Advanced Colorectal Cancer

Modifiable Risk Factors and Risk of Colorectal and Endometrial Cancers in Lynch Syndrome: A Systematic Review and Meta-Analysis

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Abstract

Purpose

Lynch syndrome is the most common hereditary cause of colorectal and endometrial cancers. Modifiable risk factors, including obesity, physical activity, alcohol intake, and smoking, are well-established in sporadic cancers but are less studied in Lynch syndrome.

Methods

Searches were conducted on MEDLINE, Embase, and Web of Science for cohort studies that investigated the association between modifiable risk factors and the risk of colorectal or endometrial cancer in people with Lynch syndrome. Adjusted hazard ratios (HRs) and 95% CIs for colorectal and endometrial cancers were pooled using a random effects model. The protocol was prospectively registered on PROSPERO (CRD 42022378462), and the meta-analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology reporting guidelines.

Results

A total of 770 citations were reviewed. Eighteen studies were identified for qualitative synthesis, with seven colorectal cancer (CRC) studies eligible for meta-analysis. Obesity (HR, 2.38 [95% CI, 1.52 to 3.73]) was associated with increased CRC risk. There was no increased CRC risk associated with smoking (HR, 1.04 [95% CI, 0.82 to 1.32]) or alcohol intake (HR, 1.32 [95% CI, 0.97 to 1.81]). Type 2 diabetes mellitus (T2DM) and some dietary factors might increase risk of CRC although more studies are needed. In a qualitative synthesis of three endometrial cancer cohort studies, female hormonal risk factors and T2DM may affect the risk of endometrial cancer, but obesity was not associated with an increased risk.

Conclusion

Lifestyle recommendations related to weight and physical activity may also be relevant to cancer prevention for individuals with Lynch syndrome. Further high-quality prospective cohort studies, in particular, including endometrial cancer as an end point, are needed to inform evidence-based cancer prevention strategies in this high-risk population.

Introduction

Lynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer (CRC), is a cancer predisposition syndrome caused by inherited pathogenic variants in one of MLH1, MSH2, MSH6, PMS2, or epCAM genes.1,2 It is the most common cause of inherited CRC and endometrial cancer, accounting for approximately 3% and 2%-5% of each malignancy, respectively.3 Individuals with Lynch syndrome are also at an increased risk of cancer of the ovary, stomach, small bowel, pancreas, and the genitourinary system, among others.4–7

Studies in the general population have shown that obesity, diabetes mellitus, and insulin resistance increase the risk of both colorectal and endometrial cancers.8–10 Although diabetes and other cardiometabolic risk factors are not classical modifiable risk factors, they are elements of the metabolic syndrome through which lifestyle affects cancer risk and can be ameliorated by behavioral changes.11 For this reason, they have similar public health importance and are targets for intervention. Tobacco consumption and red and processed meat intake increase the risk of CRC, whereas physical activity and a diet rich in fiber, fruit, and vegetables may be protective.12–15

Female hormonal factors, including age at menarche, age at menopause, parity, use of hormonal contraceptives, and hormonal replacement therapy, influence endometrial cancer risk.15–17 The most recent recommendations from the World Cancer Research Fund Continuous Update Project Expert Report advise reducing excess body weight, increasing physical activity, and minimizing alcohol and tobacco consumption to reduce risk of colorectal and endometrial cancers.18 Reducing processed and red meat consumption is advised for CRC prevention.18

Although established in the general population, the association between these potentially modifiable lifestyle risk factors and the development of colorectal and endometrial cancers in Lynch syndrome is less well-characterized. A systematic review of energy-related lifestyle factors and risk of colorectal and endometrial cancers in Lynch syndrome was published previously.19 However, it was a qualitative evidence synthesis without meta-analysis, and it did not include studies of female hormonal or broader cardiometabolic risk factors. In addition, important studies have been published since and updated assessment of the data is warranted.

A better understanding of these risk factors in the Lynch syndrome population will directly contribute to the implementation of adjunctive cancer prevention strategies. To this end, we conducted a systematic review and meta-analysis of additional modifiable and nonmodifiable risk factors for colorectal and endometrial cancers in individuals with Lynch syndrome. Through this, we aim to inform evidence-based lifestyle recommendations in this high-risk cohort.

Discussion

Determining whether potentially modifiable lifestyle and environmental risk factors for sporadic malignancies are also applicable in germline cancer predisposition syndromes is an important clinical question. As the lifetime risk of cancer is many times higher, there may be a greater absolute benefit to positive health behaviors compared with the general population.44 This systematic review and meta-analysis evaluated the association between lifestyle risk factors and colorectal and endometrial cancers in people with Lynch syndrome. In the case of CRC, obesity and a lack of physical activity were found to be associated with an increased risk, while there was insufficient evidence to conclude that alcohol or tobacco intake had a consistent association. As Lynch syndrome–associated malignancies are highly immunogenic, the immunosuppressive effect of the aforementioned risk factors45,46 may plausibly amplify their already carcinogenic actions. Limited evidence suggests that certain dietary habits might be protective, but more robust studies are needed to inform public health recommendations. In endometrial cancer, the data are particularly limited, and it is challenging to draw conclusions. The limited available evidence suggests that T2DM and the same female hormonal risk factors that affect sporadic endometrial cancer also hold in those with inherited mismatch repair deficiency. Interestingly, obesity may be less of a risk factor in Lynch syndrome–associated endometrial cancer. This finding contrasts with the strong and consistent relationship between obesity and sporadic endometrial cancer, which is believed to be mediated through hormonal, insulinemic, and proinflammatory mechanisms of carcinogenesis.47 Lynch syndrome–associated endometrial cancer is biologically distinct, in terms of both tumor histology and molecular subtype.48–52 A hypothesis for this lack of association is related to the fact that Lynch syndrome–associated endometrial cancer occurs in the setting of a constantly replenishing endometrium, with a high level of replication. In the error-prone mismatch repair phenotype in Lynch syndrome, the high level of cellular turnover may increase the generation of oncogenic mutations.51 In comparison, in women with functioning mismatch repair system, errors occurring during this frequent turnover are repaired. It is possible that the high estrogenic drive associated with obesity11 is a greater driver of malignancy in that context.

Our results are generally consistent with another systematic review that examined energy-related lifestyle factors and the risk of colorectal and endometrial cancers in patients with Lynch syndrome.19 The review’s conclusion that health recommendations for the general public are generally relevant to Lynch syndrome, with a few caveats, is consistent with this article. Our results are also in agreement with a recent meta-analysis of obesity and the risk of CRC in patients with Lynch syndrome.53 The authors found a twofold increased risk of CRC in obese men compared with nonobese men, but this was not statistically significant in women. A recent case-control study examined the association between obesity and the risk of CRC in the general population across five Jass molecular subtypes.54 Interestingly, subtype 5, most commonly associated with Lynch syndrome,55 was the only subtype in which obesity did not increase odds of CRC (odds ratio, 1.04 [95% CI, 0.9 to 1.2]). This discordance in results between this study and the rest of the literature may be due to assuming the presence of Lynch syndrome by tumor molecular subtype rather than a confirmed diagnosis, the use of a case-control methodology, and the use of cohorts from different populations. Further high-quality cohort studies including those with germline-proven Lynch syndrome are needed to determine the exact extent to which BMI determines the risk of CRC.

Among the strengths of this study is the substantial amount of recently published studies, assessing a large number of individuals, with long-term follow-up. It is the most comprehensive evidence synthesis of nongenetic risk factors and their association with cancer in Lynch syndrome to date, providing up-to-date results that may inform public health recommendations. Nevertheless, our study had several limitations. First, most cohort studies were retrospective in methodology, which are subject to recall bias, especially as many risk factors were self-reported. Second, few studies assessed each MMR mutation individually and, in many cases, the mutations were pooled. This meant how different risk factors interact with the different Lynch syndrome genotypes was not explored. One study36 included 17% of participants diagnosed with Lynch syndrome by the Amsterdam criteria, which are neither sensitive nor specific.56,57 We included this cohort as this small subset is unlikely to have affected the strong association between obesity and CRC found in the study. There were few studies assessing certain risk factors and very few studies overall on endometrial cancer. Because of this, just two studies were eligible for meta-analysis of obesity in CRC. This limits the precision of the pooled estimate of the risk of CRC and assessment of between-study heterogeneity.58 There was just one high-quality study investigating diet and the risk of CRC.24 Although it found an association between calcium and multivitamin intake and cancer, the fact that these risk factors are not conclusively associated with sporadic CRC18 precludes any definitive conclusion in this genetic subpopulation. A major limitation of our meta-analysis is that, for most risk factors examined, extreme values were dichotomized (eg, BMI >30 v <25 kg/m2) in the meta-analysis. This was performed to ensure that comparable end points were being pooled but have reduced the precision of our pooled estimate. This dichotomization may also account for our finding that alcohol and tobacco intake is not associated with Lynch syndrome–associated CRC, in contrast to the general population. A dose-response meta-analysis can be performed to overcome this issue.59 The relative lack of dose-response data in the included cohort studies means that this is not feasible for this analysis. However, if more granular data related to modifiable risk factors and cancer risk in Lynch syndrome are available in the future, this would be a worthwhile approach. Finally, our study was limited in that it just included studies looking at the risk of colorectal and endometrial cancers. Other Lynch syndrome–associated cancers were usually not accounted for in most cohort studies, or if they were, they were grouped as non-CRCs,36 preventing an effective evidence synthesis.

Our findings highlight several areas that warrant further research. There is a paucity of research investigating risk factors for endometrial cancer among people with Lynch syndrome, with our literature search identifying just three studies. Given that sporadic endometrial cancer is among the cancers with the greatest lifestyle risk,60 and there is no established benefit of endometrial surveillance,61 determining whether these risk factors apply to the Lynch syndrome population would have a substantial public health benefit. Future research should also examine how gene-environment and environment-environment interactions can affect risk. The risk of cancer among people with Lynch syndrome depends on the genotype, with MLH1 and MSH2 generally being the most penetrant.62–65 The differential risk between genotypes is also likely to affect the magnitude of a given lifestyle risk factor. Two studies included in this review found that MLH1 mutation carriers had the greatest increase in the risk of CRC because of obesity,34,36 and this was also seen in a recent meta-analysis.53 However, most other studies did not stratify the risk of CRC by specific MMR gene variant, so more research is needed to explore gene-specific recommendations for cancer risk reduction. Interactions between multiple nongenetic risk factors are also an emerging research focus. A cohort study on the basis of the CAPP2 trial of aspirin for CRC prevention in Lynch syndrome found that, although obesity was associated with an increased risk of CRC, this was abrogated in those taking aspirin. This suggests that the protective association of aspirin may counteract the carcinogenic mechanism of obesity, and those with obesity may be more likely to benefit from aspirin use.36 This example of interaction between two different nongenetic risk factors could be a future method of precision cancer prevention, on the basis of not just one’s genotype but also the lifestyle risk profile.

In conclusion, this systematic review and meta-analysis demonstrates that public health lifestyle recommendations, with some caveats, apply to the Lynch syndrome population. Obesity and lack of physical activity may be associated with an increased risk of CRC among individuals with Lynch syndrome. Female hormonal risk factors and type 2 diabetes might confer an increased risk of endometrial cancer. These findings can inform adjunctive cancer prevention strategies. Further high-quality prospective cohort studies, particularly in endometrial cancer, are needed to inform more robust, evidence-based lifestyle recommendations for people living with a diagnosis of Lynch syndrome.

Tucatinib and Trastuzumab Combination Approved for Advanced Colorectal Cancer

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Some people with colorectal cancer that can’t be removed surgically or has spread elsewhere in the body have a new treatment option. On January 19, the Food and Drug Administration (FDA) granted accelerated approval to the combination of two targeted drugs, tucatinib (Tukysa) and trastuzumab (Herceptin) for people with advanced colorectal cancer that produces an excess amount of a protein called HER2.

An illustration showing two cancer cells side by side with different amounts of HER2 on its surface.
Tucatinib (Tukysa) and trastuzumab (Herceptin) are now approved by FDA to treat some people with colorectal cancer whose tumors produce an excess of HER2 proteins. The drugs block the activity of HER2 proteins but in different ways.

To be eligible to receive the new combination, people’s tumors must also not have changes in a group of genes called RAS, and people must have previously received at least two standard treatments, including chemotherapy.

In the clinical trial that led to the accelerated approval, called MOUNTAINEER, 38% of people who received the drug combination had their tumors shrink or disappearExit Disclaimer. In another 33%, tumors stopped growing for some time. At the time the study results were presented last July, more than half the participants who received the drugs were still alive 2 years after beginning treatment.

The available treatment options for people whose metastatic colorectal cancer has returned or started growing again after receiving standard treatments are not very effective, explained John Strickler, M.D., of Duke University, who led the trial. 

“That [approach] has a response rate of less than 5%, and generally controls disease for around 2 to 4 months,” Dr. Strickler said. “So this treatment represents a fairly substantial breakthrough for patients who have HER2-positive disease” that has returned or started growing again.

HER2-positive tumors make up a small minority of colorectal cancers: only about 3% overall. Focusing on smaller and smaller groups of patients with targeted therapies can make recruiting enough people to run clinical trials challenging, said Carmen Allegra, M.D., who works with NCI’s Cancer Therapy Evaluation Program and was not involved with the study.

“But when you do find something that helps small subsets of patients, the results are often quite impressive like this,” Dr. Allegra said

Cutting off fuel for cancer cells

HER2 plays a role in normal cell growth. In many cancer types, tumor cells make extra copies of the gene that produces the HER2 protein, known as gene amplification.

The resulting flood of HER2 protein causes cancer cells to grow uncontrollably. But, on the flip side, cancer cells may also become dependent on this extra HER2 and cutting off the flow of the protein can cause them to stop growing or die.

HER2’s role is best understood in breast cancer, where up to 30% of tumors overexpress HER2 and HER2-targeted treatments are commonly used. In the last few years, researchers have discovered that HER2 is also overproduced in some stomach and esophageal cancers, Dr. Strickler said, and researchers are teasing out its contribution to other cancer types.

An image of breast cancer cells with strong HER2 amplification.

More and more, people with newly diagnosed metastatic colorectal cancer undergo certain types of gene sequencing, explained Dr. Strickler. This sequencing looks for gene changes that can be targeted with approved drugs, as well as mutations that can predict resistance to certain treatments.

“Increasingly, when we were sequencing tumors to look for mutations, we were incidentally finding HER2 amplification. But we had no FDA-approved therapies targeting HER2” for colorectal cancer, Dr. Strickler said.

He and his colleagues began a small study of two drugs targeting HER2: trastuzumab, which has been the backbone of treatment for HER2-postive breast cancer, and tucatinib, a newer drug which has proven to be particularly effective in combination with trastuzumab in breast cancer.

In studies in mice, “it had been shown repeatedly that these drugs work better when given together,” Dr. Strickler said. “Each drug by itself has modest antitumor effects in colorectal cancer, but when you give them together, the effect is what I’d call one plus one equals three.”

The team saw something similar in study participants. When they gave them only tucatinib, some people’s tumors stopped growing for a while but none shrank, and they ended up having trastuzumab added to their treatment, he explained.

Long-lasting tumor control for some people

Seagen Inc., which manufactures tucatinib, funded the team to conduct the larger MOUNTAINEER trial, which tested the combination of tucatinib and trastuzumab in 84 study participants whose advanced colorectal cancer had come back or hadn’t shrunk after previous treatments. Most participants had metastatic tumors in their liver and lungs. 

Participants also had to have genetic tests showing that their cancer didn’t have RAS mutations. Such mutations are thought to allow cancer cells to keep growing even if HER2 is blocked, rendering that treatment useless, explained Dr. Strickler.

MOUNTAINEER participants received tucatinib and trastuzumab until their cancer started growing again, or until they experienced side effects.

At the time the trial results were presented at the European Society for Medical Oncology World Congress on Gastrointestinal Cancers in 2022, participants’ tumors had continued to respond to the treatment for a median of just over a year. 

It will be important to keep following the remaining patients in the MOUNTAINEER trial for a while, said Dr. Allegra. “For those patients who did get a response, it lasted a long time, relatively speaking,” he said. “But whether that response rate will translate into a survival advantage over other treatments isn’t known yet.”

Median overall survival in the MOUNTAINEER trial was just over 2 years. In large clinical trials, said Dr. Allegra, overall survival has been about 7 months for people with advanced colorectal cancer who have already had several treatments. However, those whose tumors overexpress HER2 and don’t have RAS mutations may tend to live longer regardless of what treatment they receive, he added.

The most common side effects seen during the MOUNTAINEER trial were diarrhea, fatigue, rash, nausea, fever, and reactions to the trastuzumab infusions such as chills. The most common serious side effect was high blood pressure. Doses of tucatinib were reduced or stopped for 6% of the 84 participants due to side effects.

However, the severity and frequency of side effects with the targeted drug combination was less than that seen with the chemotherapy drugs that would normally be used for these patients, said Dr. Strickler. 

Combination therapies for longer responses?

These results of the MOUNTAINEER trial led to an ongoing follow-up study called MOUNTAINEER-03. This randomized clinical trial is testing the addition of tucatinib and trastuzumab to standard treatment regimens using chemotherapy and other targeted therapies, as initial treatment for metastatic HER2-positive colorectal cancer. 

Other trials are also testing combinations of other targeted drugs in patients with previously treated advanced colorectal cancer to see if they, like tucatinib and trastuzumab, work better when given together. 

For example, explained Dr. Allegra, another phase 3 clinical trial recently tested the combination of bevacizumab (Avastin) with trifluridine and tipiracil (Lonsurf) in people with advanced colorectal cancer who had received at least two previous treatments. Those participants lived for a median of almost a year after starting treatment. Participants in that trial could receive the study drug combination regardless of the gene mutations found in their tumors.

For people with advanced HER2-positive tumors, researchers are interested in testing other treatments that target the protein, such as trastuzumab deruxtecan (Enhertu), which is a type of drug called an antibody-drug conjugate, Dr. Strickler explained.

If these could be used after a recurrence to delay chemotherapy even further for these patients, “that could give them more options and better quality of life,” he said.