, identifying these differences has been a byproduct and not the entire focus of the research; there were many inconsistencies [such as] the genes tested, not all [individual] had prostate cancer, or only 10% of the population was African American and 90% were of other ethnicities. This study was specifically designed to evaluate the differences we see in genetic test results in African Americans compared to white males.

We were delighted to be able to help Giri with this as we have such a huge dataset which is one of the benefits of working with Ambry [Genetics]; we can use that volume to find meaningful results.

What methods were used during the research?

We had our existing dataset results of genetic testing in white men with prostate cancer from 2016 to 2017 and [all individuals] had the same multigene panel test – a 14 gene panel targeting hereditary prostate cancer. We had the population needed for white individuals, but wanted to make sure we enrich for African Americans as well, so we extended our timeline and recruiting for African Americans to 2020.

We also looked at the personal history and reviewed the clinic notes provided, [such as] pathology [reports] to see if there were any differences in when? [individuals] were sent for testing. [For example,] we wanted to see if African Americans were only sent if they were at extremely high risk, but we didn’t find a huge difference in who was sent for testing in terms of the severity of the presentation. However, we saw a big difference in the positive and VUS rates, with white individuals almost twice as likely to have a positive outcome compared to African Americans. The VUS rate was half in white individuals compared to African Americans.

Was there anything particularly surprising in the findings?

There is precedent that we see a higher VUS rate in underrepresented populations across most genetic testing indications. However, one thing was quite new: [in this study] was that we found about half of the positive findings in genes that are exclusive to white individuals. We need to improve our interpretation of the existing variants, and the fact that half of the genes were exclusive to white individuals indicates to me that there may be room to improve our gene discovery.

We may not have found all the risk genes for prostate cancer predisposition in African Americans; there are 2 genes where the positive rate is driven by a single mutation in white individuals. So maybe there’s a gene that has a mutation in an underrepresented group, and we just haven’t been able to find it because that’s not who has historically been presented for testing.

What effect could this data have on testing in the future? What action steps would you like to pass on to your colleagues to address these differences?

There is now a shift towards identifying inequalities and when we want to spotlight the inequalities it allows us to find out what is really going on and provides an opportunity to improve those inequalities and reduce. I hope this helps motivate [individuals] to rethink the idea of ​​gene discovery in different populations and to devise new ways for different interpretations that are agnostic to race and ethnicity, that do not rely on volume to accurately interpret variants. The more accurate we can get a test, especially in the hereditary prostate cancer space, the more opportunities there are for targeted drugs for PARP inhibitors like olaparib [Lynparza].

It’s a multi level [issue]. At the grassroots level, we should]try to come up with better ways to engage underrepresented communities in genetic testing. We’ve seen studies that showed underrepresented groups prefer genetic testing and adopt genetic testing at lower rates. [Solutions may include] look more at genetic testing recruitment through non-traditional settings, such as health fairs or community gatherings. We must first [individuals] at the door to even get their result.

A more diverse population improves the accuracy with which we can interpret the results, both in reference population databases, but also in the clinical and research cohorts. For labs, I would encourage them to look at health disparities and what to do to get around existing gaps in the evidence. For example, there are newer ways to derive functional evidence that do not rely on the accumulation of observing a variant multiple times.


Giri VN, Hartman R, Pritzlaff M, Horton C, Keith SW. Germline variant spectrum in African American men undergoing prostate cancer germline testing: need for equity in genetic testing. JCO JCO Precis Oncol. 2022;6(1):e2200234. doi:10.1200/PO.22.00234

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