Smad4 loss in colorectal cancer patients correlates with recurrence, loss of immune infiltrate, and chemoresistance

Isaac Wasserman, Lik Hang Lee, Shuji Ogino, Michael R. Marco, Chao Wu, Xi Chen, Jashodeep Datta, Eran Sadot, Bryan Szeglin, Jose G. Guillem, Philip B. Paty, Martin R. Weiser, Garrett M. Nash, Leonard Saltz, Afsar Barlas, Katia Manova-Todorova, Srijaya Prakash Babu Uppada, Arthur E. Elghouayel, Peter Ntiamoah, Jonathan N. Glickman & 15 others Tsuyoshi Hamada, Keisuke Kosumi, Kentaro Inamura, Andrew T. Chan, Reiko Nishihara, Andrea Cercek, Karuna Ganesh, Nancy E. Kemeny, Punita Dhawan, Rona Yaeger, Charles L. Sawyers, Julio Garcia-Aguilar, Marios Giannakis, Jinru Shia, J. Joshua Smith

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Purpose: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death. Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. Results: The discovery cohort consisted of 364 patients with stage I–IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (inter-quartile range, 2.3–8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P ¼ 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P ¼ 0.002 and P ¼ 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. Conclusions: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.

Original languageEnglish (US)
Pages (from-to)1948-1956
Number of pages9
JournalClinical Cancer Research
Volume25
Issue number6
DOIs
StatePublished - Jan 1 2019

Fingerprint

Colorectal Neoplasms
Recurrence
Survival
Tumor-Infiltrating Lymphocytes
Neoplasms
Fluorouracil
Lymphocytes
Drug Therapy
Heterografts
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Smad4 loss in colorectal cancer patients correlates with recurrence, loss of immune infiltrate, and chemoresistance. / Wasserman, Isaac; Lee, Lik Hang; Ogino, Shuji; Marco, Michael R.; Wu, Chao; Chen, Xi; Datta, Jashodeep; Sadot, Eran; Szeglin, Bryan; Guillem, Jose G.; Paty, Philip B.; Weiser, Martin R.; Nash, Garrett M.; Saltz, Leonard; Barlas, Afsar; Manova-Todorova, Katia; Uppada, Srijaya Prakash Babu; Elghouayel, Arthur E.; Ntiamoah, Peter; Glickman, Jonathan N.; Hamada, Tsuyoshi; Kosumi, Keisuke; Inamura, Kentaro; Chan, Andrew T.; Nishihara, Reiko; Cercek, Andrea; Ganesh, Karuna; Kemeny, Nancy E.; Dhawan, Punita; Yaeger, Rona; Sawyers, Charles L.; Garcia-Aguilar, Julio; Giannakis, Marios; Shia, Jinru; Joshua Smith, J.

In: Clinical Cancer Research, Vol. 25, No. 6, 01.01.2019, p. 1948-1956.

Research output: Contribution to journalArticle

Wasserman, I, Lee, LH, Ogino, S, Marco, MR, Wu, C, Chen, X, Datta, J, Sadot, E, Szeglin, B, Guillem, JG, Paty, PB, Weiser, MR, Nash, GM, Saltz, L, Barlas, A, Manova-Todorova, K, Uppada, SPB, Elghouayel, AE, Ntiamoah, P, Glickman, JN, Hamada, T, Kosumi, K, Inamura, K, Chan, AT, Nishihara, R, Cercek, A, Ganesh, K, Kemeny, NE, Dhawan, P, Yaeger, R, Sawyers, CL, Garcia-Aguilar, J, Giannakis, M, Shia, J & Joshua Smith, J 2019, 'Smad4 loss in colorectal cancer patients correlates with recurrence, loss of immune infiltrate, and chemoresistance', Clinical Cancer Research, vol. 25, no. 6, pp. 1948-1956. https://doi.org/10.1158/1078-0432.CCR-18-1726
Wasserman, Isaac ; Lee, Lik Hang ; Ogino, Shuji ; Marco, Michael R. ; Wu, Chao ; Chen, Xi ; Datta, Jashodeep ; Sadot, Eran ; Szeglin, Bryan ; Guillem, Jose G. ; Paty, Philip B. ; Weiser, Martin R. ; Nash, Garrett M. ; Saltz, Leonard ; Barlas, Afsar ; Manova-Todorova, Katia ; Uppada, Srijaya Prakash Babu ; Elghouayel, Arthur E. ; Ntiamoah, Peter ; Glickman, Jonathan N. ; Hamada, Tsuyoshi ; Kosumi, Keisuke ; Inamura, Kentaro ; Chan, Andrew T. ; Nishihara, Reiko ; Cercek, Andrea ; Ganesh, Karuna ; Kemeny, Nancy E. ; Dhawan, Punita ; Yaeger, Rona ; Sawyers, Charles L. ; Garcia-Aguilar, Julio ; Giannakis, Marios ; Shia, Jinru ; Joshua Smith, J. / Smad4 loss in colorectal cancer patients correlates with recurrence, loss of immune infiltrate, and chemoresistance. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 6. pp. 1948-1956.
@article{aeee1a3fae9d4329854a487c680d6f8f,
title = "Smad4 loss in colorectal cancer patients correlates with recurrence, loss of immune infiltrate, and chemoresistance",
abstract = "Purpose: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death. Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. Results: The discovery cohort consisted of 364 patients with stage I–IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61{\%} left-sided tumors and 62{\%} stage II/III patients. Median follow-up was 5.4 years (inter-quartile range, 2.3–8.2). SMAD4 loss, noted in 13{\%} of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P ¼ 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P ¼ 0.002 and P ¼ 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. Conclusions: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.",
author = "Isaac Wasserman and Lee, {Lik Hang} and Shuji Ogino and Marco, {Michael R.} and Chao Wu and Xi Chen and Jashodeep Datta and Eran Sadot and Bryan Szeglin and Guillem, {Jose G.} and Paty, {Philip B.} and Weiser, {Martin R.} and Nash, {Garrett M.} and Leonard Saltz and Afsar Barlas and Katia Manova-Todorova and Uppada, {Srijaya Prakash Babu} and Elghouayel, {Arthur E.} and Peter Ntiamoah and Glickman, {Jonathan N.} and Tsuyoshi Hamada and Keisuke Kosumi and Kentaro Inamura and Chan, {Andrew T.} and Reiko Nishihara and Andrea Cercek and Karuna Ganesh and Kemeny, {Nancy E.} and Punita Dhawan and Rona Yaeger and Sawyers, {Charles L.} and Julio Garcia-Aguilar and Marios Giannakis and Jinru Shia and {Joshua Smith}, J.",
year = "2019",
month = "1",
day = "1",
doi = "10.1158/1078-0432.CCR-18-1726",
language = "English (US)",
volume = "25",
pages = "1948--1956",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - Smad4 loss in colorectal cancer patients correlates with recurrence, loss of immune infiltrate, and chemoresistance

AU - Wasserman, Isaac

AU - Lee, Lik Hang

AU - Ogino, Shuji

AU - Marco, Michael R.

AU - Wu, Chao

AU - Chen, Xi

AU - Datta, Jashodeep

AU - Sadot, Eran

AU - Szeglin, Bryan

AU - Guillem, Jose G.

AU - Paty, Philip B.

AU - Weiser, Martin R.

AU - Nash, Garrett M.

AU - Saltz, Leonard

AU - Barlas, Afsar

AU - Manova-Todorova, Katia

AU - Uppada, Srijaya Prakash Babu

AU - Elghouayel, Arthur E.

AU - Ntiamoah, Peter

AU - Glickman, Jonathan N.

AU - Hamada, Tsuyoshi

AU - Kosumi, Keisuke

AU - Inamura, Kentaro

AU - Chan, Andrew T.

AU - Nishihara, Reiko

AU - Cercek, Andrea

AU - Ganesh, Karuna

AU - Kemeny, Nancy E.

AU - Dhawan, Punita

AU - Yaeger, Rona

AU - Sawyers, Charles L.

AU - Garcia-Aguilar, Julio

AU - Giannakis, Marios

AU - Shia, Jinru

AU - Joshua Smith, J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death. Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. Results: The discovery cohort consisted of 364 patients with stage I–IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (inter-quartile range, 2.3–8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P ¼ 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P ¼ 0.002 and P ¼ 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. Conclusions: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.

AB - Purpose: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death. Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. Results: The discovery cohort consisted of 364 patients with stage I–IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (inter-quartile range, 2.3–8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P ¼ 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P ¼ 0.002 and P ¼ 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. Conclusions: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.

UR - http://www.scopus.com/inward/record.url?scp=85062971771&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062971771&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-1726

DO - 10.1158/1078-0432.CCR-18-1726

M3 - Article

VL - 25

SP - 1948

EP - 1956

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 6

ER -