(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL was host to the session Advancing Prostate Cancer Care: Treatment Approaches to Precision Medicine, Biomarker Innovations, and Equitable Access. Dr. Timothy Rebbeck discuss how to do responsible and equitable biomarker stewardship, and how to ensure access to all patients, and how to determine who is going to benefit from testing.
Dr. Rebbeck began his presentation by discussing that healthcare is generally aimed at prevention, detection (diagnosis), and therapy. He outlined two main approaches to achieving these goals.
The first is the population-based approach, where a "one size fits all" strategy is applied. The second is the precision approach, which can be further divided into two subcategories. The first subcategory is the stratified approach, which is based on risk factors, genetics, family history, and other variables. The second subcategory is the adaptive approach, which typically follows a dynamic response to patterns of care, changes over time, and keeps pace with knowledge updates.
He summarized this in the algorithm below:
Desirable interventions can create or exacerbate disparities. As an example in the United States, age-adjusted breast cancer mortality is about 40% higher among Black women than among non-Hispanic White women (27.7 vs. 20.0 deaths per 100,000 women from 2014 through 2018), despite a lower incidence of breast cancer among Black women (125.8 vs. 139.2 cases per 100,000 women). Notably, before 1980, breast cancer mortality was slightly lower among Black women compared to their White counterparts. However, after 1980, the death rates diverged sharply, leading to a persistent disparity over time.1
The main reason behind this intricate racial disparity in breast cancer mortality can be attributed to the introduction of new medical interventions in the 1980s. Two significant interventions widely implemented during that period were mammography screening and adjuvant endocrine therapy. Racial disparities in access to these interventions likely precipitated the divergence in mortality rates, as Black women were more likely than White women to lack health insurance or have inadequate coverage. This has limited their access to both mammography screening and adjuvant endocrine therapies.1
Similarly, multiple myeloma (MM), the most common hematologic malignancy among non-Hispanic Black individuals, has been shown to have inferior survival rates in this population compared to White individuals. Dr. Rebbeck presented a large-scale population-based study that included 5,798 Black and 28,939 White patients with MM, using data from the Surveillance, Epidemiology, and End Results (SEER) registries.
The investigators found that between 1973 and 1993, relative survival rates were higher for Black individuals compared to White individuals. However, between 1994 and 2005, 5-year relative survival rates for White individuals increased significantly. This disparity is likely due to unequal access to care, particularly since autologous stem cell transplants were introduced in the 1990s. Additionally, there was unequal access to and disparate responsiveness to novel therapies, such as immunomodulatory drugs, which further contributed to the survival rate differences.2
Dr. Rebbeck discussed that in prostate cancer significant shifts in mortality rates have occurred in correlation with county-level poverty, comparing two distinct periods: 1970-1974 and 2012-2016. This trend is partly attributable to the PSA (Prostate-Specific Antigen) era, which has exacerbated mortality inequalities, particularly affecting Black men, and even more so for those residing in impoverished counties. In the 2012-2016 period, black men who lived in poor counties had a much higher mortality ratio compared to black men who lived in affluent counties. This could be used as a surrogate for healthcare access. Please refer to the figure below for visual representation.3
Furthermore, in prostate cancer, there are very clear molecular signatures that determine prognosis and response to therapies. He presented a study in which the investigators assessed immune differences within the prostate tumor microenvironment of African American and white men of European ancestry in 1,173 radiation-naïve radical prostatectomy samples, which underwent whole transcriptome analysis using data from the Decipher GRID registry. The researchers focused on transcriptomic expressions of 1,260 immune-specific genes.4
Notably, the authors discovered significant enrichment of major immune-oncologic pathways in prostate tumors of African American men. These pathways included proinflammatory cytokines such as IFITM3 (IFN-inducible transmembrane protein 3), IFNα, IFNγ, TNFα signaling, CD4+, and CD8+ cells. Furthermore, they observed that tumors in African American men exhibited lower DNA damage repair and appeared to be genomically radiosensitive compared to those in White men. (Figure below)
In the Research Project GENIE (Genomics Evidence Neoplasia Information Exchange), mutational profiles of 474 genes were scrutinized based on race (White, Black, or Asian) and tumor stage (primary or metastatic). A total of 2,393 patients were analyzed, comprising 2,109 White, 204 Black, and 80 Asian individuals. The mutational profiles of these patients are depicted in the figure below. Overall, while the frequencies of genes with actionable mutations and mutations in DNA-repair genes did not show substantial differences among the racial groups, they were observed more frequently in Black patients.5 If black men are not as likely to be tested for these actionable mutations, there would be a disparity that we have created with genetic testing and potentially affects these individuals.
Dr. Rebbeck also shared data from a study examining polygenic risk scores (PRS) in men of African descent. This study assessed the test characteristics of PRS derived from three previous studies using data from 2,631 individuals from the UK Biobank (mostly white) and a novel dataset consisting of 1,233 individuals from the 1000 Genomes and 2,631 from MADCaP (African).
The study revealed that allele frequency differences lead to variations in predicted risks of prostate cancer across populations. Importantly, it found that polygenic predictions are more effective for European individuals (with AUC ranging from 0.707 to 0.541) compared to African individuals (with AUC ranging from 0.671 to 0.585). Moreover, the study suggested that PRS developed from European genome-wide association studies (GWAS) may not be suitable for application in white populations and could perpetuate existing health disparities.6 This adds to the point that if we don’t study diverse data, we will get wrong answers and risk classifications, predominantly in the populations that are understudied.
To add to the point that diverse research data improves disease, management for all population, Dr Rebbeck presented data from a study involving patients with hypertrophic cardiomyopathy, where risk stratification has been refined through targeted genetic testing. Regrettably, data from Black Americans have not been incorporated into risk stratification efforts. Utilizing exome data, the study uncovered that mutations most prevalent in the general population were notably more frequent among Black Americans compared to White Americans (P<0.001). Confirming that the absence of Black Americans in risk stratification PRS synthesis results in misclassification of benign variants as pathogenic.7
Dr. Rebbeck wrapped up his presentation by delivering strong takeaway messages and giving some recommendations for responsible and equitable biomarker stewardship:
- Include diverse populations in the development and implementation of biomarker-based tools (GWAS analysis, PRS synthesis, risk classification assessment)
- Use molecular variation to develop and implement tests
- We should not be creating race-based medicine (White people vs. Black people mutations and treatment patterns) we should be using diverse testing to get better data for all populations
- Consider equity of access to screening tests, treatments, molecular testing, due to economic, cultural, and behavioral differences among different ethnicities and populations.
Presented by: Timothy Rebbeck, PhD, Professor of Medical Oncology at the Dana-Farber Cancer Institute
Written by: Julian Chavarriaga, MD – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @chavarriagaj on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024.
References:
- Jatoi I, Sung H, Jemal A. The Emergence of the Racial Disparity in U.S. Breast-Cancer Mortality. N Engl J Med. 2022 Jun 23;386(25):2349-2352. doi: 10.1056/NEJMp2200244. Epub 2022 Jun 18. PMID: 35713541.
- Waxman AJ, Mink PJ, Devesa SS, Anderson WF, Weiss BM, Kristinsson SY, McGlynn KA, Landgren O. Racial disparities in incidence and outcome in multiple myeloma: a population-based study. Blood. 2010 Dec 16;116(25):5501-6. doi: 10.1182/blood-2010-07-298760. Epub 2010 Sep 7. PMID: 20823456; PMCID: PMC3031400.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan;69(1):7-34. doi: 10.3322/caac.21551. Epub 2019 Jan 8. PMID: 30620402.
- Awasthi S, Berglund A, Abraham-Miranda J, Rounbehler RJ, Kensler K, Serna A, Vidal A, You S, Freeman MR, Davicioni E, Liu Y, Karnes RJ, Klein EA, Den RB, Trock BJ, Campbell JD, Einstein DJ, Gupta R, Balk S, Lal P, Park JY, Cleveland JL, Rebbeck TR, Freedland SJ, Yamoah K. Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer. Clin Cancer Res. 2021 Jan 1;27(1):320-329. doi: 10.1158/1078-0432.CCR-20-2925. Epub 2020 Oct 9. PMID: 33037017; PMCID: PMC8042600.
- Mahal BA, Alshalalfa M, Kensler KH, Chowdhury-Paulino I, Kantoff P, Mucci LA, Schaeffer EM, Spratt D, Yamoah K, Nguyen PL, Rebbeck TR. Racial Differences in Genomic Profiling of Prostate Cancer. N Engl J Med. 2020 Sep 10;383(11):1083-1085. doi: 10.1056/NEJMc2000069. PMID: 32905685; PMCID: PMC8971922.
- Kim MS, Naidoo D, Hazra U, Quiver MH, Chen WC, Simonti CN, Kachambwa P, Harlemon M, Agalliu I, Baichoo S, Fernandez P, Hsing AW, Jalloh M, Gueye SM, Niang L, Diop H, Ndoye M, Snyper NY, Adusei B, Mensah JE, Abrahams AOD, Biritwum R, Adjei AA, Adebiyi AO, Shittu O, Ogunbiyi O, Adebayo S, Aisuodionoe-Shadrach OI, Nwegbu MM, Ajibola HO, Oluwole OP, Jamda MA, Singh E, Pentz A, Joffe M, Darst BF, Conti DV, Haiman CA, Spies PV, van der Merwe A, Rohan TE, Jacobson J, Neugut AI, McBride J, Andrews C, Petersen LN, Rebbeck TR, Lachance J. Testing the generalizability of ancestry-specific polygenic risk scores to predict prostate cancer in sub-Saharan Africa. Genome Biol. 2022 Sep 13;23(1):194. doi: 10.1186/s13059-022-02766-z. PMID: 36100952; PMCID: PMC9472407.
- Manrai AK, Funke BH, Rehm HL, Olesen MS, Maron BA, Szolovits P, Margulies DM, Loscalzo J, Kohane IS. Genetic Misdiagnoses and the Potential for Health Disparities. N Engl J Med. 2016 Aug 18;375(7):655-65. doi: 10.1056/NEJMsa1507092. PMID: 27532831; PMCID: PMC5292722.