Addressing the Disparities in Prostate Cancer Care and Outcomes

FIGURE: Vitamin D infl ammation pathways of prostate cancer.

Rick Kittles, PhD

Dr. Kittles discusses the race-based health disparities in prostate cancer, and one genetic-environmental crossover that is clinically significant.

There are significant race-based disparities in prostate cancer care and outcomes. Recent research has shed more light on the divergent causes of these disparities. ONCOLOGY spoke with Rick Kittles, Professor and Founding Director of the Division of Health Equities within the Department of Population Sciences at City of Hope Comprehensive Cancer Center in Duarte, California, where he is also Associate Director of Health Equities. Among other health disparity topics, Dr. Kittles conducts research on why African-Americans have a disproportionately higher burden of prostate cancer compared to European-Americans.

Q: First, could you lay out the research questions that you address, as they relate to health disparities and prostate cancer specifically among African-Americans? What are the main issues?

Dr. Kittles: There are several issues dealing with prostate cancer disparities that we focus on. What we are attempting to do is to try to understand why there’s an increased burden and incidence of prostate cancer for men of West African descent in particular. There are mortality differences, too, and other different outcomes compared with other populations. We’re trying to understand if there is a strong genetic component to this, or is it environmental or the interaction of both of these factors? We’re doing a lot of genetic studies and behavioral and dietary studies in this area.

Q: You and your colleagues recently conducted a study analyzing the role of calcium and vitamin D in prostate cancer pathogenesis and progression. Could you tell us about the genesis of this study and what you found?

Dr. Kittles: The calcium study emerged after we started studying vitamin D. Vitamin D, calcium, and parathyroid hormone interact and regulate each other in one way or another, and this relates not only to what we historically have known in terms of bone mineralization and bone development, but also to immune surveillance. This is something that we started to really focus in on-specifically the role vitamin D plays in immune surveillance. Our calcium study showed that there was this higher incidence or higher risk of aggressive prostate cancer among African-American men whose daily calcium intake was over 800 mg.[1] This was quite surprising, but there have been other studies that have shown similar results.

Q: Can you talk about vitamin D research and how vitamin D might be linked to prostate cancer?

Dr. Kittles: Is vitamin D linked to prostate cancer? Some have said that there’s an association and others say there is not. A lot of the differences in results has to do with how you are collecting and analyzing data. Our group has found that there are many different modifiers of serum vitamin D levels, and there are differences in levels of prostatic vitamin D, the amount of vitamin D in the prostate. And those levels, whether they are sufficient or deficient, could lead to differences in gene expression, many of which are related to immune response, inflammation, and immune surveillance. Vitamin D deficiency can lead to altered immune surveillance in the prostate tissue, which could potentially lead to prostate cancer.

Q: Are there other factors that may affect this higher prevalence of prostate cancer among African-Americans that you have found in your research?

Dr. Kittles: When we look at the difference between African-American men and men of European descent, we find that genes are playing a strong role. In fact, upwards of maybe 40% to 50% of the difference we see is genetic. There are some strong genetic signals that emerged over the last 10 years related to a region on chromosome 8 that appear to be enriched in men of West African descent. (The region of risk on chromosome 8, specifically, is the 8q24 region.) There may be some sort of increased inherited predisposition based on ancestry that could be driving a lot of the differences that we see. We don’t know the mechanism of action, but we do know that the markers and biomarkers are pretty consistent and replicable.

Q: Using those genetic markers, has your group or other groups followed up this work to potentially screen men for higher risk of prostate cancer or does this still need to be confirmed in additional studies?

Dr. Kittles: Well, a lot of this work on biomarkers was work from a consortium, what we call GWAS or genome-wide association studies on prostate cancer where multiple groups around the country put their samples together for these big meta-analyses. This was not just our group; many groups actually helped find the signals. The sad part is that there hasn’t been a focus, let’s say from the National Institutes of Health or other funding agencies, to really say, “Look, now there are these signals that have been replicated across the world, actually.” We see these signals in all populations: European, Asian, Indian, South African. The problem is that there has not been a concerted effort to say, “Let’s look at mechanism of action now to see the real inherited mechanism that is increasing this burden.” I say this all the time: once you find something and there’s next steps that could be done, you need to have that increased attention on those next steps if you really want to peel apart what’s going on. Right now, there are several groups still working on this––not as many as before––and there’s also a marker panel that is just emerging and might actually be able to predict risk for certain outcomes. But still, no clear evidence of mechanism has been shown yet.

Q: Are you conducting other studies to identify other potential factors or the role of the environment in this health disparity connection?

Dr. Kittles: The vitamin D study was actually a gene environment study. We’re looking at genes, their pathways, the steroid synthesis pathway, and the steroid signaling pathways. We are also looking at dietary behavioral factors that influence vitamin D levels in serum and in the prostate. This is a really good model of a disparity project that has a strong gene-environment interaction. We are also studying methylation and dietary folate, folic acid in particular. We are looking at some of the clinical outcomes as they relate to the heterogeneity among these tumors. What we’re finding is that there’s no overburden of particular genetic changes in these prostate tumors. There’s a subset of different types of signals and mutations in various tumors in the African-American men who have prostate cancer. What we’re trying to do now is to uncover some of the outcomes from these particular signatures. For example, HER2, which is a clear breast cancer subtype and is used as a biomarker in breast cancer, actually has a therapeutic potential. We need to identify markers like this for prostate cancer.

Q: More recently, you had a study that looks at different cancer cell lines and highlighted disadvantages for minorities in accessing personalized therapy strategies for prostate and other tumor types. Can you tell us about that work and what you found?

Dr. Kittles: The challenges and problems have been the lack of diversity in biorepositories and biospecimens. This has limited the progress in disparities research. What we wanted to do was really examine if, in fact, cell lines that were labeled or characterized as African-American were really from African-American patients. And, in fact, many were not,[2] and so this is hopefully bringing some attention to this fact that we still, in particular for prostate cancer, have this enormous disparity difference among ethnic groups. We really need to focus in on collecting more diverse samples for our research models of prostate cancer, and also other tumor types.

Q: Lastly, can you talk about your efforts and efforts by the broader scientific community to make bioscience research more inclusive to different ethnic populations?

Dr. Kittles: My whole career has been focused on studying disparities in Black and Hispanic populations. I focus on going out, educating the community, getting them excited about research, and then getting them to participate. For me, there is no challenge in terms of getting access to samples, of getting people excited about the research. I think a lot of times the community really just needs to see themselves in the research. When I say that I mean they need to see something that is impactful for them, something that they want to see resolved in their community. They also want to see themselves reflected in the research, as it relates to participating researchers, clinicians, nurses, and students. Let’s say the principal investigator of a study is not of African-American descent and staff isn’t either. This does play a role in the ability of the researcher to recruit a diverse population and get diverse samples.

Q: Anything else you would like to add on your research and increasing diversity in scientific research?

Dr. Kittles: I think this issue of increasing diversity in scientific research is going to have a major role in the future of research here in the United States. As everybody knows, the country is becoming more and more diverse. If we do not have adequate representation, not just in biomedical samples and biospecimen repositories, but also in representation in the pipeline and workforce, that lack of diversity is going to have some major ramifications downstream. I get excited when I go out into the community and talk about these issues. I’m trying to get folks to be more aggressive in terms of their advocacy for themselves and support for diversity in the biomedical workforce.

Financial Disclosure:Dr. Kittles has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

PERSPECTIVE

Unraveling the Research on Prostate Disparities

E. David Crawford, MD,

Although we have known for decades that African American men with prostate cancer are at an extreme disadvantage, scientists are still seeking the translational answers that might reverse this reality. The literature includes a wide variety of genetic, social, and environmental theories that they hope will explain, individually or in combination, the higher risk and poorer outcomes seen in these patients. Dr. Kittles has discussed some of these in his interview, and focuses specifically on a genetic predisposition and vitamin D. This and other factors have been examined, including diet, exercise, testosterone levels, androgen receptor variations, immunological responses, and many more. A major component includes access to medical care and treatment. In some equal access situations, such as the military, disparities in survival seemed to be lessened and in some cases eliminated. We published an article in 2004 looking at outcomes of African-American men in the Henry Ford system regarding local prostate cancer outcomes. Some of the discrepancies appear to be related to choices of therapy. When African American men, who represented 30% of the men in the system, chose the same treatment as Caucasians, they had similar survival. [1] Interestingly, Dr Oliver Sartor, reported recently that African-American men with advanced prostate actually had a survival advantage over Caucasian man when treated with immunotherapeutic regimen of sipuleucel-T (Provenge). As we continue to explore all the research on prevalence and prognosis, we may find that we can increase favorable outcomes based on multiple factors. I applaud Dr. Kittles‘s work and appreciate the comments.

Financial Disclosure:Dr. Crawford has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

REFERENCES

[1] Tewari A, Johnson CC, Divine G, Crawford ED, Gamito EJ, Demers R and Menon: Long-term survival probability in men with clinically localized prostate cancer: a case-control, propensity modeling study stratified by race, age, treatment and comorbidities. Jour Urology 171(4):1513–1519, 2004.

[2] Sartor AO, Andrew J, Armstrong, CA, et al.

References:

1. Batai K, Murphy AB, Ruden M, et al. Race and BMI modify associations of calcium and vitamin D intake with prostate cancer. BMC Cancer. 2017; 17(1):64.

2. Hooker SE, Woods-Burnham L, Bathina M, et al. Genetic ancestry analysis reveals misclassification of commonly used cancer cell lines. Cancer Epidemiol Biomarkers Prev. 2019;28(6):1003-1009, doi: 10.1158/1055-9965.EPI-18-1132.