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Rita Akumuo*1,2, Sai Reddy3, Karthik Devarajan2, Dany Barrak2, Jason Castellanos2, Jeffrey M. Farma2, Sanjay S. Reddy2, Anthony Villano2
1Temple University Health System Inc, Philadelphia, PA; 2Fox Chase Cancer Center, Philadelphia, PA; 3Lewis Katz School of Medicine at Temple University, Philadelphia, PA

Background: Differential treatment responses to neoadjuvant therapy (NAT) are common in pancreatic ductal adenocarcinoma (PDAC), however the underlying biology driving these responses are poorly understood. Tobacco smoke is a common risk factor for PDAC, and nicotine-induced chemoresistance has been observed in other cancers including bladder and lung. Herein, we aimed to explore the potential association between smoking status and neoadjuvant treatment responses in PDAC.

Methods: In this single center, retrospective analysis, we examined all consecutive patients with PDAC from 1991-2020 who underwent surgical resection following NAT, had treatment response reported on pathologic analysis, and had a documented smoking history (N=208). Treatment response was measured as fibrosis after NAT, stratified as none, minor (< 50%), partial (51-95%), and major (> 95%). Multivariable models controlled for covariates including AJCC disease stage, preoperative CA19-9, and type of neoadjuvant treatment received. Survival was modeled with the Kaplan-Meier method and compared by log-rank tests.

Results: Of the 208 patients included, 111 (53.4%) were non-smokers and 97 (46.6%) had a history of smoking. There were no differences in age at diagnosis, performance status, or comorbidities amongst the two groups (all p>0.05). Further, there were no differences in preoperative AJCC clinical stage (p=0.662), mean pre-treatment CA19-9 (1246.9 U/mL non-smokers vs. 1095.2 U/mL smokers, p=0.98), tumor location in the gland, or NCCN anatomic resectability classification (p=0.626). Patients received similar ratios of neoadjuvant strategies including chemotherapy alone (8.1% vs. 7.2%), chemoradiation (42.3% vs. 47.4%), and total neoadjuvant therapy (49.5% vs. 45.4%)(p=0.808). Postoperatively, major responses to NAT were less frequently observed in smokers (13.7%) compared to non-smokers (30.4%, p=0.021). Complete pathologic responses were similarly less frequent in smokers (2.1% vs. 9.9%, p=0.023). On multivariate analysis controlling for covariates, smoking history remained independently associated with a lower odds of major fibrosis (OR=0.25, 95% CI 0.10-0.59, p=0.002) and pathologic complete response (OR=0.21, 95% CI 0.03 - 0.84, p= 0.05). Median overall survival was significantly longer in non-smokers (39.1 months) vs. smokers (26.6 months, p=0.05).

Conclusions: Tobacco use is associated with diminished pathologic responses to NAT and worse survival. Future research aims to understand the biology underlying this observation, which may inform differential NAT approaches amongst these populations.

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