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Association between Smoking History and Tumor Mutation Burden in Advanced Non-Small Cell Lung Cancer.

ABSTRACT: Lung carcinogenesis is a complex and stepwise process involving accumulation of genetic mutations in signaling and oncogenic pathways via interactions with environmental factors and host susceptibility. Tobacco exposure is the leading cause of lung cancer, but its relationship to clinically relevant mutations and the composite tumor mutation burden (TMB) has not been fully elucidated. In this study, we investigated the dose-response relationship in a retrospective observational study of 931 patients treated for advanced-stage non-small cell lung cancer (NSCLC) between April 2013 and February 2020 at the Dana Farber Cancer Institute and Brigham and Women's Hospital. Doubling smoking pack-years was associated with increased KRAS^G12C and less frequent EGFR^del19 and EGFR^L858R mutations, whereas doubling smoking-free months was associated with more frequent EGFR^L858R . In advanced lung adenocarcinoma, doubling smoking pack-years was associated with an increase in TMB, whereas doubling smoking-free months was associated with a decrease in TMB, after controlling for age, gender, and stage. There is a significant dose-response association of smoking history with genetic alterations in cancer-related pathways and TMB in advanced lung adenocarcinoma. SIGNIFICANCE: This study clarifies the relationship between smoking history and clinically relevant mutations in non-small cell lung cancer, revealing the potential of smoking history as a surrogate for tumor mutation burden.

SUBMITTER: Wang X

PROVIDER: S-EPMC8137661 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cigarette smoking exerts a significant impact on metabolic phenotypes and epidermal growth factor receptor (EGFR) mutation status; however, their correlation remains insufficiently established. Therefore, the aim of this study was to investigate the association between cigarette smoking history, metabolic phenotypes, and EGFR mutation status in patients with non-small cell lung cancer (NSCLC). We retrospectively analyzed 198 consecutive patients with NSCLC who underwent 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) before treatment and were tested for EGFR mutation status between September 2019 and March 2022. Metabolic phenotypes, including the maximum standardized uptake value (SUVmax) of the primary tumors (pSUVmax), metastatic lymph nodes (nSUVmax), and distant metastases (mSUVmax) were assessed. Patients were classified into never-smokers and smokers based on detailed smoking history. The correlations between smoking status, metabolic parameters, and EGFR mutation status were evaluated in patients with NSCLC. We observed EGFR mutations in 73 (60.3%) of 121 never-smokers and 18 (23.4%) of 77 smokers (P<0.001). EGFR-mutant NSCLC had a lower pSUVmax than that of EGFR wild-type (WT; 8.9±4.5 vs. 12.7±6.9, P<0.001). Smokers had a higher pSUVmax than never-smokers (12.5±6.4 vs. 9.9±5.9, P=0.004). With the increase of cumulative smoking dose, the pSUVmax increased significantly (r=0.198, P=0.005). There was no significant difference between nSUVmax and mSUVmax in patients with or without EGFR mutation and smoking history. Cumulative smoking dose, pSUVmax, and their combination predicted EGFR mutation status with areas under the receiver operating characteristic (ROC) curves (AUCs) 0.688, 0.673, and 0.753, respectively. Our findings indicate that cigarette smoking may be one of the triggers for increased pSUVmax and decreased EGFR mutations, further suggesting that EGFR mutations are associated with low pSUVmax, which may guide clinicians in risk stratification and treatment strategy selection for patients with NSCLC.

Project description:ImportanceThere is a need to tailor treatments to patients who are most likely to derive the greatest benefit from them to improve patient outcomes and enhance cost-effectiveness of cancer therapies.ObjectiveTo compare overall survival (OS) between patients with a current or former history of smoking with patients who never smoked and initiated pembrolizumab monotherapy as first-line (1L) treatment for advanced non-small lung cancer (NSCLC).Design, setting, and participantsThis retrospective cohort study compared patients diagnosed with advanced NSCLC aged 18 or higher selected from a nationwide real-world database originating from more than 280 US cancer clinics. The study inclusion period was from January 1, 2011, to October 1, 2019.ExposuresSmoking status at the time of NSCLC diagnosis.Main outcomes and measuresOS measured from initiation of 1L pembrolizumab monotherapy.ResultsIn this retrospective cohort study, a total of 1166 patients (median [IQR] age, 72.9 [15.3] years; 581 [49.8%] men and 585 [50.2%] women) were assessed in the primary analysis, including 91 patients [7.8%] with no history of smoking (ie, never-smokers) and 1075 patients [92.2%] who currently or formerly smoked (ie, ever-smokers). Compared with ever-smokers, never-smokers were older (median age [IQR] of 78.2 [12.0] vs 72.7 [15.5] years), more likely to be female (61 [67.0%] vs 524 [48.7%]) and to have been diagnosed with nonsquamous tumor histology (70 [76.9%] vs 738 [68.7%]). After adjustment for baseline covariates, ever-smokers who initiated 1L pembrolizumab had significantly prolonged OS compared to never-smokers (median OS: 12.8 [10.9-14.6] vs 6.5 [3.3-13.8] months; hazard ratio (HR): 0.69 [95% CI, 0.50-0.95]). This trend was observed across all sensitivity analyses for the 1L pembrolizumab cohort, but not for initiators of 1L platinum chemotherapy, for which ever-smokers showed significantly shorter OS compared with never-smokers (HR, 1.2 [95% CI, 1.07-1.33]).Conclusions and relevanceIn patients with advanced NSCLC who received 1L pembrolizumab monotherapy in routine clinical practices in the US, patients who reported a current or former history of smoking at the time of diagnosis had consistently longer OS than never-smokers. This finding suggests that in never-smoking advanced NSCLC, 1L pembrolizumab monotherapy may not be the optimal therapy selection, and genomic testing for potential genomically matched therapies should be prioritized over pembrolizumab in never-smokers.

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Association between Smoking History and Tumor Mutation Burden in Advanced Non-Small Cell Lung Cancer.

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