What is the prognosis of mismatch repair deficient endometrial cancer associated with Lynch syndrome and higher Body Mass Index (BMI)?

From the Guidelines

Mismatch repair deficient (dMMR) endometrial cancer is indeed associated with Lynch syndrome and higher BMI, typically carrying an intermediate prognosis. Lynch syndrome is an inherited condition caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2), predisposing patients to various cancers including endometrial cancer, as noted in the guidelines for genetic/familial high-risk assessment 1. When endometrial cancer develops in these patients, it often shows mismatch repair deficiency, characterized by microsatellite instability (MSI) and loss of MMR protein expression on immunohistochemistry. Some key points to consider in the management of these patients include:

• Screening for genetic mutations, such as Lynch syndrome, should be considered in all patients with endometrial cancer, especially those younger than 50 years or with a significant family history of endometrial and/or colorectal cancer, as recommended in the guidelines for uterine neoplasms 1.
• Universal testing of endometrial tumors for defects in DNA mismatch repair is recommended, with further evaluation for promoter methylation in cases of MLH1 loss to assess for an epigenetic process rather than a germline mutation, as outlined in the 2018 guidelines for uterine neoplasms 1.
• Women with Lynch syndrome are at a higher lifetime risk for endometrial cancer, and close monitoring and discussion of risk-reducing strategies, such as yearly endometrial biopsy or prophylactic hysterectomy/bilateral salpingo-oophorectomy, are recommended, as discussed in the guidelines for genetic/familial high-risk assessment 1 and uterine neoplasms 1. Additionally, dMMR endometrial cancer is frequently seen in patients with higher BMI, as obesity is an independent risk factor for endometrial cancer through increased estrogen production in adipose tissue. Regarding prognosis, dMMR endometrial cancers generally have an intermediate outlook - better than some aggressive subtypes like serous carcinoma but not as favorable as low-grade endometrioid tumors with intact MMR. These tumors often respond well to immunotherapy due to their high mutational burden and neoantigen production, with pembrolizumab being approved for dMMR solid tumors. Patients with suspected Lynch syndrome should undergo genetic counseling and testing, and their first-degree relatives should be considered for screening, as recommended in the guidelines for genetic/familial high-risk assessment 1 and uterine neoplasms 1.

From the Research

Mismatch Repair Deficient Endometrial Cancer

• Mismatch repair deficient endometrial cancer can be associated with Lynch syndrome, which is an autosomal dominant familial cancer risk syndrome that occurs due to a germline mutation in one of several mismatch repair genes 2.
• The risk of endometrial cancer equals or exceeds that of colorectal cancer in women with Lynch syndrome, and the diagnosis of gynecologic cancer precedes that of colorectal cancer in over half of women with metachronous gynecologic and colon cancers 2.
• Studies have shown that Lynch syndrome-associated endometrial cancer has a distinct immunological profile compared to sporadic mismatch repair deficient endometrial cancer, with higher infiltrations of immune cells such as CD3+, CD8+, CD45RO+, FoxP3+, and PD1+ 3.
• The prognosis of Lynch syndrome-associated endometrial cancer is generally better than that of sporadic mismatch repair deficient endometrial cancer, with a 5-year recurrence-free survival rate of 91.7% compared to 78.6% for MLH1-hypermethylated mismatch repair deficient endometrial cancer 4.

Association with Higher BMI and Intermediate Prognosis

• There is limited evidence directly linking higher BMI to the prognosis of mismatch repair deficient endometrial cancer.
• However, studies have shown that Lynch syndrome-associated endometrial cancer has a trend towards better recurrence-free survival compared to sporadic mismatch repair deficient endometrial cancer, but the impact of BMI on this prognosis is not well established 4.
• Further research is needed to determine the relationship between BMI and the prognosis of mismatch repair deficient endometrial cancer, particularly in the context of Lynch syndrome.

Immunological Differences and Prognostic Implications

• The immunological differences between Lynch syndrome-associated and sporadic mismatch repair deficient endometrial cancer have important implications for treatment and prognosis 3.
• Predictive modeling can accurately determine mismatch repair status based on CD8+ T-cell counts within the tumor center alone, which may have implications for personalized treatment approaches 3.
• The distinct immunological profile of Lynch syndrome-associated endometrial cancer may also have implications for the development of targeted therapies and immunotherapies 3.