PHS290: a novel scoring algorithm provides a promising approach to screening for prostate cancer in diverse populations

A novel polygenic hazard score (PHS), PHS290, accurately predicts lifetime risks of developing metastatic or terminal prostate cancer across multiple ancestries, providing the potential to improve outcomes via more precise treatment decision making for patients with prostate cancer. ¹

Prostate cancer is the second leading cause of cancer death in men in the United States. ² However, the field of screening and early methods of detection remains contended due to the overdiagnosis and thus unnecessary treatment of low-risk patients. ³ The current method for prostate cancer screening frequently involves a prostate-specific antigen (PSA) test, although this method has been demonstrated to be unreliable due to rates of false-positives and overdiagnoses. ⁴ The development of a reliable PHS could provide an equitable measurement of the risk of developing prostate cancer to thereby aid in treatment decision making. Previous genetic studies of prostate cancer have predominantly focused on men of European ancestry, including in the production of a PHS. ⁵ Indeed, it has been well established that vast quantities of genomic data focusing on European ancestry have contributed to healthcare disparities and generates a PHS that predicts individual risk considerably more accurately in Europeans compared to non-Europeans. ⁵ Disparities across ancestral populations in prostate cancer incidence and mortality rates have previously been well documented. Age, race, positive family history and germline variation are all established risk factors for prostate cancer. Thus, the population disparities observed in prostate cancer incidence rates may, at least in part, be due to genetic makeup, further emphasizing a rationale for the generation of a screening process utilizing genomic data derived from multiple ancestries.⁶

The PHS290 algorithm incorporates the genetic data from a diverse population of men who are a part of the Veterans Administration Health Care System. The study included 582,515 participants, approximately 425,000 had a European ancestry, 105,000 were of an African ancestry, and the remaining participants were either Asian or Hispanic, all of whom donated blood for genotyping. Moreover, whereas commercially available tests of risk utilize approximately a dozen cancer-related genes, 290 single-nucleotide polymorphisms (SNPs) that were previously identified to be associated with prostate cancer were used to generate the PHS290 algorithm. The existence of each of the 290 SNPs in participants were considered, as well as the participants’ age, enabling the association of prostate cancer diagnosis with age.

The results of the study were presented at the 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium. Participants who were in the top 20% for PHS290 had a 5.66 and 4.18 greater risk of developing prostate cancer or metastatic disease than those in the lowest 20%, respectively. Additionally, risk of death was 4.41 times greater in men with PHS290 scores in the top 20% than those with scores in the lowest 20%.

European ancestry was used as a reference group to determine ancestry associated risk of prostate cancer. Men of African ancestry were shown to have a 1.84 greater risk of developing prostate cancer than those of European ancestry, as well as a 2.27 times greater risk of prostate cancer metastasis and 1.97-time greater risk of death, based on a PHS290 score. Risk for those of Hispanic ancestry was similar to that of European ancestry and the number of participants with Asian ancestry was not large enough to generate a reliable risk estimate. Via the PHS290 score, the risk of prostate cancer development and mortality was also associated with family history of prostate cancer.

Lead study author Meghana Pagadala, MD, PhD from VA Health Care System, La Jolla, CA, comments that:

“We hope PHS290 will help men decide if they want to implement earlier screening or if they want to implement earlier interventions like healthy lifestyle changes in order to mitigate their risk of dying from prostate cancer.”

Meghana Pagadala, MD, PhD from VA Health Care System, La Jolla, CA, additionally states that:

“We also hope that this study will pave the way to investigating genetic screening methods in more diverse populations, especially considering Africans have a higher rate of prostate cancer and mortality rate from prostate cancer.”

The incorporation of a large variety of genetic variants from multiple ancestries in producing PHS290 are encouraging for the execution of personalized treatment decision making for diverse populations of patients with prostate cancer. The PHS290 algorithm has yet to be commercially available. The researchers intend to identify additional prostate cancer risk variants associated with ancestry to further improve the incorporation of ancestry into genetic risk estimation of prostate cancer, as well as explore the interaction between genetic risk and environmental factors.¹ Nevertheless, the current results are promising and with further refinement, the PHS290 algorithm may hold the potential to enhance outcomes for patients with prostate cancer, as well as improve parity within precision medicine.

References

1. New Genetic Risk Score Stratifies Lifetime Risk of Dying of Prostate Cancer in Diverse Populations. American Society of Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022 Annual Meeting. Available from: https://www.asco.org/about-asco/press-center/news-releases/new-genetic-risk-score-stratifies-lifetime-risk-dying-prostate
2. Prostate Cancer – Statistics. Cancer.Net. 2021. Available from: https://www.cancer.net/cancer-types/prostate-cancer/statistics
3. McCaffery K, Nickel B, Pickles K, et al. Resisting recommended treatment for prostate cancer: a qualitative analysis of the lived experience of possible overdiagnosis. BMJ Open. 2019
4. Fenton J, Weyrich M, Durbin S, et al. Prostate-Specific Antigen–Based Screening for Prostate Cancer. JAMA. 2018
5. Martin A, Kanai M, Kamatani Y, et al. Clinical use of current polygenic risk scores may exacerbate health disparities. Nature Genetics. 2019
6. Weise N, Shaya J, Javier-Desloges J, et al. Disparities in germline testing among racial minorities with prostate cancer. Prostate Cancer and Prostatic Diseases. 2021

Written by Ellie Jackson

Edited by Esther Drain