Study Results Support Expanded Role for Genetic Testing in Colorectal Cancer


Matthew B. Yurgelun, MD, discusses a colorectal cancer study which found nearly 10% of the individuals had an inherited mutation in a cancer susceptibility gene.

Matthew B. Yurgelun, MD

Matthew B. Yurgelun, MD

A recent study conducted at the Dana-Farber Cancer Institute, which analyzed more than 1000 patients diagnosed with colorectal cancer (CRC), revealed that nearly 10% of the individuals had an inherited mutation in a cancer susceptibility gene. These results suggest an expanded role for genetic testing of inherited risk, says lead investigator Matthew B. Yurgelun, MD.

In an interview withTargeted Oncology, Yurgelun, assistant professor of Medicine, Harvard Medical School, discussed the study and its implications for patients with CRC and their families.

TARGETED ONCOLOGY:Can you give an overview of your study?


We analyzed 1058 individuals who had a diagnosis of colon cancer who were seeking care at the Dana-Farber Cancer Institute. As a part of their clinical care here, they consented to have blood drawn for the purposes of research. For this study, we then went on to perform germline testing on all individuals using a commercially available 25-gene panel to look for inherited mutations in genes associated with inherited cancer risk. Some of the genes are linked to inherited CRC risk, and some genes are linked to inherited risk of other cancers, but not necessarily CRC.

For a long time, we’ve known that inherited factors do play a large role in the ideology and risk of CRC, although historically we thought that that accounts for a pretty small fraction of individuals with colorectal cancer, probably around 3% to 4%.

One of the key findings from our study here, however, was that inherited mutations in a cancer susceptibility gene were found in nearly 10% of individuals who we analyzed with this 25-gene panel. These individuals were not specifically selected for factors we traditionally associate with inherited risks of cancer. For example, these individuals were not specifically selected for being young at the time of their colon cancer diagnosis, they were not specifically selected based on factors in their tumor, or based on any sort of family history of cancer.

The fraction of individuals found to have inherited mutations in cancer susceptibility genes was quite a bit higher than what we would have expected in the past.

TARGETED ONCOLOGY:WasBRCAincluded in the gene panel?


BRCA1andBRCA2were analyzed as part of this 25-gene panel, and those are genes that historically have been known to confer particularly high lifetime risks for female breast cancer, ovarian cancer, and to a lesser extent, male breast cancer, pancreatic cancer, and prostate cancer, but have never really been linked to CRC risk.

Within this study, as part of the 25-gene panel, individuals were tested for germline mutations inBRCA1andBRCA2. We found that over 1% of these individuals, who again, were not specifically selected for any high-risk features, indeed did have inherited mutations inBRCA1orBRCA2, which is quite a bit higher than what we would expect if we just did testing on random people selected from the general population.

To us, this at least suggested that there may be a true link between mutations in these genes and CRC risk, but certainly more studies are needed to tease that out definitively.

TARGETED ONCOLOGY:Which patients with CRC should receive molecular testing, and at what point?


One of the tricky things from our study is to answer the question of which individuals need germline testing. We’ve historically recommended germline testing for any CRC patient who has a particularly strong family history of colon cancer; any colon cancer patient with a strong family history of endometrial cancer, ovarian cancer, and other cancers linked to Lynch syndrome; and any CRC patient who has a significant number of colorectal adenomas or other polyps.

Our study found that if you look beyond Lynch syndrome, which has historically been known as the most common inherited CRC syndrome, you end up finding a lot of inherited mutations and there doesn’t seem to be, at least from our data, a lot of specific factors that tell us which individuals need germline testing. It raises the question of if we should be performing germline testing on all individuals with CRC, which is a pretty slippery slope.

I think the counterargument to that is that some of these inherited mutations still have a lot of questions behind them, even when we find these mutations, so we’re not quite ready to be recommending germline testing for all individuals with CRC. I think we would come up with as many questions as we do answers if we were to do that.

At the very least, my current recommendation to my patients is to undergo germline testing, certainly if there is any evidence of mismatch repair deficiency (dMMR) in their tumor to suggest Lynch syndrome. If there is any evidence of inherited polyposis due to their personal history of colorectal polyps, or a family history of polyps [they should undergo testing], and furthermore, to undergo germline testing if they’re diagnosed with CRC before the age of 50.

But for individuals who have less striking family histories of other cancers, I think it becomes a situation where we should be thinking about germline testing more broadly and have a much more liberal threshold for such testing than we traditionally do.

TARGETED ONCOLOGY:What would you tell a newly diagnosed patient?


I think one thing that the literature is showing us we should be moving towards is testing in early-onset individuals. Even if they don’t have some of these traditional features such as dMMR in their tumor, even if they don’t have an obvious family history of colorectal or other cancers, and even if they don’t have a personal history of significant polyposis, that young age of diagnosis in particular is something that we should be thinking about for germline testing even if these other factors aren’t present.

TARGETED ONCOLOGY:Is mismatch repair standard for everyone?


Current guidelines recommend dMMR testing or microsatellite instability (MSI) testing—they’re essentially interchangeable. But current guidelines recommend that type of testing for all CRC patients. Certainly, it has been recommended in particular for patients in the metastatic setting to help guide immunotherapy use, such as the use of checkpoint inhibitors, but we have had data in the literature now for several years saying that dMMR testing really should be standard for all CRC patients, specifically to screen for Lynch syndrome.

Our study showed that if you go 1 or 2 steps beyond that and you start looking for other syndromes, you do indeed find them. Lynch syndrome is far and away the most common inherited syndrome, but our data showed it’s not the only syndrome we should be looking for.

TARGETED ONCOLOGY:What kind of questions should patients be asking their healthcare team?


It’s certainly important for patients who have had prior genetic testing to readdress that with their healthcare team. Patients with a prior history of CRC who maybe underwent germline testing in the past and were found to have no abnormalities may want to reconsider testing now that there are tests available that can test a little bit more broadly, especially if they had particularly concerning personal or family histories of cancer. The testing has become more sophisticated over the past several years and we’re finding patients who we tested in the past and now go back and retest with these broader panels where we do indeed find explanations for their high-risk histories.

For patients who are newly diagnosed or who have never had testing in the first place, I think it’s important that patients bring up the notion of familial risk. Many cancer patients, especially those with more advanced disease, have a lot on their plate, and their healthcare providers are often distracted by making sure they’re getting the right chemotherapy, the right social supports, the right symptomatic supports, and unfortunately, genetics often fall a little bit further down in priority in some cases.

I certainly encourage patients to advocate for themselves about any concerns they might have about inherited risks, especially as it applies to family members, because the testing is quite widely available at this point, and it is something that many patients should be considering.

TARGETED ONCOLOGY:What would you suggest if the patient doesn’t know they have a history?


For patients who don’t know their family history, there still can be reasons to consider germline testing. If they have certain features in their tumor, such as dMMR or MSI, then that would absolutely be a reason to consider germline testing. If they have a history of other cancers, or a history of significant degrees of colorectal polyps, they should be considering testing regardless of whether or not they know their family history. Certainly, patients with CRC who are diagnosed at a young age should consider germline testing even if they have an unknown family history. Family history is a big part of how we access risk, it’s not the only piece though.

TARGETED ONCOLOGY:Right now, there are no therapies that directly target the susceptibility genes. What is in the works in this area?


As far as interventions that we consider for individuals found to have certain types of inherited susceptibility, screening is an incredibly powerful tool. In the setting of Lynch syndrome, for example, individuals are typically recommended to undergo colonoscopies every 1 to 2 years. I often recommend every year, usually beginning in their early 20s, if they have a diagnosis of Lynch syndrome. The reason for such an aggressive recommendation is because we know it works. We know that colonoscopies are an incredibly powerful tool, not just at early detection, but also as CRC prevention.

One of the key benefits to making a genetic diagnosis in somebody who has a degree of inherited risk is that it helps us understand what the risks are, and just as importantly, how to manage them, how to prevent cancers. It’s more than early detection. For individuals with these types of inherited risks, beginning colonoscopies at a young age can be incredibly powerful at truly preventing a cancer from developing in the first place.

TARGETED ONCOLOGY:We have recently seen a rise in young adults diagnosed with colon cancer. What are your thoughts on what might be contributing to this and what recommendations do you have for prevention?


Certainly, we have seen an increase in the incidence of young adults with CRC, particularly rectal cancer, and particularly in individuals in their 40s and late 30s. It doesn’t seem that genetics is a driving force behind that increasing incidence. We would assume that genetic factors should be remaining relatively stable throughout the generations, so I think the assumption has been that it’s lifestyle factors, environmental factors, or interplays between the 2, and maybe interplays with some more subtle genetic factors that we haven’t come to understand just yet.

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