Analysis of delayed surgical treatment and oncologic outcomes in clinical stage I non-small cell lung cancer

Importance: The association between delayed surgical treatment and oncologic outcomes in patients with non-small cell lung cancer (NSCLC) is poorly understood given that prior studies have used imprecise definitions for the date of cancer diagnosis. Objective: To use a uniform method to quantify surgical treatment delay and to examine its association with several oncologic outcomes. Design, Setting, and Participants: This retrospective cohort study was conducted using a novel data set from the Veterans Health Administration (VHA) system. Included patients had clinical stage I NSCLC and were undergoing resection from 2006 to 2016 within the VHA system. Time to surgical treatment (TTS) was defined as the time between preoperative diagnostic computed tomography imaging and surgical treatment. We evaluated the association between TTS and several delay-associated outcomes using restricted cubic spline functions. Data analyses were performed in November 2021. Exposure: Wait time between cancer diagnosis and surgical treatment (ie, TTS). Main Outcomes and Measures: Several delay-associated oncologic outcomes, including pathologic upstaging, resection with positive margins, and recurrence, were assessed. We also assessed overall survival. Results: Among 9904 patients who underwent surgical treatment for clinical stage I NSCLC, 9539 (96.3%) were men, 4972 individuals (50.5%) were currently smoking, and the mean (SD) age was 67.7 (7.9) years. The mean (SD) TTS was 70.1 (38.6) days. TTS was not associated with increased risk of pathologic upstaging or positive margins. Recurrence was detected in 4158 patients (42.0%) with median (interquartile range) follow-up of 6.15 (2.51-11.51) years. Factors associated with increased risk of recurrence included younger age (hazard ratio [HR] for every 1-year increase in age, 0.992; 95% CI, 0.987-0.997; P = .003), higher Charlson Comorbidity Index score (HR for every 1-unit increase in composite score, 1.055; 95% CI, 1.037-1.073; P \u3c .001), segmentectomy (HR vs lobectomy, 1.352; 95% CI, 1.179-1.551; P \u3c .001) or wedge resection (HR vs lobectomy, 1.282; 95% CI, 1.179-1.394; P \u3c .001), larger tumor size (eg, 31-40 mm vs \u3c10 mm; HR, 1.209; 95% CI, 1.051-1.390; P = .008), higher tumor grade (eg, II vs I; HR, 1.210; 95% CI, 1.085-1.349; P \u3c .001), lower number of lymph nodes examined (eg, ≥10 vs \u3c10; HR, 0.866; 95% CI, 0.803-0.933; P \u3c .001), higher pathologic stage (III vs I; HR, 1.571; 95% CI, 1.351-1.837; P \u3c .001), and longer TTS, with increasing risk after 12 weeks. For each week of surgical delay beyond 12 weeks, the hazard for recurrence increased by 0.4% (HR, 1.004; 95% CI, 1.001-1.006; P = .002). Factors associated with delayed surgical treatment included African American race (odds ratio [OR] vs White race, 1.267; 95% CI, 1.112-1.444; P \u3c .001), higher area deprivation index [ADI] score (OR for every 1 unit increase in ADI score, 1.005; 95% CI, 1.002-1.007; P = .002), lower hospital case load (OR for every 1-unit increase in case load, 0.998; 95% CI, 0.998-0.999; P = .001), and year of diagnosis, with less recent procedures more likely to have delay (OR for each additional year, 0.900; 95% CI, 0.884-0.915; P \u3c .001). Patients with surgical treatment within 12 weeks of diagnosis had significantly better overall survival than those with procedures delayed more than 12 weeks (HR, 1.132; 95% CI, 1.064-1.204; P \u3c .001). Conclusions and Relevance: Using a more precise definition for TTS, this study found that surgical procedures delayed more than 12 weeks were associated with increased risk of recurrence and worse survival. These findings suggest that patients with clinical stage I NSCLC should undergo expeditious treatment within that time frame

Inhaled medications for chronic obstructive pulmonary disease predict surgical complications and survival in stage I non-small cell lung cancer

BACKGROUND: Lung function is routinely assessed prior to surgical resection for non-small cell lung cancer (NSCLC). Further assessment of chronic obstructive pulmonary disease (COPD) using inhaled COPD medications to determine disease severity, a readily available metric of disease burden, may predict postoperative outcomes and overall survival (OS) in lung cancer patients undergoing surgery. METHODS: We retrospectively evaluated clinical stage I NSCLC patients receiving surgical treatment within the Veterans Health Administration from 2006-2016 to determine the relationship between number and type of inhaled COPD medications (short- and long-acting beta2-agonists, muscarinic antagonists, or corticosteroids prescribed within 1 year before surgery) and postoperative outcomes including OS using multivariable models. We also assessed the relationship between inhaled COPD medications, disease severity [measured by forced expiratory volume in 1 second (FEV1)], and diagnosis of COPD. RESULTS: Among 9,741 veterans undergoing surgery for clinical stage I NSCLC, patients with COPD were more likely to be prescribed inhaled medications than those without COPD [odds ratio (OR) =5.367, 95% confidence interval (CI): 4.886-5.896]. Increased severity of COPD was associated with increased number of prescribed inhaled COPD medications (P\u3c0.0001). The number of inhaled COPD medications was associated with prolonged hospital stay [adjusted OR (aOR) =1.119, 95% CI: 1.076-1.165), more major complications (aOR =1.117, 95% CI: 1.074-1.163), increased 90-day mortality (aOR =1.088, 95% CI: 1.013-1.170), and decreased OS [adjusted hazard ratio (aHR) =1.061, 95% CI: 1.042-1.080]. In patients with FEV1 ≥80% predicted, greater number of prescribed inhaled COPD medications was associated with increased 30-day mortality (aOR =1.265, 95% CI: 1.062-1.505), prolonged hospital stay (aOR =1.130, 95% CI: 1.051-1.216), more major complications (aOR =1.147, 95% CI: 1.064-1.235), and decreased OS (aHR =1.058, 95% CI: 1.022-1.095). When adjusting for other drug classes and covariables, short-acting beta2-agonists were associated with increased 90-day mortality (aOR =1.527, 95% CI: 1.120-2.083) and decreased OS (aHR =1.087, 95% CI: 1.005-1.177). CONCLUSIONS: In patients with early-stage NSCLC, inhaled COPD medications prescribed prior to surgery were associated with both short- and long-term outcomes, including in patients with FEV1 ≥80% predicted. Routine assessment of COPD medications may be a simple method to quantify operative risk in early-stage NSCLC patients

¹⁸F-FDG PET intensity correlates with a hypoxic gene signature and other oncogenic abnormalities in operable non-small cell lung cancer

<div><p>Background</p><p>¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) is critical for staging non-small-cell lung cancer (NSCLC). While PET intensity carries prognostic significance, the genetic abnormalities associated with increased intensity remain unspecified.</p><p>Methods</p><p>NSCLC samples (N = 34) from 1999 to 2011 for which PET data were available were identified from a prospectively collected tumor bank. PET intensity was classified as mild, moderate, or intense based on SUVmax measurement or radiology report. Associations between genome-wide expression (RNAseq) and PET intensity were determined. Associations with overall survival were then validated in two external NSCLC cohorts.</p><p>Results</p><p>Overall survival was significantly worse in patients with PET-intense (N = 11) versus mild (N = 10) tumors (p = 0.039). Glycolytic gene expression patterns were markedly similar between intense and mild tumors. Gene ontology analysis demonstrated significant enhancement of cell-cycle and proliferative processes in FDG-intense tumors (p<0.001). Gene set enrichment analysis (GSEA) suggested associations between PET-intensity and canonical oncogenic signaling pathways including <i>MYC</i>, <i>NF-κB</i>, and <i>HIF-1</i>. Using an external cohort of 25 tumors with PET and genomic profiling data, common genes and gene sets were validated for additional study (P<0.05). Of these common gene sets, 20% were associated with hypoxia or HIF-1 signaling. While <i>HIF-1</i> expression did not correlate with poor survival in the NSCLC validation cohort (N = 442), established targets of hypoxia signaling (<i>PLAUR</i>, <i>ADM</i>, <i>CA9</i>) were significantly associated with poor overall survival.</p><p>Conclusions</p><p>PET-intensity is associated with a variety of oncogenic alterations in operable NSCLC. Adjuvant targeting of these pathways may improve survival among patients with PET-intense tumors.</p></div

Genetic analysis of study group.

<p>(a) Selected genes upregulated in high PET intensity tumors (fold-change high vs. low >2, p<0.05). (b) Kaplan-Meier survivor curve representing overall survival (in months) for patients with high PET-intensity tumors (N = 11), medium intensity tumors (N = 13), and low intensity tumors (N = 10). (c) The most significantly enriched genes in PET-high tumors (p<0.05, fold change>2.0) were interrogated by DAVID gene ontology pathway analysis [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199970#pone.0199970.ref024" target="_blank">24</a>]. Significant functional groups are shown. P-values are quantified as log units. (d) Average rank-based GSEA results for MSigDB Hallmark pathways. (e) RNA levels of core glycolysis enzymes (red) versus all genes (gray) in PET high (y axis) versus low (x-axis) tumors. “Core” enzymes were labeled such according to the KEGG gene set database.</p

Validated radiogenomic abnormalities in two cohorts of patients with early-stage NSCLC.

<p>(a) The most significantly enriched genes in PET-intense tumors (p<0.05, fold change>2.0) were selected from the study and PET validation cohort. Selected genes that overlapped are displayed in the table. (b) Average rank-based GSEA results for all pathways in the MSigDB database that were enriched in high-intensity tumors in both the study and PET validation cohorts and (c) quantified relative to hypoxia. (d) Kaplan-Meier survivor curves and log-rank test of <i>HIF1A</i> expression in prognostic validation cohort (N = 442) using median gene expression as cutoff to divide low and high expression.</p

Patient clinical characteristics.

<p>Patient clinical characteristics.</p

Patient demographics.

<p>Patient demographics.</p

Kaplan-Meier survivor curves and log-rank test of selected targets of HIF signaling in prognostic validation cohort (N = 442) using median gene expression as cutoff to divide low and high expression.

<p>Downstream targets of HIF including (a) <i>GLUT3</i>, (b) <i>ADM</i>, (c) <i>CA9</i>, and (d) <i>PLAUR</i> were associated with worse survival. Genes were selected according to validated MSigDB gene sets related to hypoxia signaling.</p

Clonal Hematopoiesis and Risk of Incident Lung Cancer

PURPOSE: To prospectively examine the association between clonal hematopoiesis (CH) and subsequent risk of lung cancer. METHODS: Among 200,629 UK Biobank (UKBB) participants with whole-exome sequencing, CH was identified in a nested case-control study of 832 incident lung cancer cases and 3,951 controls (2006-2019) matched on age and year at blood draw, sex, race, and smoking status. A similar nested case-control study (141 cases/652 controls) was conducted among 27,975 participants with whole-exome sequencing in the Mass General Brigham Biobank (MGBB, 2010-2021). In parallel, we compared CH frequency in published data from 5,003 patients with solid tumor (2,279 lung cancer) who had pretreatment blood sequencing performed through Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. RESULTS: In UKBB, the presence of CH was associated with increased risk of lung cancer (cases: 12.5% v controls: 8.7%; multivariable-adjusted odds ratio [OR], 1.36; 95% CI, 1.06 to 1.74). The association remained robust after excluding participants with chronic obstructive pulmonary disease. No significant interactions with known risk factors, including polygenic risk score and C-reactive protein, were identified. In MGBB, we observed similar enrichment of CH in lung cancer (cases: 15.6% v controls: 12.7%). The meta-analyzed OR (95% CI) of UKBB and MGBB was 1.35 (1.08 to 1.68) for CH overall and 1.61 (1.19 to 2.18) for variant allele frequencies ≥ 10%. In Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, CH with a variant allele frequency ≥ 10% was enriched in pretreatment lung cancer compared with other tumors after adjusting for age, sex, and smoking (OR for lung v breast cancer: 1.61; 95% CI, 1.03 to 2.53). CONCLUSION: Independent of known risk factors, CH is associated with increased risk of lung cancer