Tobacco Use Tied to Immunotherapy Response and Gastric Cancer Mortality

Research has long shown a link between tobacco use and development of gastric and esophageal cancers, with those who smoke cigarettes or cigars or those who use a pipe or chewing tobacco twice as likely to develop esophageal cancer compared with nonsmokers—in particular, squamous cell carcinoma and adenocarcinoma.¹ This exposure to increased risk of cancer development is preventable,^1-3 especially considering that cigarette smoke alone contains more than 40 substances implicated as cancer-causing and promoters of cancer cell growth.⁴

Research presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium explored this relationship, focusing on the impact smoking history has for patients receiving immunotherapy (IO) for gastric, gastro-esophageal junction, and esophageal cancers, as well as correlations between tobacco use and gastric cancer (GC) mortality.^5,6

Impact of Smoking on Immunotherapy

According to researchers from Princess Margaret Cancer Centre in Toronto, Ontario, Canada, the true impact of smoking on the efficacy of IO for gastric, gastro-esophageal junction, and esophageal cancers is still a mystery.⁵ Outcomes of these cancers are already poor against a backbone of IO plus chemotherapy, the authors explain, but IO also shows promise against other cancer types for patients with a smoking history. They decided to investigate this relationship among a cohort of 204 patients at their hospital, finding that disease type and treatment setting were closely linked to IO outcomes.

The median patient age was 61.9 years; 54% (n = 111) were ever-smokers, and 46% (n = 93) were never-smokers. Primary outcomes of interest were relapse-free survival (RFS) and overall survival (OS) from 2 types of treatment intent: curative (15%; n = 31) and palliative (85%; n = 173). Seventy-eight percent of patients had adenocarcinoma, making it the most common histology, with most tumors being gastric (38%), followed by gastro-esophageal (34%) and esophageal (28%). Nivolumab was the most used IO.

Ever-smokers had superior RFS and OS vs never-smokers, but worse risk of relapse and increased risk of death when treatment intent was curative:

• RFS: 17.2 vs 13.6 months (HR, 0.80; 95% CI, 0.49-1.32; P = .39)
• OS: 14.1 vs 12.4 months (HR, 0.92; 95% CI, 0.56-1.51; P = .75)
• Risk of relapse: HR, 4.07 (95% CI, 1.26-13.1; P = .019)
• Risk of death: HR, 3.38 (95% CI, 0.40-28.41; P = .26)

For those receiving treatment with palliative intent, the majority (70%; n = 121) had de novo metastatic disease, and among these patients, ever-smokers vs never-smokers had longer RFS (15.8 vs 7.7 months; HR, 0.66; 95% CI, 0.36-1.18; P = .16) and OS (15.7 vs 9.7 months; HR, 0.63; 95% CI, 0.33-1.20; P = .16). Among the patients with recurrent disease (30%; n = 52), however, survival outcomes were worse: 9.1 vs 25.8 months (HR, 4.62; 95% CI, 1.15-18.56; P = .031).

“Future analyses should incorporate biomarkers, such as PD-L1 combined positive score and TMB [tumor mutational burden], to better evaluate the association between smoking and IO outcomes,” the authors concluded.

Impact of Tobacco Use on Mortality

Despite tobacco being a known modifiable risk factor of mortality for GC, the authors of this second study believe more research is needed to adequately characterize this relationship over the long term—compared with the relationships known to exist with other modifiable risk factors such as infection, diet, and genetics.⁶ They retrospectively analyzed data on 17,357 adults from the CDC WONDER Multiple Cause of Death database, most being male patients (75.5%; n = 13,099) and of a White ethnicity (79.5%; n = 13,805). Hispanic patients had the fewest reported deaths (7.7%; n = 1341).

This study population was 25 years and older, with diagnoses of GC and tobacco use disorder confirmed using International Classification of Diseases, Tenth Edition codes. Trends were analyzed per 100,000 population between 1999 and 2023, with deaths and age-adjusted mortality rates (AAMRs) being the outcomes of interest. Male patients vs female patients had a higher overall AAMR, at 0.58 vs 0.15, but this increased over time among both groups. The overall average annual percentage change (AAPC) was 4.60% (95% CI, 3.11-6.18), with AAPCs from both groups being close to equal, with 4.59% seen among the male patients and 4.58% seen among the female patients.

Drilling down to yearly ranges, however, the results gap widens, with the highest AAPC change of 23.29% seen for male patients in 2003-2006 compared with 14.75% for female patients in 2003-2008. The peak change for region of the US also occurred during this time, 2003-2005, with the Midwest experiencing the greatest rise in AAMR of 0.45 and rural areas having higher growth vs urban areas (0.43 vs 0.30). Also, for their study population, the highest AAMR rise was seen among non-Hispanic Black/African American patients, followed by non-Hispanic White and Hispanic patients.

“These findings,” the authors point out, “highlight the urgency of enhanced tobacco cessation, early GC screening, and focused public health strategies for at-risk populations.”

References

1. Can smoking cause esophageal cancer? Roswell Park Comprehensive Cancer Center. April 12, 2022. Accessed January 8, 2026. https://www.roswellpark.org/cancertalk/202204/can-smoking-cause-esophageal-cancer
2. DCEG staff. Gastric and esophageal cancers largely attributable to preventable exposure. National Cancer Institute Division of Cancer Epidemiology & Genetics. September 29, 2021. Accessed January 8, 2026. https://dceg.cancer.gov/news-events/news/2021/par-esophageal-gastric-cancer
3. Smoking and the digestive system. Johns Hopkins Medicine. Accessed January 8, 2026. https://www.hopkinsmedicine.org/health/conditions-and-diseases/smoking-and-the-digestive-system
4. Qi W. Smoking and malignant GI cancers. Cook Medical. Accessed January 8, 2026. https://www.cookmedical.com/endoscopy/smoking-and-malignant-gi-cancers/
5. Ghazali N, Aoyama H, Bach Y, et al. Impact of smoking on immunotherapy outcomes in gastric, gastro-esophageal junction, and esophageal cancers (G/GEJ/EC): a real-world analysis. Presented at: American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 8-10, 2026; San Francisco, CA. Abstract 320.
6. Mohamed AA, Hemida MF, Ibrahim AA, et al. Examining the link between tobacco use and gastric cancer mortality: a US population-based perspective (1999-2023). Presented at: American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 8-10, 2026; San Francisco, CA. Abstract 324.