Smoking Status at Diagnosis and Colorectal Cancer Prognosis According to Tumor Lymphocytic Reaction

Author:

Fujiyoshi Kenji12ORCID,Chen Yang1ORCID,Haruki Koichiro1ORCID,Ugai Tomotaka1,Kishikawa Junko1,Hamada Tsuyoshi1ORCID,Liu Li1,Arima Kota1,Borowsky Jennifer1,Väyrynen Juha P134,Zhao Melissa1,Lau Mai Chan1,Gu Simeng1,Shi Shanshan1,Akimoto Naohiko1ORCID,Twombly Tyler S1,Drew David A56ORCID,Song Mingyang567,Chan Andrew T5689,Giovannucci Edward L7810,Meyerhardt Jeffrey A4ORCID,Fuchs Charles S111213,Nishihara Reiko171014,Lennerz Jochen K15,Giannakis Marios41617,Nowak Jonathan A1,Zhang Xuehong8,Wu Kana7810,Ogino Shuji1101618ORCID

Affiliation:

1. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

2. Department of Surgery, Kurume University, Kurume, Fukuoka, Japan

3. Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland

4. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

5. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA

6. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA

7. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

8. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA

9. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA

10. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

11. Yale Cancer Center, New Haven, CT, USA

12. Department of Medicine, Yale School of Medicine, New Haven, CT, USA

13. Smilow Cancer Hospital, New Haven, CT, USA

14. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

15. Department of Pathology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA

16. Broad Institute of MIT and Harvard, Cambridge, MA, USA

17. Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

18. Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA, USA

Abstract

Abstract 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 = .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.

Funder

US National Institutes of Health

NIH

Cancer Research UK’s Grand Challenge Award

Nodal Award

Dana-Farber Harvard Cancer Center

Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant

American Association for Cancer Research

Project P Fund

Uehara Memorial Foundation

The Clinical Research Promotion Foundation

Chinese Scholarship Council

Mitsukoshi Health and Welfare Foundation

Overseas Research Fellowship

Japan Society for the Promotion of Science

Stuart and Suzanne Steele MGH Research Scholar

ASCO Conquer Cancer Foundation Career Development Award

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

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