University of Oulu

Kenji Fujiyoshi, MD, PhD, Yang Chen, MD, PhD, Koichiro Haruki, MD, PhD, Tomotaka Ugai, MD, PhD, Junko Kishikawa, MD, PhD, Tsuyoshi Hamada, MD, PhD, Li Liu, MD, PhD, Kota Arima, MD, PhD, Jennifer Borowsky, MBChB, Juha P Väyrynen, MD, PhD, Melissa Zhao, MD, Mai Chan Lau, PhD, Simeng Gu, MB, Shanshan Shi, PhD, Naohiko Akimoto, MD, PhD, Tyler S Twombly, BS, David A Drew, PhD, Mingyang Song, MD, ScD, Andrew T Chan, MD, MPH, Edward L Giovannucci, MD, ScD, Jeffrey A Meyerhardt, MD, MPH, Charles S Fuchs, MD, MPH, Reiko Nishihara, PhD, Jochen K Lennerz, MD, PhD, Marios Giannakis, MD, PhD, Jonathan A Nowak, MD, PhD, Xuehong Zhang, MD, ScD, Kana Wu, MD, PhD, Shuji Ogino, MD, PhD, MS, Smoking Status at Diagnosis and Colorectal Cancer Prognosis According to Tumor Lymphocytic Reaction, JNCI Cancer Spectrum, Volume 4, Issue 5, October 2020, pkaa040,

Smoking status at diagnosis and colorectal cancer prognosis according to tumor lymphocytic reaction

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Author: Fujiyoshi, Kenji1,2,3; Chen, Yang1,2; Haruki, Koichiro1,2;
Organizations: 1Brigham & Womens Hosp, Dept Pathol, Program MPE Mol Pathol Epidemiol, 221 Longwood Ave,EBRC Room 404A, Boston, MA 02115 USA.
2Harvard Med Sch, 221 Longwood Ave,EBRC Room 404A, Boston, MA 02115 USA.
3Kurume Univ, Dept Surg, Kurume, Fukuoka, Japan.
4Oulu Univ Hosp, Med Res Ctr Oulu, Canc & Translat Med Res Unit, Oulu, Finland.
5Univ Oulu, Oulu, Finland.
6Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
7Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Boston, MA 02114 USA.
8Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA.
9Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.
10Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.
11Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA.
12Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
13Yale Canc Ctr, New Haven, CT USA.
14Yale Sch Med, Dept Med, New Haven, CT USA.
15Smilow Canc Hosp, New Haven, CT USA.
16Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA.
17Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.
18Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
19Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.
20Dana Farber Harvard Canc Ctr, Canc Immunol & Canc Epidemiol Programs, Boston, MA USA.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.3 MB)
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Language: English
Published: Oxford University Press, 2020
Publish Date: 2021-03-10


Background: Smoking has been associated with worse colorectal cancer patient survival and may potentially suppress the immune response in the tumor microenvironment. We hypothesized that the prognostic association of smoking behavior at colorectal cancer diagnosis might differ by lymphocytic reaction patterns in cancer tissue.

Methods: Using 1474 colon and rectal cancer patients within 2 large prospective cohort studies (Nurses’ Health Study and Health Professionals Follow-up Study), we characterized 4 patterns of histopathologic lymphocytic reaction, including tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral lymphocytic reaction, and Crohn’s-like lymphoid reaction. Using covariate data of 4420 incident colorectal cancer patients in total, an inverse probability weighted multivariable Cox proportional hazards regression model was conducted to adjust for selection bias due to tissue availability and potential confounders, including tumor differentiation, disease stage, microsatellite instability status, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations.

Results: The prognostic association of smoking status at diagnosis differed by TIL status. Compared with never smokers, the multivariable-adjusted colorectal cancer–specific mortality hazard ratio for current smokers was 1.50 (95% confidence interval = 1.10 to 2.06) in tumors with negative or low TIL and 0.43 (95% confidence interval = 0.16 to 1.12) in tumors with intermediate or high TIL (2-sided Pinteraction = 0.009). No statistically significant interactions were observed in the other patterns of lymphocytic reaction.

Conclusions: The association of smoking status at diagnosis with colorectal cancer mortality may be stronger for carcinomas with negative or low TIL, suggesting a potential interplay of smoking and lymphocytic reaction in the colorectal cancer microenvironment.

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Series: JNCI cancer spectrum
ISSN: 2515-5091
ISSN-E: 2515-5091
ISSN-L: 2515-5091
Volume: 4
Issue: 5
Article number: pkaa040
DOI: 10.1093/jncics/pkaa040
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This work was supported by US National Institutes of Health (NIH) grants (P01 CA87969; UM1 CA186107; P01 CA55075; UM1 CA167552; U01 CA167552; P50 CA127003 to C.S.F.; R01 CA118553 to C.S.F.; R01 CA169141 to C.S.F.; R01 CA137178 to A.T.C.; K24 DK098311 to A.T.C.; R35 CA197735 to S.O.; R01 CA151993 to S.O.; R01 CA248857 to S.O.; K07 CA190673 to R.N.; K07 CA188126 to X.Z., and R01 CA225655 to J.K.L.); by Cancer Research UK’s Grand Challenge Award (OPTIMISTICC; UK C10674/A27140 to M.G. and S.O.); by Nodal Award (2016-20) from the Dana-Farber Harvard Cancer Center (to S.O.); by Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17 to C.S.F. and M.G.), administered by the American Association for Cancer Research, a scientific partner of SU2C; and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance and SU2C. K.F. and K.H. were supported by fellowship grants from the Uehara Memorial Foundation. K.F. was supported by fellowship grants from the Grant of The Clinical Research Promotion Foundation (2018). Y.C. and L.L. were supported by a scholarship grant from Chinese Scholarship Council. K.H. was supported by fellowship grants from the Mitsukoshi Health and Welfare Foundation. T.U. and K.A. were supported by a grant from Overseas Research Fellowship (201960541 to T.U.; 201860083 to K.A) from Japan Society for the Promotion of Science. A.T.C. is a Stuart and Suzanne Steele MGH Research Scholar. M.G. is supported by an ASCO Conquer Cancer Foundation Career Development Award.
Copyright information: © The Author(s) 2020. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.