Mismatch repair phenotype determines the implications of tumor grade and CDX2 expression in stage II–III colon cancer

Abstract

Mismatch repair (MMR) deficiency is an indicator of good prognosis in localized colon cancer but also associated with lack of expression of caudal-type homeobox transcription factor 2 (CDX2) and high tumor grade; markers that in isolation indicate a poor prognosis. Our study aims to identify clinically relevant prognostic subgroups by combining information about tumor grade, MMR phenotype, and CDX2 expression. Immunohistochemistry for MMR proteins and CDX2 was performed in 544 patients with colon cancer stage II–III, including a cohort from a randomized trial. In patients with proficient MMR (pMMR) and CDX2 negativity, hazard ratio (HR) for cancer death was 2.93 (95% CI 1.23–6.99, p = 0.015). Cancer-specific survival for pMMR/CDX2-negative cases was 35.8 months (95% CI 23.4–48.3) versus 52.1–53.5 months (95% CI 45.6–58.6, p = 0.001) for the remaining cases (CDX2-positive tumors or deficient MMR (dMMR)/CDX2-negative tumors). In our randomized cohort, high tumor grade was predictive of response to adjuvant fluorouracil–levamisole in pMMR patients, with a significant interaction between tumor grade and treatment (p = 0.036). For pMMR patients, high tumor grade was a significant marker of poor prognosis in the surgery-only group (HR 4.60 (95% CI 1.68–12.61), p = 0.003) but not in the group receiving chemotherapy (HR 0.66 (95% CI 0.15–3.00), p = 0.587). To conclude, patients with pMMR and CDX2 negativity have a very poor prognosis. Patients with pMMR and high-graded tumors have a poor prognosis but respond well to adjuvant chemotherapy. CDX2 expression and tumor grade did not impact prognosis in patients with dMMR.

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Fig. 1: Immunohistochemical staining for CDX2.
Fig. 2: Euler diagram showing the overlap between number of patients with deficient mismatch repair, CDX2 negativity, and high tumor grade.
Fig. 3: Prognostic impact of CDX2 expression status illustrated by Kaplan–Meier curves for the whole study cohort stratified by mismatch repair (MMR) phenotype.
Fig. 4: Prognostic impact of tumor grade illustrated by Kaplan–Meier curves stratified by mismatch repair (MMR) phenotype.
Fig. 5: Predictive impact of tumor grade illustrated by separate Kaplan–Meier curves for patients randomized to surgery only versus adjuvant chemotherapy with fluorouracil–levamisole after surgery.

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Acknowledgements

We thank the Department of Pathology Ålesund for performing MMR protein staining, the Department of Pathology, Haukeland University Hospital for performing CDX2 staining and the Mohn Laboratory for Cancer Research for excellent facilities. We want to give a special acknowledgement to Ole Johnny Steffensen for invaluable technical support.

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Correspondence to Kjersti Elvestad Hestetun.

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Hestetun, K.E., Aasebø, K., Rosenlund, N.B. et al. Mismatch repair phenotype determines the implications of tumor grade and CDX2 expression in stage II–III colon cancer. Mod Pathol (2020). https://doi.org/10.1038/s41379-020-0634-9

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