Molecular testing for lymph node metastases as a determinant of colon cancer recurrence: Results from a retrospective multicenter study

Daniel J. Sargent, Qian D Shi, Sharlene Gill, Christophe Louvet, Richard B. Everson, Udo Kellner, Thomas E. Clancy, J. Marc Pipas, Murray B. Resnick, Michael O. Meyers, Tsung Teh Wu, David Huntsman, Pierre Validire, Umar Farooq, Emily S. Pavey, Guillaume Beaudry, Jean Francois Haince, Yves Fradet

Research output: Contribution to journalArticle

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Abstract

Purpose: Recurrence risk assessment to make treatment decisions for early-stage colon cancer patients is a major unmet medical need. The aim of this retrospective multicenter study was to evaluate the clinical utility of guanylyl cyclase C (GCC) mRNA levels in lymph nodes on colon cancer recurrence. Methods: The proportion of lymph nodes with GCC-positive mRNA (LNR) was evaluated in 463 untreated T3N0 patients, blinded to clinical outcomes. One site's (n = 97) tissue grossing method precluded appropriate lymph node assessment resulting in post hoc exclusion. Cox regression models tested the relationship between GCC and the primary endpoint of time to recurrence. Assay methods, primary analyses, and cut points were all prespecified. Results: Final dataset contained 366 patients, 38 (10%) of whom had recurrence. Presence of four or more GCC-positive lymph nodes was significantly associated with risk of recurrence [hazard ratio (HR) = 2.46, 95% confidence interval (CI), 1.07-5.69, P = 0.035], whereas binary GCC LNR risk class (HR = 1.87, 95%CI, 0.99-3.54, P = 0.054) and mismatch repair (MMR) status (HR = 0.77,95% CI, 0.36-1.62, P = 0.49) were not. In a secondary analysis using a 3-level GCC LNR risk group classification of high (LNR > 0.20), intermediate (0.10 < LNR ≤ 0.20), and low (LNR ≤ 0.10), high-risk patients had a 2.5 times higher recurrence risk compared with low-risk patients (HR = 2.53, 95% CI, 1.24-5.17, P = 0.011). Conclusions: GCC status is a promising prognostic factor independent of traditional histopathology risk factors in a contemporary population of patients with stage IIa colon cancer not treated with adjuvant therapy, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique.

Original languageEnglish (US)
Pages (from-to)4361-4369
Number of pages9
JournalClinical Cancer Research
Volume20
Issue number16
DOIs
StatePublished - Aug 15 2014

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Colonic Neoplasms
Multicenter Studies
Retrospective Studies
Lymph Nodes
Neoplasm Metastasis
Recurrence
Confidence Intervals
Tissue Fixation
Messenger RNA
DNA Mismatch Repair
Tissue and Organ Procurement
enterotoxin receptor
Proportional Hazards Models
Therapeutics
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Molecular testing for lymph node metastases as a determinant of colon cancer recurrence : Results from a retrospective multicenter study. / Sargent, Daniel J.; Shi, Qian D; Gill, Sharlene; Louvet, Christophe; Everson, Richard B.; Kellner, Udo; Clancy, Thomas E.; Pipas, J. Marc; Resnick, Murray B.; Meyers, Michael O.; Wu, Tsung Teh; Huntsman, David; Validire, Pierre; Farooq, Umar; Pavey, Emily S.; Beaudry, Guillaume; Haince, Jean Francois; Fradet, Yves.

In: Clinical Cancer Research, Vol. 20, No. 16, 15.08.2014, p. 4361-4369.

Research output: Contribution to journalArticle

Sargent, DJ, Shi, QD, Gill, S, Louvet, C, Everson, RB, Kellner, U, Clancy, TE, Pipas, JM, Resnick, MB, Meyers, MO, Wu, TT, Huntsman, D, Validire, P, Farooq, U, Pavey, ES, Beaudry, G, Haince, JF & Fradet, Y 2014, 'Molecular testing for lymph node metastases as a determinant of colon cancer recurrence: Results from a retrospective multicenter study', Clinical Cancer Research, vol. 20, no. 16, pp. 4361-4369. https://doi.org/10.1158/1078-0432.CCR-13-2659
Sargent, Daniel J. ; Shi, Qian D ; Gill, Sharlene ; Louvet, Christophe ; Everson, Richard B. ; Kellner, Udo ; Clancy, Thomas E. ; Pipas, J. Marc ; Resnick, Murray B. ; Meyers, Michael O. ; Wu, Tsung Teh ; Huntsman, David ; Validire, Pierre ; Farooq, Umar ; Pavey, Emily S. ; Beaudry, Guillaume ; Haince, Jean Francois ; Fradet, Yves. / Molecular testing for lymph node metastases as a determinant of colon cancer recurrence : Results from a retrospective multicenter study. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 16. pp. 4361-4369.
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abstract = "Purpose: Recurrence risk assessment to make treatment decisions for early-stage colon cancer patients is a major unmet medical need. The aim of this retrospective multicenter study was to evaluate the clinical utility of guanylyl cyclase C (GCC) mRNA levels in lymph nodes on colon cancer recurrence. Methods: The proportion of lymph nodes with GCC-positive mRNA (LNR) was evaluated in 463 untreated T3N0 patients, blinded to clinical outcomes. One site's (n = 97) tissue grossing method precluded appropriate lymph node assessment resulting in post hoc exclusion. Cox regression models tested the relationship between GCC and the primary endpoint of time to recurrence. Assay methods, primary analyses, and cut points were all prespecified. Results: Final dataset contained 366 patients, 38 (10{\%}) of whom had recurrence. Presence of four or more GCC-positive lymph nodes was significantly associated with risk of recurrence [hazard ratio (HR) = 2.46, 95{\%} confidence interval (CI), 1.07-5.69, P = 0.035], whereas binary GCC LNR risk class (HR = 1.87, 95{\%}CI, 0.99-3.54, P = 0.054) and mismatch repair (MMR) status (HR = 0.77,95{\%} CI, 0.36-1.62, P = 0.49) were not. In a secondary analysis using a 3-level GCC LNR risk group classification of high (LNR > 0.20), intermediate (0.10 < LNR ≤ 0.20), and low (LNR ≤ 0.10), high-risk patients had a 2.5 times higher recurrence risk compared with low-risk patients (HR = 2.53, 95{\%} CI, 1.24-5.17, P = 0.011). Conclusions: GCC status is a promising prognostic factor independent of traditional histopathology risk factors in a contemporary population of patients with stage IIa colon cancer not treated with adjuvant therapy, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique.",
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T1 - Molecular testing for lymph node metastases as a determinant of colon cancer recurrence

T2 - Results from a retrospective multicenter study

AU - Sargent, Daniel J.

AU - Shi, Qian D

AU - Gill, Sharlene

AU - Louvet, Christophe

AU - Everson, Richard B.

AU - Kellner, Udo

AU - Clancy, Thomas E.

AU - Pipas, J. Marc

AU - Resnick, Murray B.

AU - Meyers, Michael O.

AU - Wu, Tsung Teh

AU - Huntsman, David

AU - Validire, Pierre

AU - Farooq, Umar

AU - Pavey, Emily S.

AU - Beaudry, Guillaume

AU - Haince, Jean Francois

AU - Fradet, Yves

PY - 2014/8/15

Y1 - 2014/8/15

N2 - Purpose: Recurrence risk assessment to make treatment decisions for early-stage colon cancer patients is a major unmet medical need. The aim of this retrospective multicenter study was to evaluate the clinical utility of guanylyl cyclase C (GCC) mRNA levels in lymph nodes on colon cancer recurrence. Methods: The proportion of lymph nodes with GCC-positive mRNA (LNR) was evaluated in 463 untreated T3N0 patients, blinded to clinical outcomes. One site's (n = 97) tissue grossing method precluded appropriate lymph node assessment resulting in post hoc exclusion. Cox regression models tested the relationship between GCC and the primary endpoint of time to recurrence. Assay methods, primary analyses, and cut points were all prespecified. Results: Final dataset contained 366 patients, 38 (10%) of whom had recurrence. Presence of four or more GCC-positive lymph nodes was significantly associated with risk of recurrence [hazard ratio (HR) = 2.46, 95% confidence interval (CI), 1.07-5.69, P = 0.035], whereas binary GCC LNR risk class (HR = 1.87, 95%CI, 0.99-3.54, P = 0.054) and mismatch repair (MMR) status (HR = 0.77,95% CI, 0.36-1.62, P = 0.49) were not. In a secondary analysis using a 3-level GCC LNR risk group classification of high (LNR > 0.20), intermediate (0.10 < LNR ≤ 0.20), and low (LNR ≤ 0.10), high-risk patients had a 2.5 times higher recurrence risk compared with low-risk patients (HR = 2.53, 95% CI, 1.24-5.17, P = 0.011). Conclusions: GCC status is a promising prognostic factor independent of traditional histopathology risk factors in a contemporary population of patients with stage IIa colon cancer not treated with adjuvant therapy, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique.

AB - Purpose: Recurrence risk assessment to make treatment decisions for early-stage colon cancer patients is a major unmet medical need. The aim of this retrospective multicenter study was to evaluate the clinical utility of guanylyl cyclase C (GCC) mRNA levels in lymph nodes on colon cancer recurrence. Methods: The proportion of lymph nodes with GCC-positive mRNA (LNR) was evaluated in 463 untreated T3N0 patients, blinded to clinical outcomes. One site's (n = 97) tissue grossing method precluded appropriate lymph node assessment resulting in post hoc exclusion. Cox regression models tested the relationship between GCC and the primary endpoint of time to recurrence. Assay methods, primary analyses, and cut points were all prespecified. Results: Final dataset contained 366 patients, 38 (10%) of whom had recurrence. Presence of four or more GCC-positive lymph nodes was significantly associated with risk of recurrence [hazard ratio (HR) = 2.46, 95% confidence interval (CI), 1.07-5.69, P = 0.035], whereas binary GCC LNR risk class (HR = 1.87, 95%CI, 0.99-3.54, P = 0.054) and mismatch repair (MMR) status (HR = 0.77,95% CI, 0.36-1.62, P = 0.49) were not. In a secondary analysis using a 3-level GCC LNR risk group classification of high (LNR > 0.20), intermediate (0.10 < LNR ≤ 0.20), and low (LNR ≤ 0.10), high-risk patients had a 2.5 times higher recurrence risk compared with low-risk patients (HR = 2.53, 95% CI, 1.24-5.17, P = 0.011). Conclusions: GCC status is a promising prognostic factor independent of traditional histopathology risk factors in a contemporary population of patients with stage IIa colon cancer not treated with adjuvant therapy, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique.

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