Mismatch repair phenotype determines the implications of tumor grade and CDX2 expression in stage II–III colon cancer
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 clinica...
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| Veröffentlicht in: | Modern pathology 2021-01, Vol.34 (1), p.161-170 |
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| creator | Hestetun, Kjersti Elvestad Aasebø, Kristine Rosenlund, Nina Benedikte Müller, Yvonne Dahl, Olav Myklebust, Mette Pernille |
| description | 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. |
| doi_str_mv | 10.1038/s41379-020-0634-9 |
| format | Article |
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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.</description><identifier>ISSN: 0893-3952</identifier><identifier>EISSN: 1530-0285</identifier><identifier>DOI: 10.1038/s41379-020-0634-9</identifier><identifier>PMID: 32737450</identifier><language>eng</language><publisher>New York: Elsevier Inc</publisher><subject>5-Fluorouracil ; 631/1647/664/1257 ; 631/337/1427/2121 ; 631/67/1504/1885/1393 ; 692/53/2422 ; 692/53/2423 ; 82 ; 82/51 ; Aged ; Biomarkers, Tumor - analysis ; CDX2 protein ; CDX2 Transcription Factor - analysis ; Chemotherapy ; Chemotherapy, Adjuvant ; Colectomy ; Colon cancer ; Colonic Neoplasms - chemistry ; Colonic Neoplasms - genetics ; Colonic Neoplasms - pathology ; Colonic Neoplasms - therapy ; Colorectal cancer ; DNA Mismatch Repair ; DNA Repair Enzymes - analysis ; Female ; Homeobox ; Humans ; Immunohistochemistry ; Laboratory Medicine ; Levamisole ; Male ; Medical prognosis ; Medicine ; Medicine & Public Health ; Middle Aged ; Mismatch repair ; Neoplasm Grading ; Neoplasm Staging ; Pathology ; Patients ; Phenotype ; Phenotypes ; Prognosis ; Randomized Controlled Trials as Topic ; Surgery ; Treatment Outcome ; Tumors</subject><ispartof>Modern pathology, 2021-01, Vol.34 (1), p.161-170</ispartof><rights>2020 United States & Canadian Academy of Pathology</rights><rights>The Author(s), under exclusive licence to United States & Canadian Academy of Pathology 2020</rights><rights>The Author(s), under exclusive licence to United States & Canadian Academy of Pathology 2020.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c467t-87ed5577e74d5c0aca8dd3b36c4501b3b73d15d696f3fbca280bf34337c2f0cc3</citedby><cites>FETCH-LOGICAL-c467t-87ed5577e74d5c0aca8dd3b36c4501b3b73d15d696f3fbca280bf34337c2f0cc3</cites><orcidid>0000-0001-7357-0440</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32737450$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hestetun, Kjersti Elvestad</creatorcontrib><creatorcontrib>Aasebø, Kristine</creatorcontrib><creatorcontrib>Rosenlund, Nina Benedikte</creatorcontrib><creatorcontrib>Müller, Yvonne</creatorcontrib><creatorcontrib>Dahl, Olav</creatorcontrib><creatorcontrib>Myklebust, Mette Pernille</creatorcontrib><title>Mismatch repair phenotype determines the implications of tumor grade and CDX2 expression in stage II–III colon cancer</title><title>Modern pathology</title><addtitle>Mod Pathol</addtitle><addtitle>Mod Pathol</addtitle><description>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.</description><subject>5-Fluorouracil</subject><subject>631/1647/664/1257</subject><subject>631/337/1427/2121</subject><subject>631/67/1504/1885/1393</subject><subject>692/53/2422</subject><subject>692/53/2423</subject><subject>82</subject><subject>82/51</subject><subject>Aged</subject><subject>Biomarkers, Tumor - analysis</subject><subject>CDX2 protein</subject><subject>CDX2 Transcription Factor - analysis</subject><subject>Chemotherapy</subject><subject>Chemotherapy, Adjuvant</subject><subject>Colectomy</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - chemistry</subject><subject>Colonic Neoplasms - genetics</subject><subject>Colonic Neoplasms - pathology</subject><subject>Colonic Neoplasms - therapy</subject><subject>Colorectal cancer</subject><subject>DNA Mismatch Repair</subject><subject>DNA Repair Enzymes - analysis</subject><subject>Female</subject><subject>Homeobox</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Laboratory Medicine</subject><subject>Levamisole</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Mismatch repair</subject><subject>Neoplasm Grading</subject><subject>Neoplasm Staging</subject><subject>Pathology</subject><subject>Patients</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Prognosis</subject><subject>Randomized Controlled Trials as Topic</subject><subject>Surgery</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><issn>0893-3952</issn><issn>1530-0285</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kb2O1DAUhS0EYoeBB6BBlmhoArZvEieiQsNfpEU0INFZjn0z41USB9tZ2I534A15ErzKAhLFVpbt75x7dQ4hjzl7zhk0L2LJQbYFE6xgNZRFe4fseAX5JprqLtmxpoUC2kqckQcxXjDGy6oR98kZCAmyrNiOfPvg4qSTOdGAi3aBLiecfbpakFpMGCY3Y6TphNRNy-iMTs7PkfqBpnXygR6Dtkj1bOnh9RdB8fsSMMbMUDfTmPQRadf9-vGz6zpq_JjfjZ4Nhofk3qDHiI9uzj35_PbNp8P74vzju-7w6rwwZS1T0Ui0VSUlytJWhmmjG2uhh9rk7XkPvQTLK1u39QBDb7RoWD9ACSCNGJgxsCfPNt8l-K8rxqQmFw2Oo57Rr1GJUrSyrssc2548_Q-98GuY83aZkjmwBmrIFN8oE3yMAQe1BDfpcKU4U9etqK0VlVtR162oNmue3Div_YT2r-JPDRkQGxDz13zE8G_0ba4vNxHm_C5dFkXjMIdrXUCTlPXuFvVvRRGsLA</recordid><startdate>202101</startdate><enddate>202101</enddate><creator>Hestetun, Kjersti Elvestad</creator><creator>Aasebø, Kristine</creator><creator>Rosenlund, Nina Benedikte</creator><creator>Müller, Yvonne</creator><creator>Dahl, Olav</creator><creator>Myklebust, Mette Pernille</creator><general>Elsevier Inc</general><general>Nature Publishing Group US</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7357-0440</orcidid></search><sort><creationdate>202101</creationdate><title>Mismatch repair phenotype determines the implications of tumor grade and CDX2 expression in stage II–III colon cancer</title><author>Hestetun, Kjersti Elvestad ; Aasebø, Kristine ; Rosenlund, Nina Benedikte ; Müller, Yvonne ; Dahl, Olav ; Myklebust, Mette Pernille</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c467t-87ed5577e74d5c0aca8dd3b36c4501b3b73d15d696f3fbca280bf34337c2f0cc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>5-Fluorouracil</topic><topic>631/1647/664/1257</topic><topic>631/337/1427/2121</topic><topic>631/67/1504/1885/1393</topic><topic>692/53/2422</topic><topic>692/53/2423</topic><topic>82</topic><topic>82/51</topic><topic>Aged</topic><topic>Biomarkers, Tumor - 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Academic</collection><jtitle>Modern pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hestetun, Kjersti Elvestad</au><au>Aasebø, Kristine</au><au>Rosenlund, Nina Benedikte</au><au>Müller, Yvonne</au><au>Dahl, Olav</au><au>Myklebust, Mette Pernille</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mismatch repair phenotype determines the implications of tumor grade and CDX2 expression in stage II–III colon cancer</atitle><jtitle>Modern pathology</jtitle><stitle>Mod Pathol</stitle><addtitle>Mod Pathol</addtitle><date>2021-01</date><risdate>2021</risdate><volume>34</volume><issue>1</issue><spage>161</spage><epage>170</epage><pages>161-170</pages><issn>0893-3952</issn><eissn>1530-0285</eissn><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.</abstract><cop>New York</cop><pub>Elsevier Inc</pub><pmid>32737450</pmid><doi>10.1038/s41379-020-0634-9</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-7357-0440</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 5-Fluorouracil 631/1647/664/1257 631/337/1427/2121 631/67/1504/1885/1393 692/53/2422 692/53/2423 82 82/51 Aged Biomarkers, Tumor - analysis CDX2 protein CDX2 Transcription Factor - analysis Chemotherapy Chemotherapy, Adjuvant Colectomy Colon cancer Colonic Neoplasms - chemistry Colonic Neoplasms - genetics Colonic Neoplasms - pathology Colonic Neoplasms - therapy Colorectal cancer DNA Mismatch Repair DNA Repair Enzymes - analysis Female Homeobox Humans Immunohistochemistry Laboratory Medicine Levamisole Male Medical prognosis Medicine Medicine & Public Health Middle Aged Mismatch repair Neoplasm Grading Neoplasm Staging Pathology Patients Phenotype Phenotypes Prognosis Randomized Controlled Trials as Topic Surgery Treatment Outcome Tumors |
| title | Mismatch repair phenotype determines the implications of tumor grade and CDX2 expression in stage II–III colon cancer |
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