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Mismatch Repair-Deficient Rectal Cancer and Resistance to Neoadjuvant Chemotherapy.

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Mismatch repair-deficient (dMMR) rectal tumors show resistance to neoadjuvant chemotherapy, with over a fourth progressing. However, these dMMR tumors respond well to chemoradiation, suggesting MMR status is crucial for treatment decisions.

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Area of Science:

  • Oncology
  • Gastroenterology
  • Genetics

Background:

  • Mismatch repair deficiency (dMMR) is a key biomarker in various cancers.
  • Rectal cancer treatment response can vary significantly based on molecular characteristics.
  • Understanding dMMR status in rectal cancer is crucial for optimizing therapeutic strategies.

Purpose of the Study:

  • To evaluate the response of mismatch repair-deficient (dMMR) rectal cancer to neoadjuvant chemotherapy.
  • To compare treatment outcomes of dMMR rectal tumors with proficient MMR (pMMR) counterparts.
  • To investigate potential genomic predictors and Lynch syndrome associations in dMMR rectal cancer.

Main Methods:

  • Retrospective review of 50 dMMR rectal tumors identified by IHC and/or MSI analysis.
  • Comparison of treatment response with a matched cohort of pMMR rectal tumors.
  • Germline and somatic mutation analyses, and assessment of patient-derived dMMR tumoroids for chemotherapy sensitivity.

Main Results:

  • 29% of dMMR rectal tumors treated with neoadjuvant chemotherapy (fluorouracil/oxaliplatin) progressed, compared to 0% in pMMR tumors (P=0.0001).
  • dMMR rectal tumors showed sensitivity to chemoradiation (93% downstaging) and surgery (92% early-stage disease).
  • 84% of dMMR patients tested positive for Lynch syndrome, with enriched MSH2/MSH6 germline mutations.

Conclusions:

  • Mismatch repair-deficient rectal tumors exhibit resistance to neoadjuvant chemotherapy but sensitivity to chemoradiation.
  • MMR status testing should be performed upfront for locally advanced rectal tumors.
  • Genetic testing for Lynch syndrome is recommended for patients with dMMR rectal cancer.