Non-small cell lung cancer in never- and ever-smokers: Is it the same disease?

Abstract

Objectives: To investigate differences in presentation, pathology, and outcomes after resection of non-small cell lung cancer (NSCLC) in never-smokers versus ever-smokers.

Methods: From January 2006 to July 2016, 172 never-smokers and 1376 ever-smokers with NSCLC underwent pulmonary resection. The 2 cohorts were matched on patient characteristics, histopathological cancer cell type, and pathological stage group using a weighted balancing score, and overall survival and cancer recurrence were compared by pathological stage. Random forests for survival was used to identify granular cancer characteristics with different survival and cancer recurrence importance between groups.

Results: In never-smokers, the prevalence of NSCLC was more frequent in women than in men (63% [n = 109] vs 45% [n = 63]). Compared with ever-smokers, never-smokers had less upper-lobe disease (53% [n = 91] vs 62% [n = 855]) and more adenocarcinoma (88% [n = 151] vs 62% [n = 845]). Postoperative complications were similar. Never-smokers had a lower prevalence of non-lung cancer deaths than ever-smokers (13% vs 23% at 5 years; P = .006). Among matched pairs, never-smokers had better overall survival at 5 years in pathological stage I (96% vs 78%), but worse survival in stage II (54% vs 78%). Tumor size, N category, and histopathological cell type were more important drivers of mortality and cancer recurrence in never-smokers than in ever-smokers.

Conclusions: NSCLC in never-smokers affects women more than men and presents with different anatomic and histopathological distributions. Matched never-smokers have better or equivalent outcomes than ever-smokers in pathological stage I cancer, but are less likely to survive and to be cured of cancer as tumor burden increases. These findings suggest that there might be unique tumor or host behaviors differentially impacting survival of never- and ever-smoking patients with NSCLC.

Keywords: cancer recurrence; pulmonary resection; risk factors; survival analysis; weighted propensity matching.

FIGURE E1.

Quality of matching of never- and ever-smoker patient pairs. A, Mirrored histogram of distribution of balancing scores for never-smokers (bars below zero line) and ever-smokers (bars above zero line). Shaded area represents matched patient pairs. B, Standardized differences of selected variables before and after matching. Vertical dashed lines at −10% and +10% indicate boundaries of desirable matching. Black triangles represent standardized differences before propensity score–based matching, with positive values indicating a variable is more common in the never-smoker group and negative values indicating variables more common in the ever-smoker group. Green squares represent characteristics after matching. FEV₁, Forced expiratory volume in 1 second; CT, cardiothoracic; CAD, coronary artery disease.

FIGURE E2.

Prevalence of never-smokers in the resected non–smallcell lung cancer (NSCLC) cohort by calendar year. (Left) Proportion of never-smokers in the population of resected NSCLCs. The solid line is a smoothing spline curve, and dots represent the percentage of never-smokers each year. (Right) Stacked histogram of frequency of ever-smokers (red) and never-smokers (blue). Note: Numbers for 2016 go to July 2016 (half-year).

FIGURE E3.

Risk-adjusted partial dependency plots of 1-year survival and cancer recurrence after lung resection for non–small cell lung cancer. Never-smokers are represented by blue lines; ever-smokers, by red lines. Parallel lines represent similar survival trajectories for never- and ever-smokers. Diverging or crossing lines represent differences in survival implications for never- and ever-smokers, such as for histopathological type, presence of metastatic disease, crossing lines for tumor size, vascular margin and invasion, and lymphovascular invasion. Histology: 1 = adenocarcinoma, 2 = squamous cell cancer; focality: 0 = unifocal, 1 = multifocal; laterality: 0 = right, 1 = left; location: 1 = right upper, 2 = right middle, 3 = right lower, 4 = left upper, 5 = left lower, 6 = right central, 7 = left central. A, Survival. B, Freedom from cancer recurrence. VPI, Visceral pleural invasion.

FIGURE 1.

Survival after resection of non–small cell lung cancer in never-smokers (blue line and squares) and ever-smokers (red line and circles). Each symbol represents a death, and vertical bars are asymmetric 68% confidence limits equivalent to ±1 standard error. Numbers below the horizontal axis are patients remaining at risk. A, Overall cohorts. B, Weighted matched cohorts.

FIGURE 2.

Cancer persistence or recurrence after resection of non–small cell lung cancer in never-smokers (blue line and squares) and ever-smokers (red line and circles). Format is as in Figure 1. A, Overall cohorts. B, Weighted matched cohorts

FIGURE 3.

Death before and after cancer recurrence following resection of non–small cell lung cancer in never-smokers (blue line and squares) and ever-smokers (red line and circles). Format is as in Figure 1, except that the plots are inverted. A, Death before cancer recurrence in overall cohorts. B, Death after cancer recurrence in overall cohorts. C, Death before cancer recurrence in weighted matched cohorts. D, Death after cancer recurrence in weighted matched cohorts.

FIGURE 3.

Death before and after cancer recurrence following resection of non–small cell lung cancer in never-smokers (blue line and squares) and ever-smokers (red line and circles). Format is as in Figure 1, except that the plots are inverted. A, Death before cancer recurrence in overall cohorts. B, Death after cancer recurrence in overall cohorts. C, Death before cancer recurrence in weighted matched cohorts. D, Death after cancer recurrence in weighted matched cohorts.

FIGURE 4.

Survival and cancer recurrence after resection of pathological stage I and stage II non–small cell lung cancer in never-smokers (blue line and squares) and ever- smokers (red line and circles). Format is as in Figure 1. A, Survival in matched stage I cohorts. B, Survival in matched stage II cohorts. C, Freedom from cancer recurrence in matched stage I cohorts. D, Freedom from cancer recurrence in matched stage II cohorts.

FIGURE 4.

Survival and cancer recurrence after resection of pathological stage I and stage II non–small cell lung cancer in never-smokers (blue line and squares) and ever- smokers (red line and circles). Format is as in Figure 1. A, Survival in matched stage I cohorts. B, Survival in matched stage II cohorts. C, Freedom from cancer recurrence in matched stage I cohorts. D, Freedom from cancer recurrence in matched stage II cohorts.

FIGURE 5.

Mirrored histogram for never-smokers and ever-smokers of risk-adjusted normalized variable importance (VIMP) for survival and cancer recurrence, showing only cancer characteristics with 95% confidence intervals and median represented by a vertical bar. Presentation is in descending order of importance for the ever-smoker cohort. A, Survival. B, Cancer recurrence. VPI, Visceral pleural invasion.

FIGURE 6.

Differences in non–small cell lung cancer (NSCLC) characteristics and outcomes in never-smokers versus ever-smokers. In both pathological stage I and stage II NSCLC, distribution of cancer differs, as does survival. Never-smokers with stage I cancer have better survival than ever-smokers, and never-smokers with stage II cancer have worse survival than ever-smokers. This may be partly related to the heterogeneity of cancer characteristics within pathological cancer stages, as well as to apparent differences in effect of risk factors for mortality and cancer recurrence, such as effect of tumor size and presence of positive lymph nodes in never-smokers versus ever-smokers.