Dr. Shannon Westin and her guest, Dr. Andreana Holowatyj, discuss the paper "Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer," recently published in JCO.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast, the podcast where we get in-depth on manuscripts and interesting papers that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, and it's my pleasure to serve not only as a GYN Oncologist but as an Associate Editor for Social Media for the JCO. And as always, I'm super excited about the paper that we're going to discuss today. This is “Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer.” This has been published in the JCO. And I am so excited to be accompanied by the last author, Dr. Andreana Holowatyj, who is an Assistant Professor of Medicine and Cancer Biology at Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center.

Welcome.

Dr. Andreana Holowatyj: Thank you, Dr. Westin, for having me. I'm really excited to get to talk about this paper.

Dr. Shannon Westin: So are we. And please note that we do not have any conflicts of interest with this work.

So let's get started. First, early-onset colorectal cancer is any colorectal cancer diagnosed before age 50. So I just wanted to level set. Can you give us a bit of background on the incidence of early-onset colorectal cancer?

Dr. Andreana Holowatyj: Sure. All of the attention recently has been drawn to the fact that in contrast to incidence of colorectal cancer decreasing among adults over age 50, we've seen over the last several decades, this uptick—alarming uptick, in fact, in colorectal cancers among individuals diagnosed younger than age 50 years, or, as you point out, we call early-onset colorectal cancer, largely with reasons that are unexplained overall, which has drawn a lot of concern and attention as to what are the factors driving this marked increase in early-onset colorectal cancer both in the United States and globally.

Dr. Shannon Westin: And what do we know about the burden of early-onset colorectal cancer across different racial and ethnic groups? Are there disparities in survival like we've seen in some of the other cancer types?

Dr. Andreana Holowatyj: Yeah. So recently, a paper published demonstrating this greater shift towards early-onset colorectal cancer, where now we're seeing approximately 1 in every 8 adults with colorectal cancer being diagnosed under age 50. Add to that prior studies have shown that the proportion of early-onset colorectal cancer cases or incidence is actually higher among individuals who identify as non-White compared to those who identify as non-Hispanic White. We previously published in JCO a paper that assessed disparities in survival among early-onset colorectal cancer patients and strikingly found that individuals who identify as non-Hispanic Black had poorer survival compared with non-Hispanic Whites, both in colon and rectal tumors, specifically for young individuals. However, and of striking interest, we did not see these survival disparities between Whites and individuals who identify as Hispanic, which further led us to question what may be some of the biological, environmental, and other factors that may actually be driving some of these disparities by race and ethnicity, both in incidence but also in outcomes.

Dr. Shannon Westin: So that kind of brings us to this study. Will you walk us through what the objective of this study was?

Dr. Andreana Holowatyj: Yeah. So the underlying question really is what could be the role of germline genetic features or germline predisposition in early-onset colorectal cancer disparities? We know from prior studies published in JCO and other journals that about 14%-25% of early-onset colorectal cancer cases have a germline predisposition. However, these populations have been of limited size and, more importantly, of limited diversity. So we really wanted to tackle that question to understand what is the prevalence and spectrum of germline genetic features in early-onset colorectal cancer by race and ethnicity. Are there differences? Where do these differences lie? And what can this information really tell us in better understanding the early-onset colorectal cancer burden?

Dr. Shannon Westin: Well, now, well, just talk us through the design that you employed to achieve these objectives.

Dr. Andreana Holowatyj: We were fortunate to partner with a nationwide clinical testing laboratory to identify individuals who were between the ages of 15 and 49 years when diagnosed with the first primary colorectal cancer over about a five-year study period. We were able to identify around 4,000, or specifically 3,980 individuals, who identified as non-Hispanic White, non-Hispanic Black, Hispanic/Spanish or Latino, Asian, or Ashkenazi Jewish who had clinical multigene panel testing uniformly for 14 genes that have a known susceptibility to colorectal cancer overall, to really examine the prevalence and spectrum of genetic features across these self-identified racial/ethnic groups.

Dr. Shannon Westin: And what was the overall prevalence of germline mutations in this population? And did it differ kind of overall in the different racial and ethnic groups?

Dr. Andreana Holowatyj: Overall, the prevalence of germline genetic features when assessing 14 colorectal cancer susceptibility genes in this population was pretty consistent with prior studies at 12.2%, seeing about 1 in every 8 patients present with germline genetic predisposition. However, when we teased these numbers apart across racial/ethnic groups, what we saw is the prevalence of these germline genetic features ranged from 9.5% in individuals who identified as Asian to 10.3% of individuals who identified as Black, 12.4% as White, 12.7% for individuals who identify as Ashkenazim, all the way up to 14% of individuals who identify as Hispanic within this population. So we saw a wide—a decently wide breadth of prevalence across these racial/ethnic groups overall.

Dr. Shannon Westin: And of course, as a gynecologic oncologist, I'm always centering myself and thinking about Lynch Syndrome. So how did the prevalence of mutations in the mismatch repair gene differ between racial and ethnic backgrounds?

Dr. Andreana Holowatyj: So really interesting question. Overall, about 7% of individuals in our cohort presented with a pathogenic or likely pathogenic variant in the mismatch repair gene. But what we saw is that the prevalence of Lynch Syndrome varied from 3% or so of Ashkenazim individuals all the way up to 9.9% of Hispanic individuals. We saw that variance in MLH1 strongly differed across racial/ethnic groups, particularly in the Hispanic population, that accounted for some of these differences.

Dr. Shannon Westin: And then were there any differences in some of the other germline mutations that you explored?

Dr. Andreana Holowatyj: Yeah, we also observed differences in the prevalence of APC mutations, although largely attributable to the p.I1307K variant in Ashkenazim individuals, as well as CHEK2, monoallelic MUTYH, and PTEN.

Dr. Shannon Westin: Okay. Interesting. I was intrigued about those findings for the monoallelic MUTYH variants. Do you think we should be potentially doing increased screening in specific populations based on your results?

Dr. Andreana Holowatyj: Yeah, so I think to kind of put this into context, most people probably know that biallelic MUTYH variants yield MUTYH-associated adenomatous polyposis and, of course, confer a strong increased risk of colorectal cancer development. In monoallelic carriers of MUTYH variants, there really is limited evidence to guide clinical management, and this is an evolving area. Per NCCN guidelines, unaffected individuals with a monoallelic MUTYH pathogenic variant and a family history of colorectal cancer in a first-degree relative are recommended to get colonoscopy screening every five years beginning at age 40 or 10 years prior to the age of that first-degree relative of colorectal cancer diagnosis.

However, for individuals with a monoallelic MUTYH variant and no known family history of colorectal cancer, it's inconclusive as to whether specialized screening and surveillance are warranted. Current studies conducted in European or predominantly White populations have reported conflicting evidence as to whether there is an increased colorectal cancer risk for carriers of a monolithic MUTYH pathogenic variant. I don't think we're quite there yet to make a conclusive decision on whether increased screening is warranted in the population or not. I think the evidence is leaning towards potentially seeing not a strong increased colorectal cancer risk, but we'll have to wait and see on some additional studies to be conclusive in that area.

Dr. Shannon Westin: I was also intrigued—the lack of difference in germline features between Blacks and Whites was stark. I mean, why do you—what do you think might have led to us not seeing a difference there?

Dr. Andreana Holowatyj: I think there's potentially two avenues for this. I want to caveat the fact that this could be attributable to a limited sample size. Although we had about over 1,000—just over 1,000 individuals who identified as non-White, there's still potential selection bias in this cohort. However, we have included about a comparable number of individuals who identified Blacks and Hispanics herein, which does raise this question of we see differences in germline genetic features between Whites and Hispanics, but the lack of difference between individuals who identify as White and Black kind of yields possibly two avenues. If germline genetic features do contribute to racial/ethnic differences in early-onset colorectal carcinogenesis and outcomes, then there's a chance that we have not yet identified ancestry-specific variants associated with early-onset colorectal cancer. This has marked implications in the development and equitable design of multigene panel tests.

However, we also know that beyond genetics, the interplay with biology, social determinants of health, and behaviors could also underlie these distinct patterns. We recently demonstrated in a separate paper that we see actually differences in the tumor mutation burden between individuals who identify as Black or White, which is supporting the idea that a distinct tumor biology may be driving early-onset colorectal cancer disparities. And if there are no germline genetic features, then the question is really how does that interplay of the environment—some of these other complex interrelated factors, how could that be driving disparities in early-onset colorectal cancer incidence and outcomes, particularly for individuals who identify as Black?

Dr. Shannon Westin: And I guess that kind of leads to my next question. The testing platform that you studied, is it all-inclusive? Are there other mutations that might be relevant, or just we don't know yet?

Dr. Andreana Holowatyj: Yeah. So I think one of the advantages of this study is that all individuals had clinical multigene panel testing for the 14 genes that we evaluated overall. However, while that's a strength of the study, it's also a limitation, given that we only queried 14 genes with unknown colorectal cancer susceptibility, which really is a first step, yet a key step, in further studies and supporting further discovery of potential ancestry-specific variants or genes associated specifically with early-onset colorectal cancer predisposition.

Dr. Shannon Westin: That makes a lot of sense. And I guess that's the next kind of natural question is so what do we do next, right? Where do we go? How do we move this forward?

Dr. Andreana Holowatyj: Yeah. So I think one of the advantages of this approach and being fortunate to partner with the clinical testing laboratory is that the study was nationwide among individuals who, of course, had multigene panel sequencing. But at the same time, we were able to accumulate a sufficient number of cases to be able to study these patterns across population groups. I think the natural next step from multigene panel testing is based upon these findings to move into clinical exome sequencing to be able to not only move towards identifying genetic ancestry, since that's, of course, the biological construct—and I would be remiss if I didn't acknowledge that race and ethnicity is a social construct but was all that was available in the context of this present study—but also will allow us to query the entire exome and understand and dive deeper into some of these questions: variants of uncertain significance and also potential ancestry-specific variants.

Dr. Shannon Westin: Well, great. Well, this is super intriguing, and I know this is going to get a lot of excitement and attention from our readership. So I just want to thank you again for taking the time to review this really important paper, “Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer.” Again, I'm Shannon Westin, and I'm just so grateful that everyone came to listen to JCO After Hours. Please do check out our website for other podcasts you might have missed. Have a great one.

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Racial/Ethnic Differences Discovered in Multigene Germline Testing of Early-Onset Colorectal Cancer