CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer

Stacey Shiovitz; Monica M. Bertagnolli; Lindsay A. Renfro; Eunmi Nam; Nathan R. Foster; Slavomir Dzieciatkowski; Yanxin Luo; Victoria Valinluck Lao; Raymond J. Monnat; Mary J. Emond; Nancy Maizels; Donna Niedzwiecki; Richard M. Goldberg; Leonard B. Saltz; Alan Venook; Robert S. Warren; William M. Grady

doi:10.1053/j.gastro.2014.05.009

CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer

Stacey Shiovitz, Monica M. Bertagnolli, Lindsay A. Renfro, Eunmi Nam, Nathan R. Foster, Slavomir Dzieciatkowski, Yanxin Luo, Victoria Valinluck Lao, Raymond J. Monnat, Mary J. Emond, Nancy Maizels, Donna Niedzwiecki, Richard M. Goldberg, Leonard B. Saltz, Alan Venook, Robert S. Warren, William M. Grady

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

111 Scopus citations

Abstract

Background & Aims The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL). Methods We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated. Results Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P =.07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P =.049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P =.01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses. Conclusions Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

Original language	English
Pages (from-to)	637-645
Number of pages	9
Journal	Gastroenterology
Volume	147
Issue number	3
DOIs	https://doi.org/10.1053/j.gastro.2014.05.009
State	Published - Sep 2014

Bibliographical note

Funding Information:
Funding The research reported in this article was supported by National Institutes of Health (NIH) National Cancer Institute (NCI) Program award P01CA77852 (RJM); NIH awards 5T32-CA009515-28/29 (SS), RO1CA115513, P30CA15704, UO1CA152756, U54CA143862, and P01CA077852 (WMG); Burroughs Wellcome Fund Translational Research Award for Clinician Scientist (WMG); ACS fellowship PF-11-086-01-TBG, NIH 2T32DK007742-16, ASCRS GSRRIG, and NIH NCI F32CA1591555-01 (VVL); CA32291 (MMB); CA77658 (RMG); CA77651 (LBS); CA60138 (AV, RSW). CALGB 89803 (Alliance) was supported partly by grants from the NCI (CA31946) to the Alliance for Clinical Trials in Oncology (MMB, Chair) and to the Alliance Statistics and Data Center (Daniel J. Sargent, PhD, CA33601) (LAR, NRF, DN). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Keywords

CALGB (Alliance) 89803
CRC
Chemotherapy
Epigenetic Factors

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10.1053/j.gastro.2014.05.009

Cite this

Shiovitz, S., Bertagnolli, M. M., Renfro, L. A., Nam, E., Foster, N. R., Dzieciatkowski, S., Luo, Y., Lao, V. V., Monnat, R. J., Emond, M. J., Maizels, N., Niedzwiecki, D., Goldberg, R. M., Saltz, L. B., Venook, A., Warren, R. S., & Grady, W. M. (2014). CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer. Gastroenterology, 147(3), 637-645. https://doi.org/10.1053/j.gastro.2014.05.009

@article{229fa8e08d3b457d838b04cd3fd5b756,

title = "CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer",

abstract = "Background & Aims The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL). Methods We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated. Results Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P =.07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P =.049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P =.01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses. Conclusions Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.",

keywords = "CALGB (Alliance) 89803, CRC, Chemotherapy, Epigenetic Factors",

author = "Stacey Shiovitz and Bertagnolli, {Monica M.} and Renfro, {Lindsay A.} and Eunmi Nam and Foster, {Nathan R.} and Slavomir Dzieciatkowski and Yanxin Luo and Lao, {Victoria Valinluck} and Monnat, {Raymond J.} and Emond, {Mary J.} and Nancy Maizels and Donna Niedzwiecki and Goldberg, {Richard M.} and Saltz, {Leonard B.} and Alan Venook and Warren, {Robert S.} and Grady, {William M.}",

note = "Funding Information: Funding The research reported in this article was supported by National Institutes of Health (NIH) National Cancer Institute (NCI) Program award P01CA77852 (RJM); NIH awards 5T32-CA009515-28/29 (SS), RO1CA115513, P30CA15704, UO1CA152756, U54CA143862, and P01CA077852 (WMG); Burroughs Wellcome Fund Translational Research Award for Clinician Scientist (WMG); ACS fellowship PF-11-086-01-TBG, NIH 2T32DK007742-16, ASCRS GSRRIG, and NIH NCI F32CA1591555-01 (VVL); CA32291 (MMB); CA77658 (RMG); CA77651 (LBS); CA60138 (AV, RSW). CALGB 89803 (Alliance) was supported partly by grants from the NCI (CA31946) to the Alliance for Clinical Trials in Oncology (MMB, Chair) and to the Alliance Statistics and Data Center (Daniel J. Sargent, PhD, CA33601) (LAR, NRF, DN). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. ",

year = "2014",

month = sep,

doi = "10.1053/j.gastro.2014.05.009",

language = "English",

volume = "147",

pages = "637--645",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "3",

}

Shiovitz, S, Bertagnolli, MM, Renfro, LA, Nam, E, Foster, NR, Dzieciatkowski, S, Luo, Y, Lao, VV, Monnat, RJ, Emond, MJ, Maizels, N, Niedzwiecki, D, Goldberg, RM, Saltz, LB, Venook, A, Warren, RS & Grady, WM 2014, 'CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer', Gastroenterology, vol. 147, no. 3, pp. 637-645. https://doi.org/10.1053/j.gastro.2014.05.009

TY - JOUR

T1 - CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer

AU - Shiovitz, Stacey

AU - Bertagnolli, Monica M.

AU - Renfro, Lindsay A.

AU - Nam, Eunmi

AU - Foster, Nathan R.

AU - Dzieciatkowski, Slavomir

AU - Luo, Yanxin

AU - Lao, Victoria Valinluck

AU - Monnat, Raymond J.

AU - Emond, Mary J.

AU - Maizels, Nancy

AU - Niedzwiecki, Donna

AU - Goldberg, Richard M.

AU - Saltz, Leonard B.

AU - Venook, Alan

AU - Warren, Robert S.

AU - Grady, William M.

N1 - Funding Information: Funding The research reported in this article was supported by National Institutes of Health (NIH) National Cancer Institute (NCI) Program award P01CA77852 (RJM); NIH awards 5T32-CA009515-28/29 (SS), RO1CA115513, P30CA15704, UO1CA152756, U54CA143862, and P01CA077852 (WMG); Burroughs Wellcome Fund Translational Research Award for Clinician Scientist (WMG); ACS fellowship PF-11-086-01-TBG, NIH 2T32DK007742-16, ASCRS GSRRIG, and NIH NCI F32CA1591555-01 (VVL); CA32291 (MMB); CA77658 (RMG); CA77651 (LBS); CA60138 (AV, RSW). CALGB 89803 (Alliance) was supported partly by grants from the NCI (CA31946) to the Alliance for Clinical Trials in Oncology (MMB, Chair) and to the Alliance Statistics and Data Center (Daniel J. Sargent, PhD, CA33601) (LAR, NRF, DN). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

PY - 2014/9

Y1 - 2014/9

N2 - Background & Aims The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL). Methods We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated. Results Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P =.07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P =.049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P =.01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses. Conclusions Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

AB - Background & Aims The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL). Methods We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated. Results Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P =.07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P =.049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P =.01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses. Conclusions Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

KW - CALGB (Alliance) 89803

KW - CRC

KW - Chemotherapy

KW - Epigenetic Factors

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U2 - 10.1053/j.gastro.2014.05.009

DO - 10.1053/j.gastro.2014.05.009

M3 - Article

C2 - 24859205

AN - SCOPUS:84906935203

SN - 0016-5085

VL - 147

SP - 637

EP - 645

JO - Gastroenterology

JF - Gastroenterology

IS - 3

ER -

CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer

Abstract

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