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Clin Cancer Res. 2019 Mar 15;25(6):1948-1956. doi: 10.1158/1078-0432.CCR-18-1726. Epub 2018 Dec 26.

SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance.

Author information

1
Icahn School of Medicine at Mount Sinai, New York, New York.
2
Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
6
Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
7
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
8
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
9
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
10
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
11
Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida.
12
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
13
Albert Einstein College of Medicine, New York, New York.
14
Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
15
Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
16
Department of Biochemistry and Molecular Biology, Buffet Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
17
College of William and Mary, Williamsburg, Virginia.
18
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
19
Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
20
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
21
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
22
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
23
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
24
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
25
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
26
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
27
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
28
Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York. smithj5@mskcc.org.
#
Contributed equally

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 (interquartile 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 = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P = 0.002 and P = 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.

PMID:
30587545
PMCID:
PMC6421131
[Available on 2020-03-15]
DOI:
10.1158/1078-0432.CCR-18-1726

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