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Lifestyle recommendations related to weight and physical activity may be relevant to cancer prevention for patients with Lynch syndrome, the most common hereditary cause of colorectal and endometrial cancers. 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.

The association between potentially modifiable lifestyle risk factors and the development of colorectal and endometrial cancers in Lynch syndrome has not been well characterized, noted Karen Cadoo, MB BCh BAO, of Trinity St James's Cancer Institute in Dublin, Ireland, and colleagues, They therefore conducted a systematic review and meta-analysis of additional modifiable and nonmodifiable risk factors, hoping to inform evidence-based lifestyle recommendations.

The following Q&A discusses the details of the analysis, which was published in . The authors were not available for comment, and the answers here are from the text of the report.

What does the study add to the literature?

Modifiable risk factors, including obesity, physical activity, alcohol intake, and smoking, are well established in sporadic cancers but are less studied in Lynch syndrome. We conducted a search 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 Lynch syndrome.

What are the highlights of the study specific to endometrial cancer?

We reviewed a total of 770 citations, and 18 studies were identified for qualitative synthesis. In three endometrial cancer cohort studies, female hormonal risk factors and type 2 diabetes mellitus were found to possibly affect the risk of endometrial cancer, but obesity was not associated with an increased risk.

Female hormonal factors, including age at menarche, age at menopause, parity, use of hormonal contraceptives, and hormonal replacement therapy, influence endometrial cancer risk. The most recent advise reducing excess body weight, increasing physical activity, and minimizing alcohol and tobacco consumption to reduce the risk of endometrial cancers.

What do studies on hormonal risk factors reveal?

Two retrospective cohort studies involving 1,264 individuals with Lynch syndrome investigated the relationship between female hormonal factors and the risk of endometrial cancer. A of 1,128 patients using the Colon Cancer Family Registry found that age at menarche over age 13 increased parity, and use of hormonal contraceptives was associated with a reduced risk of endometrial cancer. Notably, the protective association of hormonal contraceptive use is proportional to its duration, with an HR of 0.92 per year.

There was no statistically significant association between endometrial cancer and age at first and last live birth or age at menopause. The study also found no association with postmenopausal hormone therapy use, including subgroups that used estrogen-only preparations, and use lasting longer than 1 year.

A of 136 patients with Lynch syndrome found that duration of postmenopausal hormone use was associated with endometrial cancer in multivariable analysis (HR 1.07, 95% CI 1.02-1.13), but no association was found among other hormonal risk factors, including combined hormonal contraceptive use (HR 1.06, 95% CI 0.59-1.9).

What did you find about obesity as a risk factor in endometrial cancer in Lynch syndrome?

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.

Lynch syndrome–associated endometrial cancer is biologically distinct, in terms of both tumor histology and molecular subtype. 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. 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 obesity is a greater driver of malignancy in that context.

What about future research?

There is a paucity of research investigating risk factors for endometrial cancer among patients 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, and there is no established benefit of endometrial surveillance, determining whether these risk factors apply to the Lynch syndrome population would have a substantial public health benefit.

What is the main message for practicing oncologists?

This systematic review and meta-analysis demonstrate that public health lifestyle recommendations, with some caveats, apply to the Lynch syndrome population. Female hormonal risk factors and type 2 diabetes might confer an increased risk of endometrial cancer among individuals with Lynch syndrome, and obesity and lack of physical activity may be associated with an increased risk of colorectal cancer. These findings can inform adjunctive cancer prevention strategies.

Read the study here.