Model-based prediction of defective DNA mismatch repair using clinicopathological variables in sporadic colon cancer patients

Frank A Sinicrope, Nathan R. Foster, Daniel J. Sargent, Stephen N Thibodeau, Thomas Christopher Smyrk, Michael J. O'Connell

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Colon cancers with defective DNA mismatch repair (MMR) have a favorable prognosis and may lack benefit from 5-fluorouracil-based adjuvant chemotherapy. The authors developed models to predict MMR deficiency in sporadic colon cancer patients using routine clinical and pathological data. METHODS: TNM stage II and III colon carcinomas (n=982) from 6 5-fluorouracil-based adjuvant therapy trials were analyzed for microsatellite instability and/or MMR protein expression. Tumor-infiltrating lymphocytes (TILs) were quantified (n=326). Logistic regression and a recursive partitioning and amalgamation analysis were used to identify predictive factors for MMR status. RESULTS: Defective MMR was detected in 147 (15%) cancers. Tumor site and histologic grade were the most important predictors of MMR status. Distal tumors had a low likelihood of defective MMR (3%; 13 of 468); proximal tumors had a greater likelihood (26%; 130 of 506). By using tumor site, grade, and sex, the logistic regression model showed excellent discrimination (c statistic=0.81). Proximal site, female sex, and poor differentiation showed a positive predictive value (PPV) of 51% for defective MMR. In a patient subset (n=326), a model including proximal site, TILs (>2/ high-power field), and female sex showed even better discrimination (c statistic=0.86), with a PPV of 81%. CONCLUSIONS: Defective MMR is rare in distal, sporadic colon cancers, which should generally not undergo MMR testing. Proximal site, poor differentiation, and female sex detect 51% of tumors with defective MMR; substituting TILs for grade increases the PPV to 81%. These data can increase the efficiency of MMR testing to assist in clinical decisions.

Original languageEnglish (US)
Pages (from-to)1691-1698
Number of pages8
JournalCancer
Volume116
Issue number7
DOIs
StatePublished - Apr 1 2010

Fingerprint

DNA Mismatch Repair
Colonic Neoplasms
Tumor-Infiltrating Lymphocytes
Neoplasms
Sex Differentiation
Logistic Models
Fluorouracil
Microsatellite Instability
Adjuvant Chemotherapy
Colon
Carcinoma

Keywords

  • Colon cancer
  • DNA mismatch repair
  • Microsatellite instability
  • Sporadic
  • Tumor-infiltrating lymphocytes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Model-based prediction of defective DNA mismatch repair using clinicopathological variables in sporadic colon cancer patients. / Sinicrope, Frank A; Foster, Nathan R.; Sargent, Daniel J.; Thibodeau, Stephen N; Smyrk, Thomas Christopher; O'Connell, Michael J.

In: Cancer, Vol. 116, No. 7, 01.04.2010, p. 1691-1698.

Research output: Contribution to journalArticle

Sinicrope, Frank A ; Foster, Nathan R. ; Sargent, Daniel J. ; Thibodeau, Stephen N ; Smyrk, Thomas Christopher ; O'Connell, Michael J. / Model-based prediction of defective DNA mismatch repair using clinicopathological variables in sporadic colon cancer patients. In: Cancer. 2010 ; Vol. 116, No. 7. pp. 1691-1698.
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abstract = "BACKGROUND: Colon cancers with defective DNA mismatch repair (MMR) have a favorable prognosis and may lack benefit from 5-fluorouracil-based adjuvant chemotherapy. The authors developed models to predict MMR deficiency in sporadic colon cancer patients using routine clinical and pathological data. METHODS: TNM stage II and III colon carcinomas (n=982) from 6 5-fluorouracil-based adjuvant therapy trials were analyzed for microsatellite instability and/or MMR protein expression. Tumor-infiltrating lymphocytes (TILs) were quantified (n=326). Logistic regression and a recursive partitioning and amalgamation analysis were used to identify predictive factors for MMR status. RESULTS: Defective MMR was detected in 147 (15{\%}) cancers. Tumor site and histologic grade were the most important predictors of MMR status. Distal tumors had a low likelihood of defective MMR (3{\%}; 13 of 468); proximal tumors had a greater likelihood (26{\%}; 130 of 506). By using tumor site, grade, and sex, the logistic regression model showed excellent discrimination (c statistic=0.81). Proximal site, female sex, and poor differentiation showed a positive predictive value (PPV) of 51{\%} for defective MMR. In a patient subset (n=326), a model including proximal site, TILs (>2/ high-power field), and female sex showed even better discrimination (c statistic=0.86), with a PPV of 81{\%}. CONCLUSIONS: Defective MMR is rare in distal, sporadic colon cancers, which should generally not undergo MMR testing. Proximal site, poor differentiation, and female sex detect 51{\%} of tumors with defective MMR; substituting TILs for grade increases the PPV to 81{\%}. These data can increase the efficiency of MMR testing to assist in clinical decisions.",
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AU - Foster, Nathan R.

AU - Sargent, Daniel J.

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AU - Smyrk, Thomas Christopher

AU - O'Connell, Michael J.

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N2 - BACKGROUND: Colon cancers with defective DNA mismatch repair (MMR) have a favorable prognosis and may lack benefit from 5-fluorouracil-based adjuvant chemotherapy. The authors developed models to predict MMR deficiency in sporadic colon cancer patients using routine clinical and pathological data. METHODS: TNM stage II and III colon carcinomas (n=982) from 6 5-fluorouracil-based adjuvant therapy trials were analyzed for microsatellite instability and/or MMR protein expression. Tumor-infiltrating lymphocytes (TILs) were quantified (n=326). Logistic regression and a recursive partitioning and amalgamation analysis were used to identify predictive factors for MMR status. RESULTS: Defective MMR was detected in 147 (15%) cancers. Tumor site and histologic grade were the most important predictors of MMR status. Distal tumors had a low likelihood of defective MMR (3%; 13 of 468); proximal tumors had a greater likelihood (26%; 130 of 506). By using tumor site, grade, and sex, the logistic regression model showed excellent discrimination (c statistic=0.81). Proximal site, female sex, and poor differentiation showed a positive predictive value (PPV) of 51% for defective MMR. In a patient subset (n=326), a model including proximal site, TILs (>2/ high-power field), and female sex showed even better discrimination (c statistic=0.86), with a PPV of 81%. CONCLUSIONS: Defective MMR is rare in distal, sporadic colon cancers, which should generally not undergo MMR testing. Proximal site, poor differentiation, and female sex detect 51% of tumors with defective MMR; substituting TILs for grade increases the PPV to 81%. These data can increase the efficiency of MMR testing to assist in clinical decisions.

AB - BACKGROUND: Colon cancers with defective DNA mismatch repair (MMR) have a favorable prognosis and may lack benefit from 5-fluorouracil-based adjuvant chemotherapy. The authors developed models to predict MMR deficiency in sporadic colon cancer patients using routine clinical and pathological data. METHODS: TNM stage II and III colon carcinomas (n=982) from 6 5-fluorouracil-based adjuvant therapy trials were analyzed for microsatellite instability and/or MMR protein expression. Tumor-infiltrating lymphocytes (TILs) were quantified (n=326). Logistic regression and a recursive partitioning and amalgamation analysis were used to identify predictive factors for MMR status. RESULTS: Defective MMR was detected in 147 (15%) cancers. Tumor site and histologic grade were the most important predictors of MMR status. Distal tumors had a low likelihood of defective MMR (3%; 13 of 468); proximal tumors had a greater likelihood (26%; 130 of 506). By using tumor site, grade, and sex, the logistic regression model showed excellent discrimination (c statistic=0.81). Proximal site, female sex, and poor differentiation showed a positive predictive value (PPV) of 51% for defective MMR. In a patient subset (n=326), a model including proximal site, TILs (>2/ high-power field), and female sex showed even better discrimination (c statistic=0.86), with a PPV of 81%. CONCLUSIONS: Defective MMR is rare in distal, sporadic colon cancers, which should generally not undergo MMR testing. Proximal site, poor differentiation, and female sex detect 51% of tumors with defective MMR; substituting TILs for grade increases the PPV to 81%. These data can increase the efficiency of MMR testing to assist in clinical decisions.

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KW - Sporadic

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