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Purpose: As more treatments emerge for advanced, stage IV non-small-cell lung cancer (NSCLC), oncologists have difficulty predicting functional resiliency versus functional decline throughout cancer treatment. Our study evaluates functional resilience among patients with advanced NSCLC., Methods: Functional status was evaluated through 12 months of follow-up based on disability score using the modified EQ-5D-5L (mEQ-5D-5L) survey. Participants were classified into 4 groups: functional maintenance, decline, resilient, or variable. Characteristics of 207 participants with newly diagnosed NSCLC included demographics, comorbidities, baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS), mEQ-5D-5L scores, psychological symptoms, and lung cancer-specific symptoms. Treatment toxicity and grade were recorded. Resilience was defined as improvement from baseline disability scores. A 1-point increase in functional status score represents a 0.5 standard deviation change on the mEQ-5D-5L. Differences between the 4 groups were determined through Fisher's exact test or ANOVA. Kaplan-Meier curves describe overall survival (baseline through 18 months) stratified by baseline mEQ-5D-5L scores., Results: Among participants, 42.0 % maintained functional status, 37.7 % experienced functional decline, 10.6 % were resilient, and 9.7 % had variable functional status. Participants with the best baseline function (score of 0) had the longest overall survival and participants with the worst baseline function (score of 5 + ) had the shortest overall survival. Among the healthiest patients, early score increases indicated shorter overall survival. Baseline ECOG PS was not associated with overall survival (p = 0.47)., Conclusion: Baseline functional status may help better predict functional resiliency and overall survival than ECOG PS among patients receiving treatment for advanced NSCLC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Wong reported conflicts of interest outside of the submitted work (royalties from UpToDate, immediate family member is an employee of Genentech with stock ownership). No other authors have conflicts to report., (Copyright © 2024. Published by Elsevier B.V.)

Background: Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined., Methods: We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations., Results: A total of 471 patients with lung cancer were included, of which 402 had non-small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69-16.92; P<.001; and HR, 2.81; 95% CI, 1.50-5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17-18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3-5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p., Conclusions: Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.

Introduction: Patients treated with immune checkpoint inhibitors (ICIs) may not response to treatment and are at risk for immune-related adverse events (irAEs). Platelet function has been linked to both oncogenesis and immune evasion. We studied the association between the change in mean platelet volume (MPV), platelet count, survival, and the risk of developing irAEs in patients with metastatic non-small cell lung cancer (NSCLC) who have received first-line ICI., Methods: In this retrospective study, delta (∆) MPV was defined as the difference between cycle 2 and baseline MPV. Patient data were collected via chart review, and Cox proportional hazard and Kaplan-Meier method were used to assess the risk and estimate median overall survival., Results: We identified 188 patients treated with first-line pembrolizumab, with or without concurrent chemotherapy. There were 80 (42.6%) patients received pembrolizumab monotherapy, and 108 (57.4%) received pembrolizumab in combination with platinum-based chemotherapy. Patients whose MPV (∆MPV ≤ 0) decreased had hazard ratio (HR) = 0.64 (95% CI 0.43-0.94) for death with p = 0.023. Patients with ∆MPV ≤ - 0.2 fL (median), there was a 58% increase in the risk of developing irAE (HR = 1.58, 95% CI 1.04-2.40, p = 0.031). Thrombocytosis at baseline and cycle 2 was associated with shorter OS with p = 0.014 and 0.039, respectively., Conclusion: Change in MPV after 1 cycle of pembrolizumab-based treatment was significantly associated with overall survival as well as the occurrence of irAEs in patients with metastatic NSCLC in the first-line setting. In addition, thrombocytosis was associated with poor survival., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Lung cancer is a product of inflammation and a dysfunctional immune system, and depression has similar dysregulation. Depression disproportionately affects lung cancer patients, having the highest rates of all cancers. Systemic inflammation and depression are both predictive of non-small cell lung cancer (NSCLC) survival, but the existence and extent of any co-occurrence is unknown. Studied is the association between systemic inflammation ratio (SIR) biomarker levels and patients' depressive symptoms, with the hypothesis that depression severity would be significantly associated with prognostically poor inflammation. Newly diagnosed stage-IV non-small cell lung cancer (NSCLC; N = 186) patients were enrolled (ClinicalTrials.gov Identifier: NCT03199651) and blood draws and depression self-reports (Patient Health Questionnaire-9) were obtained. For SIRs, cell counts of neutrophils (N), lymphocytes (L), and platelets (P) were abstracted for ratio (R) calculations for NLR, PLR, and the Advanced Lung cancer Inflammation Index (ALI). Patients were followed and biomarkers were tested as predictors of 2-year overall survival (OS) to confirm their relevance. Next, multivariate linear regressions tested associations of depression with NLR, PLR, and ALI. Overall 2-year mortality was 61% (113/186). Cox model analyses confirmed higher NLR [hazard ratio (HR) = 1.91; p = 0.001] and PLR (HR = 2.08; p<0.001), along with lower ALI (HR = 0.53; p = 0.005), to be predictive of worse OS. Adjusting for covariates, depression was reliably associated with biomarker levels (p ≤ 0.02). Patients with moderate/severe depressive symptoms were 2 to 3 times more likely to have prognostically poor biomarker levels. Novel data show patients' depressive symptoms were reliably associated with lung-relevant systemic inflammation biomarkers, all assessed at diagnosis/pretreatment. The same SIRs were found prognostic for patients' 2-year OS. Intensive study of depression, combined with measures of cell biology and inflammation is needed to extend these findings to discover mechanisms of depression toxicity for NSCLC patients' treatment responses and survival., Competing Interests: BLA, JM, TB, KRP, RMS, SR, and WEC have no competing interests to declare. DPC reports personal fees from Abbvie, Adaptimmune, Agenus, Amgen, Ariad, AstraZeneca, Biocept, Boehringer Ingelheim, Celgene, Clovis, Daiichi Sankyo, Inc. (DSI), EMD Serono, Flame Biosciences, Foundation Medicine, G1Therapeutics/Intellisphere, GenePlus, Genentech/Roche, Glaxo-Smith-Kline, Gloria Biosciences, Gritstone, Guardant Health, Humana, Incyte, Inivata, Inovio, Janssen, Kyowa Kirin, Loxo Oncology, Merck, MSD, Nexus Oncology, Novartis, Oncocyte, Palobiofarma, Pfizer, prIME Oncology, Stemcentrx, Takeda Oncology, and Teva; and grants and personal fees from Bristol Myers-Squibb (BMS) outside the submitted work during the conduct of the study. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Andersen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Importance: Adverse social determinants of health (SDHs) (eg, poverty) are associated with poor oncologic outcomes among patients with lung cancer. However, no studies have evaluated biological correlates of adverse SDHs, operationalized as allostatic load (AL), with mortality due to lung cancer., Objective: To examine the association among AL, SDHs, and mortality among patients with metastatic non-small cell lung cancer (NSCLC)., Design, Setting, and Participants: This cross-sectional study of an observational cohort was performed at a National Cancer Institute-designated comprehensive cancer center with data accrued from June 1, 2017, to August 31, 2019. Patients with metastatic (stage IV) NSCLC enrolled at diagnosis into a prospective observational cohort study were included in the present analysis if they had all the biomarkers to calculate an AL score (N = 143). Follow-up was completed on August 31, 2021, and data were analyzed from July 1 to September 30, 2021., Exposures: Social determinants of health., Main Outcomes and Measures: Overall mortality and AL., Results: A total of 143 patients met the study criteria with a median age of 63 (IQR, 55-71) years (89 men [62.2%] and 54 women [37.8%]). In terms of race and ethnicity, 1 patient (0.7%) was Asian, 7 (4.9%) were Black, 117 (81.8%) were White, 17 (11.9%) were of multiple races, and 1 (0.7%) was of other race or ethnicity. The mean (SD) AL was 2.90 (1.37). Elevated AL covaried with lower educational level (r = -0.26; P = .002), male sex (r = 0.19; P = .02), limited mobility (r = 0.19; P = .04), worsening self-care (r = 0.30; P < .001), problems engaging in usual activities (r = 0.21; P = .01), depressive symptoms (r = 0.23; P = .005), and a high number of stressful life events (r = 0.30; P < .001). Multivariable analysis found only increasing difficulty with mobility (r = 0.37 [95% CI, 0.13-0.60]; P = .002) and male sex (r = 0.63 [95% CI, 0.19-1.08]; P = .005) associated with higher AL. On adjusted analysis, elevated AL (hazard ratio, 1.43 [95% CI, 1.16-1.79]; P = .001) and low educational level (hazard ratio, 2.11 [95% CI, 1.03-4.34]; P = .04) were associated with worse overall mortality., Conclusions and Relevance: The findings of this cross-sectional study suggest that higher AL was associated with adverse SDHs and worse overall mortality among patients with advanced NSCLC. These results provide a framework for replication and further studies of AL as a biological correlate for SDH and future prognostic marker.

Background: Cancer cachexia exhibits decreased albumin and associates with short overall survival (OS) in patients with non-small cell lung cancer (NSCLC), but whether on-treatment albumin changes associate with OS in NSCLC patients treated with immune checkpoint inhibitors (ICIs) and combination chemoimmunotherapy has not been thoroughly evaluated., Patients and Methods: We conducted a single-center retrospective study of patients with advanced NSCLC who received first-line ICI with or without chemotherapy between 2013 and 2020. The association of pretreatment albumin and early albumin changes with OS was evaluated using Kaplan-Meier method and Cox regression models., Results: A total of 210 patients were included: 109 in ICI cohort and 101 in ICI + Chemo cohort. Within a median of 21 days from treatment initiation, patients with ≥ 10% of albumin decrease had significantly shorter OS compared to patients without albumin decrease in ICI cohort. Pretreatment albumin and albumin decrease within the first or second cycle of treatment were significantly and independently associated with OS in ICI cohort, but not in ICI + Chemo cohort. The lack of association between albumin and OS with the addition of chemotherapy was more pronounced among patients with ≥ 1% PD-L1 expression in subgroup analysis., Conclusion: Pretreatment serum albumin and early albumin decrease in ICI monotherapy was significantly associated with OS in advanced NSCLC. Early albumin change, as a routine lab value tested in clinic, may be combined with established biomarkers to improve outcome predictions of ICI monotherapy. The underlying mechanism of the observed association between decreased albumin and ICI resistance warrants further investigation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Of all cancers, advanced nonsmall cell lung cancer (NSCLC) is associated with the highest burden on mental and physical health-related quality of life (HRQoL). Patients' subjective beliefs about their cancer (i.e., illness perceptions) may influence coping responses and treatment decisions and affect health. To identify cognitive and emotional perceptions and their association with patient characteristics and illness circumstances, the relationship between illness perception schemas and psychological and physical responses and symptoms were studied., Method: Patients newly diagnosed with stage IV NSCLC (N = 186) enrolled in a prospective cohort study (NCT03199651) completed measures of illness perceptions; anxiety, depression, and physical symptoms; and health status. Latent profile analysis identified illness perception profiles. Hierarchical linear regressions tested profile assignment as a correlate of responses and symptoms., Results: A three-profile solution was optimal. Patients with a "struggling" profile (n = 83; 45%) reported the most negative perceptions; patients with a "coping" profile (n = 41; 22%) reported relatively positive perceptions; and patients with a "coping but concerned" profile (n = 62; 33%) endorsed high illness concern but relatively positive perceptions otherwise. Patients with a "struggling" profile reported the highest levels of anxiety and depression symptoms, overall physical symptoms, cough, dyspnea, and pain, and the poorest self-rated health., Conclusions: New data add to the clinical portrayal of patients coping with NSCLC since the availability of new therapies and survival improvements. Other disease groups have reported a predominance of positive perceptions, rather than ones of significant cognitive and emotional struggles found here. Illness perception data may provide content-rich resources for intervention tailoring. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background: Among all patients with cancer, those with advanced non-small cell lung cancer (NSCLC) experience the most distress. Although new therapies are improving survival, it is unknown whether receiving immunotherapy or targeted therapy during the COVID-19 pandemic increases patients' psychological vulnerability. To meet clinical needs, knowledge of patients' COVID-19 perceptions and safety behaviors is essential. Thus, this study compared patients' psychological responses at diagnosis and during COVID-19 and compared patients with similar individuals without cancer during the same period., Patients and Methods: Patients with advanced NSCLC enrolled at diagnosis for cohort study participated (ClinicalTrials.gov identifier: NCT03199651). Those with follow-ups from April 28, 2020, through July 14, 2020 (n=76), were assessed again including COVID-19 measures. Simultaneously, community controls with similar sociodemographics and smoking histories were solicited (n=67). Measures were COVID-19 perceptions (Brief Illness Perception Questionnaire), social distancing, and depressive (Patient Health Questionnaire-9) and anxiety (Generalized Anxiety Disorder-7) symptoms. First, analyses evaluated differences in the psychological responses of patients with NSCLC at diagnosis and during COVID-19. Second, patients and controls were contrasted on COVID-19 perceptions, social distancing, and psychological symptoms., Results: The depressive and anxious symptoms of patients with NSCLC were greater at diagnosis (P<.02) than during COVID-19, approximately 1 year later. Patients with NSCLC and controls did not differ in terms of sociodemographics, except those with NSCLC were more racially diverse and older, and had greater smoking history (P<.03). Groups did not differ regarding concern, understanding, or perceived control over COVID-19 (P>.406). Notably, controls anticipated the COVID threat would last longer, practiced more social distancing, were more concerned about family (P<.04), and reported worse psychological symptoms (P<.023). With less depression and anxiety, patients with NSCLC viewed COVID-19 as a shorter-term threat and had fewer COVID-19-related worries than did controls. For controls, COVID-19 was more salient, heightening worries and psychological symptoms., Conclusions: Despite multiple health stressors, patients with NSCLC demonstrated resilience when receiving cancer treatment during COVID-19. Nonetheless, this population remains psychologically vulnerable, requiring support at diagnosis and thereafter.

Objective: Lung cancer remains the number one cause of cancer-related mortality worldwide, but less known is that lung cancer patients are among the most psychologically disabled of all cancer groups. Patients with stage IV non-small cell lung cancer (NSCLC) were studied to test the hypothesis that trajectories of depression and/or anxiety symptoms after diagnosis would show an adverse relationship with survival, beyond relevant controls., Methods: Patients with stage IV NSCLC (n = 157) were enrolled (ClinicalTrials.gov Identifier: NCT03199651) at diagnosis and completed validated measures for depressive symptoms (Patient Health Questionnaire-9) and anxiety symptoms (Generalized Anxiety Disorder-7). Patients were reassessed every 1 to 2 months through 24 months (16 assessments; 80% average completion rate) and survival monitored. Joint statistical models provided simultaneous modeling of longitudinal (psychological) and time-to-event (survival) processes. Control variables were age, sex, marital status, education, smoking status, cancer type, and treatment received., Results: Depression and anxiety symptoms significantly decreased with time since diagnosis. The 2-year trajectory of depressive symptoms was significantly associated with cancer survival after adjustment for covariates (hazard ratio = 1.09 per unit increase in the Patient Health Questionnaire-9, 95% confidence interval = 1.03-1.15, p = .002). Anxiety was marginally significant in the unadjusted (p = .053) but not the adjusted (p = .39) model., Conclusions: For the first time, joint model analyses test the interaction of a longitudinal trajectory of psychological symptoms, assessed from diagnosis to 24 months, and cancer survival. New data show the continuation of depressive and anxiety symptoms through treatment and thereafter. Immunotherapy and targeted therapies have dramatically improved survival for patients with advanced NSCLC; however, novel data suggest their benefit may be constrained by depressive symptoms., (Copyright © 2021 by the American Psychosomatic Society.)

Purpose: To determine patient and disease characteristics associated with functional disability among adults with advanced non-small-cell lung cancer (NSCLC)., Methods: In a prospective cohort of participants newly diagnosed with advanced NSCLC and beginning systemic treatment, functional disability in usual activities, mobility, and self-care was measured using the EuroQol-5D-5L at baseline. Demographics, comorbidities, brain metastases, Eastern Cooperative Oncology Group performance status (ECOG PS), and psychologic variables (depression [Patient Health Questionnaire-9] and anxiety [Generalized Anxiety Disorder 7-item scale]) were captured. Patients were classified into two disability groups (none-slight or moderate-severe) on the basis of total functional status scores. Differences between disability groups were determined (chi-square and t tests). Associations between patient characteristics and baseline disability were assessed using logistic regression., Results: Among 173 participants, mean age was 63.3 years, 56% were male, 83% had ECOG PS 0-1, and 41% had brain metastases. Baseline disability was present in 39% of participants, with patients having moderate to severe disability in usual activities (37.6%), mobility (26.6%), and self-care (5.2%). Depressive and/or anxiety symptoms ranged from none to severe (Patient Health Questionnaire 9-item scale M = 6.5, SD = 5.3). Depressive symptoms were the only characteristic associated with a higher odds of baseline disability (adjusted odds ratio [aOR]: 1.26; 95% CI, 1.15 to 1.38; P < .001). Participants with poorer ECOG PS (aOR: 4.64; 95% CI, 1.84 to 11.68; P = .001) and depressive symptoms (aOR: 1.15; 95% CI, 1.07 to 1.24; P < .001) had higher odds of moderate-severe mobility disability compared with the none-slight disability group., Conclusion: More than one third of all adults with advanced NSCLC have moderate-severe functional disability at baseline. Psychologic symptoms were significantly associated with moderate-severe baseline disability., Competing Interests: Carolyn J. PresleyConsulting or Advisory Role: PotentiaMetrics, Onc Live David P. CarboneEmployment: James Cancer CenterHonoraria: AstraZeneca, Nexus Pharmaceuticals IncConsulting or Advisory Role: Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, AstraZeneca, Helsinn Therapeutics, Abbvie, Inivata, Loxo, Incyte, Bristol Myers Squibb, Daiichi Sankyo, EMD Serono, GlaxoSmithKline, Inovio Pharmaceuticals, Janssen, Kyowa Hakko Kirin, TakedaResearch Funding: Bristol Myers Squibb Melisa L. WongEmployment: Roche/GenentechStock and Other Ownership Interests: Roche/GenentechNo other potential conflicts of interest were reported.

Background: Bone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort., Patients and Methods: We conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors., Results: We identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4-12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19-2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs., Conclusions: Presence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival.

Introduction: Recent clinical studies have identified tumor mutation burden (TMB) as a promising therapeutic biomarker of anti-tumor immune checkpoint blockade. However, given the relatively slow turnaround time and high expense in measuring TMB, tobacco smoking history (TSH) is an attractive replacement biomarker. The carcinogenic effects of tobacco smoking may be modified by the protective effects of genome stability genes. This study aims to test the associations between tobacco smoking, genome stability gene inactivation, and TMB., Methods: Publicly available TSH and DNA somatic alteration data from NSCLC were downloaded from The Cancer Genome Atlas. Correlations and enrichments were calculated with Spearman and Fisher's exact test methods, respectively. Multivariate modeling of TMB was performed with penalized linear regression., Results: 85% of never smokers in adenocarcinomas (LUAD) had low TMB, but a positive TSH was not predictive of hypermutancy. The limited utility of TSH in predicting TMB was reproduced on an independent LUAD dataset. To expand our search for predictors of TMB, we further investigated the contributions of genome stability related genes (GSGs) to TMB. 242/461 (52%) and 300/465 (65%) patients with LUAD and squamous carcinomas (LUSC), respectively, showed evidence of loss of function in at least one of the 182 GSGs. 182 GSGs from 16 pathways were assessed for associations with TMB high tumor status using Fisher's exact test. We performed univariate gene and pathway enrichments in TMB high tumors and found roles forPOLE, REV3L, and FANCE genes, as well as several key GSG pathways., Conclusions: This study comprehensively tested the association between GSG, tobacco smoking, and TMB in NSCLC. In LUAD, never-smoking status was predictive of low TMB, but overall TSH was not an adequate surrogate biomarker for TMB in NSCLC. Furthermore, we identified an association between GSG inactivation and TMB., (Copyright © 2020. Published by Elsevier B.V.)

Background: The risk factors for immune-related adverse events (irAEs) remain undefined. Recently, a correlation between irAEs and clinical benefit was suggested. We examined the risk factors for irAEs and their effect on survival in patients with non-small-cell lung cancer (NSCLC) who had received immunotherapy., Patients and Methods: We performed a retrospective review of patients with NSCLC treated with single-agent immunotherapy at our institution. irAEs were determined by treating physician diagnosis. A landmark analysis was performed at 3 months using log-rank tests and the Bonferroni method., Results: irAEs occurred in 27 of 91 patients (30%). The median overall survival (OS) for patients with irAEs was longer than that for patients without (24.3 vs. 5.3 months; hazard ratio, 2.75; 95% confidence interval, 1.54-4.92; P < .001). However, a landmark analysis of patients after 3 months of treatment revealed no difference in OS between patients with and without irAEs. No increased risk of pneumonitis was seen in patients with previous thoracic radiotherapy, although these patients had shorter survival (4.2 vs. 9.7 months; P = .004). Radiotherapy after the initiation of immunotherapy (n = 15) did not increase the risk of irAEs or pneumonitis; however, these patients had improved OS (17.3 vs. 6.0 months; P = .016)., Conclusion: The development of irAEs did not significantly correlate with survival when controlling for the duration of therapy in a landmark analysis. We found no increased risk of pneumonitis or irAEs in patients who had received radiotherapy. Radiotherapy before immunotherapy was associated with shorter survival, and radiotherapy after immunotherapy was associated with improved survival., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: To compare patterns of care for elderly patients versus non-elderly patients with non-surgically treated stage III non-small cell lung cancer (NSCLC) using the National Cancer Database (NCDB). We hypothesize that elderly patients are less likely to receive curative treatments, including concurrent chemoradiation (CCRT), compared to non-elderly patients., Methods: We identified patients from the NCDB between 2003 and 2014 with non-surgically treated stage III NSCLC. We defined elderly as ≥70 years old and non-elderly <70 years old. Treatment categories included: no treatment, palliative treatment (chemotherapy alone, radiation (RT) alone <59.4 Gy or chemoradiation (CRT) <59.4 Gy), or definitive treatment (RT alone ≥59.4 Gy or CRT ≥59.4 Gy). Differences in treatment between elderly and non-elderly were tested using the χ 2 test., Results: We identified 57,602 elderly and 55,928 non-elderly patients. More elderly patients received no treatment (24.5% vs. 13.2%, P < 0.0001) and the elderly were less likely to receive definitive treatment (48.5% vs. 56.3%, P < 0.0001). CCRT was delivered in a significantly smaller proportion of elderly vs. non-elderly patients (66.0% vs. 78.9%, P < 0.0001 in patients treated with definitive intent; 32.0% vs. 44.5%, P < 0.0001 in patients receiving any treatment; and 24.2% vs. 38.6%, P < 0.0001 amongst all patients)., Conclusions: In this large study of patients with non-surgically treated stage III NSCLC, elderly patients were less likely to receive any treatment or treatment with definitive intent compared to the non-elderly. The lack of use of concurrent or sequential chemotherapy in the elderly with stage III NSCLC suggests that the optimal treatment approach for this vulnerable population remains undefined.

Introduction: Elderly patients account for the majority of lung cancer diagnoses but are poorly represented in clinical trials. We evaluated the overall survival (OS) of elderly patients with stage III NSCLC treated with definitive radiation compared with that of patients treated with definitive chemoradiation., Methods: We conducted a comparative effectiveness study of radiation therapy versus chemoradiation in elderly (≥70 years old) patients with stage III NSCLC not treated surgically diagnosed from 2003 to 2014; the patients were identified by using the National Cancer Database. Two cohorts were evaluated: patients (n = 5023) treated with definitive radiation (≥59.4 Gy) and patients (n = 18,206) treated with definitive chemoradiation. Chemoradiation was further defined as concurrent (radiation and chemotherapy started within 30 days of each other) or sequential (radiation started >30 days after chemotherapy). We compared OS between the treatment groups by using the Kaplan-Meier method and Cox proportional hazards regression before and after propensity score matching (PSM)., Results: Treatment with chemoradiation was associated with improved OS versus that with radiation both before PSM (hazard ratio [HR] = 0.66, 95% confidence interval [CI]: 0.64-0.68, p < 0.001) and after PSM (HR = 0.67, 95% CI: 0.64-0.70, p < 0.001). Relative to concurrent chemoradiation, sequential chemoradiation was associated with a 9% reduction in the risk for death (HR = 0.91, 95% CI: 0.85-0.96, p = 0.002)., Conclusions: We found that definitive chemoradiation resulted in a survival advantage compared with definitive radiation in elderly patients. Sequential chemotherapy and radiation was superior to concurrent chemoradiation. Although prospective trials are needed, this analysis suggests that chemoradiation should be strongly considered for elderly patients and the optimal sequencing of chemotherapy and radiation remains an unanswered question for this patient population., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Alternative predictive end points for overall survival (OS), such as tumor response and progression-free survival (PFS), are useful in the early detection of drug efficacy; however, they have not been fully investigated in patients with advanced NSCLC treated with anti-programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies., Methods: In a systematic review of the reported prospective clinical trials, data for response rate, median PFS, and median OS were extracted from 12 arms in 10 reported clinical trials using anti-PD-1/PD-L1 antibody, and their correlation was investigated. In a retrospective analysis at our institution, OS was compared according to tumor response on 5- to 9-week computed tomography scans and status of being progression-free at 8, 16, and 24 weeks by landmark analysis in 71 patients with advanced NSCLC treated with anti-PD-1/PD-L1 antibodies between 2013 and 2015., Results: In a systematic review, moderate correlations between median OS and median PFS (p = 0.120, r = 0.473) and between median OS and response rate (p = 0.141, r = 0.452) were identified using the Spearman correlation coefficient, although these correlations were not statistically significant. In a retrospective analysis of patients treated at our institution, disease control (partial response [PR]/stable disease versus progressive disease/not evaluable), and progression-free status at 8, 16, and 24 weeks significantly predicted OS (Cox proportional hazards model, PR/stable disease versus progressive disease/not evaluable, p = 0.0104, HR = 3.041; 8-week progression-free yes versus no, p = 0.0183, HR = 2.684; 16-week progression-free yes versus no, p = 0.0036, HR = 4.009; and 24-week progression-free yes versus no, p = 0.0002, HR = 12.726)., Conclusions: Both disease control (PR plus stable disease status) and landmark progression-free survival were correlated with OS, with the longer interval landmark PFS being the best predictor of survival in patients with NSCLC treated with anti-PD-1/PD-L1 antibodies., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The number of validated biomarkers of tobacco smoke exposure is limited, and none exist for tobacco-related cancer. Additional biomarkers for smoke, effects on cellular systems in vivo are needed to improve early detection of lung cancer, and to assist the Food and Drug Administration in regulating exposures to tobacco products. We assessed the effects of smoking on the gene expression using human cell cultures and blood from a cross-sectional study. We profiled global transcriptional changes in cultured smokers' peripheral blood mononuclear cells (PBMCs) treated with cigarette smoke condensate (CSC) in vitro (n = 7) and from well-characterized smokers' blood (n = 36). ANOVA with adjustment for covariates and Pearson correlation were used for statistical analysis in this study. CSC in vitro altered the expression of 1 178 genes (177 genes with > 1.5-fold-change) at P < 0.05. In vivo, PBMCs of heavy and light smokers differed for 614 genes (29 with > 1.5-fold-change) at P < 0.05 (309 remaining significant after adjustment for age, race, and gender). Forty-one genes were persistently altered both in vitro and in vivo, 22 having the same expression pattern reported for non-small cell lung cancer. Our data provides evidence that persistent alterations of gene expression in vitro and in vivo may relate to carcinogenic effects of cigarette smoke, and the identified genes may serve as potential biomarkers for cancer. The use of an in vitro model to corroborate results from human studies provides a novel way to understand human exposure and effect. © 2015 Wiley Periodicals, Inc., Competing Interests: None., (© 2015 Wiley Periodicals, Inc.)

Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1,500 Da) were measured in urine collected from 469 patients with lung cancer and 536 population controls using unbiased liquid chromatography/mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further confirmed in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared with the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA) were each significantly (P < 0.00001) elevated in non-small cell lung cancer and associated with worse prognosis [HR = 1.81 (P = 0.0002), and 1.54 (P = 0.025), respectively]. Creatine riboside was the strongest classifier of lung cancer status in all and stage I-II cases, important for early detection, and also associated with worse prognosis in stage I-II lung cancer (HR = 1.71, P = 0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 to 0.99. Both metabolites were significantly (P < 0.03) enriched in tumor tissue compared with adjacent nontumor tissue (N = 48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis., (©2014 American Association for Cancer Research.)

Objective: To examine associations between occupation and lung cancer by gender and race., Methods: We used data from the Maryland Lung Cancer Study of nonsmall cell lung carcinoma (NSCLC), a multicenter case control study, to estimate odds ratios (ORs) of NSCLC in different occupations., Results: After adjusting for smoking, environmental tobacco smoke, and other covariates, NSCLC ORs among women but not men were elevated in clerical-sales, service, and transportation-material handling occupations; ORs were significantly increased in all three categories (OR [95% confidence interval]: 4.07 [1.44 to 11.48]; 5.15 [1.62 to 16.34]; 7.82 [1.08 to 56.25], respectively), among black women, but only in transportation-material handling occupations (OR [95% confidence interval[: 3.43 [1.02 to 11.50]) among white women., Conclusions: Women, especially black women, in certain occupations had increased NSCLC ORs.

Background: The relationship among chronic inflammation, innate immunity, and cancer is well established. Mannose-binding lectin (MBL) is a key player in innate immunity. Five polymorphisms in the promoter and first exon of the MBL2 gene alter the expression and function of MBL in humans and are associated with inflammation-related disease susceptibility. These five polymorphisms create six well-characterized haplotypes that result in lower (i.e., LYB, LYC, HYD, and LXA) or higher (i.e., HYA and LYA) serum MBL concentrations. We investigated whether survival of patients with lung cancer was associated with these polymorphisms., Methods: We used a multivariable Cox proportional hazards model to study the association between MBL2 polymorphisms and their haplotypes and diplotypes in 558 white and 173 African American patients with non-small-cell lung cancer in the Baltimore, MD, area and lung cancer mortality. Smoking history and race were obtained from interviews, tumor stage was obtained from medical records, and cause of death was obtained from the National Death Index. All statistical tests were two-sided., Results: We found a statistically significant association between the X allele of the promoter Y/X polymorphism (which results in a lower serum MBL concentration) and improved lung cancer survival among white patients (risk ratio [RR] of death from lung cancer with X/X or X/Y genotype compared with Y/Y genotype = 0.61, 95% confidence interval [CI] = 0.46 to 0.81) but not among African American patients (RR = 1.11, 95% CI = 0.69 to 1.77). The associations among white patients were strongest in heavy smokers and were independent of stage. We also found a statistically significant interaction between the Y/X polymorphism and race for lung cancer survival (P(interaction) = .019). The MBL2 LXA haplotype and XA/B diplotype, which are also associated with low serum MBL levels, were statistically significantly associated with improved lung cancer survival among white patients., Conclusion: The functional Y/X polymorphism of the innate-immunity gene MBL2 and MBL2 haplotypes and diplotypes appear to be associated with lung cancer survival among white patients.

Cell cycle checkpoints play critical roles in the maintenance of genomic integrity. The inactivation of checkpoint genes by genetic and epigenetic mechanisms is frequent in all cancer types, as a less-efficient cell cycle control can lead to genetic instability and tumorigenesis. In an on-going case-control study consisting of 216 patients with non-small cell lung cancer, 226 population-based controls, and 114 hospital-based controls, we investigated the relationship of gamma-radiation-induced G2-M arrest and lung cancer risk. Peripheral blood lymphocytes were cultured for 90 hours, exposed to 1.0 Gy gamma-radiation, and harvested at 3 hours after gamma-radiation treatment. gamma-Radiation-induced G2-M arrest was measured as the percentage of mitotic cells in untreated cultures minus the percentage of mitotic cells in gamma-radiation-treated cultures from the same subject. The mean percentage of gamma-radiation-induced G2-M arrest was significantly lower in cases than in population controls (1.18 versus 1.44, P < 0.01) and hospital controls (1.18 versus 1.40, P = 0.01). When dichotomized at the 50th percentile value in combined controls (population and hospital controls), a lower level of gamma-radiation-induced G2-M arrest was associated with an increased risk of lung cancer among African Americans after adjusting for baseline mitotic index, age, gender, and pack-years of smoking [adjusted odd ratio (OR), 2.25; 95% confidence interval (95% CI), 0.97-5.20]. A significant trend of an increased risk of lung cancer with a decreased level of G2-M arrest was observed (P(trend) = 0.02) among African Americans, with a lowest-versus-highest quartile adjusted OR of 3.74 (95% CI, 0.98-14.3). This trend was most apparent among African American females (P(trend) < 0.01), with a lowest-versus-highest quartile adjusted OR of 11.75 (95% CI, 1.47-94.04). The results suggest that a less-efficient DNA damage-induced G2-M checkpoint is associated with an increased risk of lung cancer among African Americans. Interestingly, we observed a stronger association of DNA damage-induced G2-M arrest and lung cancer among African Americans when compared with Caucasians. If replicated, these results may provide clues to the exceedingly high lung cancer incidence experienced by African Americans.

Environmental exposure to carcinogens and individual susceptibility play significant roles in cancer risk. Suboptimal DNA repair capability, measured by quantifying mutagen-induced chromosome breaks, might explain variable host susceptibility to environmental carcinogens. In an ongoing lung cancer case-control study, we compared individual sensitivity to bleomycin-induced chromosome breaks in 152 non-small cell lung cancer patients with 94 population controls and 85 hospital controls with no history of cancer. Mutagen sensitivity was measured by mean number of chromatid breaks per cell in cultured peripheral blood lymphocytes treated with bleomycin. Non-parametric tests and chi(2) tests were used to determine the statistical significance of the crude case-control comparisons, followed by logistic regression to adjust for important covariates. The mean number of bleomycin-induced breaks per cell was 1.01 for the cases compared with 0.86 for hospital controls (P < 0.01) and 0.89 for population controls (P < 0.01). The mean number of breaks per cell was 1.01 for those >65 years old and 0.81 for those < or = 65 years old (P < 0.01) among population controls. Defining bleomycin sensitive as >0.84 break/cell (the median level in population controls), 67% of the cases were bleomycin sensitive compared with 49% of the hospital controls [adjusted odds ratio (OR) = 2.69, 95% confidence interval (CI) = 1.44, 5.04], and 51% of the population controls (adjusted OR = 2.18, 95% CI = 1.13, 4.21). Our data indicate that the increased number of bleomycin-induced chromosome breaks was significantly associated with an increased risk of lung cancer in the first 331 subjects.