DNA Mismatch Repair-deficient Rectal Cancer Is Frequently Associated With Lynch Syndrome and With Poor Response to...

Area of Science:

• Oncology
• Gastroenterology
• Genetics

Background:

• Neoadjuvant therapy is standard for rectal cancer.
• DNA mismatch repair (MMR) deficiency impacts treatment response.
• Lynch syndrome is a common cause of MMR deficiency.

Purpose of the Study:

• To evaluate the impact of MMR protein status on neoadjuvant therapy response in rectal cancer.
• To investigate the association between MMR deficiency and histopathologic features, downstaging, and patient survival.
• To confirm the link between MMR-deficient rectal cancer and Lynch syndrome.

Main Methods:

• Analysis of 368 rectal cancer resections post-neoadjuvant therapy.
• Assessment of MMR protein status, tumor regression, histopathology, and survival data.
• Multivariable logistic and Cox regression analyses to identify predictors of response and survival.

Main Results:

• Only 2.4% of rectal cancers were MMR-deficient (MMRD), predominantly Lynch syndrome-associated.
• MMRD tumors showed significantly poorer response (89% vs. 23%) and less downstaging (11% vs. 57%) compared to MMR-proficient tumors.
• MMRD was an independent predictor of poor response (OR 25.11, P=0.003).

Conclusions:

• MMR deficiency in rectal cancer independently predicts poor response to neoadjuvant therapy and limited downstaging.
• MMRD rectal cancers are strongly associated with Lynch syndrome.
• MMR status can guide personalized neoadjuvant treatment strategies and predict tumor response.