From the Guidelines
Mismatch repair deficient (MMRd) colorectal cancers, which can be associated with Lynch syndrome and higher BMI, generally have an intermediate prognosis. When considering the management of MMRd colorectal cancers, it is essential to prioritize the patient's morbidity, mortality, and quality of life. According to the most recent evidence, the prognosis of MMRd colorectal cancers is intermediate compared to other molecular subtypes 1.
Key Considerations
- The incidence of rectal cancer in the European Union is significant, with 125,000 cases per year, and is predicted to increase further in both genders 1.
- High body mass index, body or abdominal fatness, and diabetes type II are seen as risk factors for rectal cancer, which may be relevant to the management of MMRd colorectal cancers 1.
- A healthy lifestyle and exercise can reduce the risk of developing rectal cancer, and consumption of garlic, milk, calcium, and high dietary fibre are regarded as protective 1.
- The majority of rectal cancers develop via the chromosomal instability (CIN) pathway, but about 13% are caused by deficient mismatch repair (dMMR), which is often associated with Lynch syndrome 1.
Management and Treatment
- Patients with MMRd tumors may benefit from immune checkpoint inhibitor therapy due to the high mutational burden and increased neoantigen production that makes these tumors more immunogenic.
- For patients with suspected Lynch syndrome, genetic counseling and testing of family members is recommended.
- Management typically includes surgical staging followed by adjuvant therapy based on stage and risk factors, with consideration of the molecular profile in treatment planning.
- Regular surveillance is important for early detection of other Lynch-associated cancers in these patients.
The most recent study on the sensitivity of metastatic colorectal cancer patients with deficient mismatch repair to standard-of-care chemotherapy and monoclonal antibodies provides valuable insights into the management of MMRd colorectal cancers 1.
From the Research
Mismatch Repair Deficient (MMRd) Tumors
- MMRd tumors can be associated with Lynch syndrome, which is an autosomal dominant inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes 2, 3.
- The frequency of MMRd in ovarian carcinoma is around 18% in endometrioid ovarian carcinoma (EOC) and 2% in clear cell carcinoma (CCC) 4.
- MMRd is also associated with increased tumor-infiltrating lymphocytes and younger age 4.
- The presence of somatic mutations in mismatch repair genes is another mechanism of MMRd in sporadic tumors 4.
Association with Lynch Syndrome
- Lynch syndrome is associated with a high risk of developing cancers of the colorectum and endometrium, among others 2, 3.
- The lifetime cumulative risk of endometrial cancer for women with Lynch syndrome is 40% to 60% 3.
- Universal screening of all newly diagnosed endometrial cancers is recommended to identify individuals with Lynch syndrome 2.
Clinical Implications
- Diagnosing endometrial cancer patients with Lynch syndrome has important clinical implications for the individual and family members 3.
- Screening and prevention practices can decrease the likelihood of developing additional cancers 3.
- The inability to determine the underlying cause of tumor MMR deficiency in "Lynch-like" or "suspected Lynch syndrome" cases has significant implications on the clinical management of these individuals and their relatives 5.