Substance use, trait measures, and subjective response to nicotine in never-smokers stratified on parental smoking history and sex

Purpose Lung adenocarcinomas with mutations in exons 19 and 21 of the epidermal growth factor receptor gene (EGFR) demonstrate sensitivity to gefitinib or erlotinib. Investigators have reported an association between EGFR mutations and the amount and duration of cigarette smoking, with the highest incidence of mutations seen in never smokers. Methods EGFR exon 19 and 21 mutation status was determined in 265 tumor samples using direct sequencing, polymerase chain reaction (PCR), or PCR-based restriction fragment length polymorphism analysis. A detailed smoking history was obtained. Patients were categorized as never smokers (< 100 lifetime cigarettes), former smokers (quit ≥ 1 year ago), or current smokers (quit < 1 year ago). Results We detected EGFR mutations in 34 (51%) of 67 never smokers (95% CI, 38% to 64%), 29 (19%) of 151 former smokers (95% CI, 13% to 27%), and two (4%) of 47 current smokers (95% CI, 1% to 16%). Significantly fewer EGFR mutations were found in people who smoked for more than 15 pack-years (P < .001) or stopped smoking less than 25 years ago (P < .02) compared with individuals who never smoked. The number of smoking pack-years and smoke-free years predicted the prevalence of EGFR mutations (areas under receiver operating characteristic curve = 0.78 and 0.77, respectively). Conclusion The likelihood of EGFR mutations in exons 19 and 21 decreases as the number of pack-years increases. Mutations were less common in people who smoked for more than 15 pack-years or who stopped smoking cigarettes less than 25 years ago. These data can assist clinicians in assessing the likelihood of exon 19 and 21 EGFR mutations in patients with lung adenocarcinoma when mutational analysis is not feasible.

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Cross-sectional study of smoking exposure: no differential effect on OCT metrics in a cohort of MS patients

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217319828400 ◽

2019 ◽

Vol 5 (1) ◽

pp. 205521731982840 ◽

Cited By ~ 1

Author(s):

Mattia Rosso ◽

Dorlan J Kimbrough ◽

Cindy T Gonzalez ◽

Bonnie I Glanz ◽

Brian C Healy ◽

...

Keyword(s):

Fixed Effects ◽

Cross Sectional Study ◽

Smoking History ◽

Retinal Layer ◽

Fiber Layer ◽

Cross Sectional ◽

Macular Volume ◽

Smoking Exposure ◽

Significant Difference ◽

Never Smokers

Background Optical coherence tomography (OCT) provides quantitative measures of retinal layer thickness. Cigarette smoking is a risk factor for multiple sclerosis (MS) onset and disease severity: its effects on OCT metrics have not been assessed. Objective The objective of this study was to assess the effect of smoking history on retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform (GCIP) of MS patients by OCT. Methods 112 MS patients were recruited from the Brigham and Women’s Hospital. Spectralis OCT scans were acquired to measure GCIP, peripapillary RNFL, and total macular volume. Multivariable linear mixed effects regression model assessed RNFL and GCIP change with fixed effects for smoking history while adjusting for optic neuritis eye status, age, disease duration, sex, baseline EDSS, and disease modifying therapies (DMTs). Results Smoking histories were available for 102 patients: 46 (45.10%) had a history of smoking cigarettes and 56 (54.90%) never smoked. No statistically significant differences were found between ever-smokers and never-smokers with respect to GCIP, RNFL, and macular volume. Conclusion Our study shows no significant difference in retinal thickness between ever-smokers and never-smokers. If confirmed, this result suggests mechanistic differences between the retina and other central nervous system (CNS) compartments in response to smoking and should be noted when considering OCT as a surrogate measure of CNS activity.

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DNA methylation is associated with lung function in never smokers

Respiratory Research ◽

10.1186/s12931-019-1222-8 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 3

Author(s):

Maaike de Vries ◽

◽

Ivana Nedeljkovic ◽

Diana A. van der Plaat ◽

Alexandra Zhernakova ◽

...

Keyword(s):

Dna Methylation ◽

Lung Function ◽

Ribosome Biogenesis ◽

Meta Analysis ◽

Smoking History ◽

Rotterdam Study ◽

Main Risk Factor ◽

Cpg Sites ◽

Never Smokers ◽

Integrative Omics

Abstract Background Active smoking is the main risk factor for COPD. Here, epigenetic mechanisms may play a role, since cigarette smoking is associated with differential DNA methylation in whole blood. So far, it is unclear whether epigenetics also play a role in subjects with COPD who never smoked. Therefore, we aimed to identify differential DNA methylation associated with lung function in never smokers. Methods We determined epigenome-wide DNA methylation levels of 396,243 CpG-sites (Illumina 450 K) in blood of never smokers in four independent cohorts, LifeLines COPD&C (N = 903), LifeLines DEEP (N = 166), Rotterdam Study (RS)-III (N = 150) and RS-BIOS (N = 206). We meta-analyzed the cohort-specific methylation results to identify differentially methylated CpG-sites with FEV1/FVC. Expression Quantitative Trait Methylation (eQTM) analysis was performed in the Biobank-based Integrative Omics Studies (BIOS). Results A total of 36 CpG-sites were associated with FEV1/FVC in never smokers at p-value< 0.0001, but the meta-analysis did not reveal any epigenome-wide significant CpG-sites. Of interest, 35 of these 36 CpG-sites have not been associated with lung function before in studies including subjects irrespective of smoking history. Among the top hits were cg10012512, cg02885771, annotated to the gene LTV1 Ribosome Biogenesis factor (LTV1), and cg25105536, annotated to Kelch Like Family Member 32 (KLHL32). Moreover, a total of 11 eQTMS were identified. Conclusions With the identification of 35 CpG-sites that are unique for never smokers, our study shows that DNA methylation is also associated with FEV1/FVC in subjects that never smoked and therefore not merely related to smoking.

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Perceptions of Continued Smoking and Smoking Cessation Among Patients With Cancer

Journal of Oncology Practice ◽

10.1200/jop.17.00029 ◽

2018 ◽

Vol 14 (5) ◽

pp. e269-e279 ◽

Cited By ~ 10

Author(s):

Devon Alton ◽

Lawson Eng ◽

Lin Lu ◽

Yuyao Song ◽

Jie Su ◽

...

Keyword(s):

Quality Of Life ◽

Smoking Cessation ◽

Cancer Diagnosis ◽

Risk Perceptions ◽

Smoking History ◽

Smoking Cessation Counseling ◽

Patients With Cancer ◽

Never Smokers ◽

Multivariable Regression Models

Purpose: Continued smoking after a cancer diagnosis leads to poorer treatment outcomes, survival, and quality of life. We evaluated the perceptions of the effects of continued smoking on quality of life, survival, and fatigue among patients with cancer after a cancer diagnosis and the effects of these perceptions on smoking cessation. Patients and Methods: Patients with cancer from all disease subsites from Princess Margaret Cancer Centre (Toronto, Ontario) were surveyed between April 2014 and May 2016 for sociodemographic variables, smoking history, and perceptions of continued smoking on quality of life, survival, and fatigue. Multivariable regression models evaluated the association between patients’ perceptions and smoking cessation and the factors influencing patients’ perceptions of smoking. Results: Among 1,121 patients, 277 (23%) were smoking cigarettes up to 1 year before diagnosis, and 54% subsequently quit; 23% had lung cancer, and 27% had head and neck cancers. The majority felt that continued smoking after a cancer diagnosis negatively affected quality of life (83%), survival (86%), and fatigue (82%). Current smokers during the peridiagnosis period were less likely to perceive that continued smoking was harmful when compared with ex-smokers and never-smokers ( P < .01). Among current smokers, perceiving that smoking negatively affected quality of life (adjusted odds ratio [aOR], 2.68 [95% CI, 1.26 to 5.72]; P = .011), survival (aOR, 5.00 [95% CI, 2.19 to 11.43]; P < .001), and fatigue (aOR, 3.57 [95% CI, 1.69 to 7.54]; P < .001) were each strongly associated with smoking cessation. Among all patients, those with a greater smoking history were less likely to believe that smoking was harmful in terms of quality of life (aOR, 0.98 [95% CI, 0.98 to 0.99]; P < .001), survival (aOR, 0.98 [95% CI, 0.98 to 0.99]; P < .001), and fatigue (aOR, 0.99 [95% CI, 0.98 to 0.99]; P < .001). Conclusion: The perceptions of continued smoking after a cancer diagnosis among patients with cancer are strongly associated with smoking cessation. Counseling about the harms of continued smoking in patients with cancer, and in particular among those who have lower risk perceptions, should be considered when developing a smoking cessation program.

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Tobacco Use Influences Disease Outcome and AML Potential in Myelodysplastic Syndromes,

Blood ◽

10.1182/blood.v118.21.3790.3790 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3790-3790 ◽

Cited By ~ 1

Author(s):

Rami S. Komrokji ◽

Dana E Rollison ◽

Najla H Al Ali ◽

Maria Corrales-Yepez ◽

Pearlie K Epling-Burnette ◽

...

Keyword(s):

Tobacco Use ◽

Lower Risk ◽

Cox Regression ◽

Smoking History ◽

Hypomethylating Agents ◽

Cox Regression Analysis ◽

Poor Risk ◽

Baseline Characteristics ◽

Never Smokers ◽

Md Anderson

Abstract Abstract 3790 Background: Several epidemiologic studies suggest a linkage between smoking history and risk of myelodysplastic syndromes (MDS). Only one study addressed the potential impact of cigarette smoking on survival in lower risk MDS. We investigated the effect of smoking on disease outcome among MDS patients treated at the Moffitt Cancer Center (MCC). Methods: MDS patients were identified through the MCC database, followed by individual chart review. Tobacco use was obtained through patient self reported questionnaire. Chi square test and t-test were used to compare baseline characteristics. Kaplan Meier estimates were used to calculate overall survival (OS); log rank test was used for comparison between the different groups and Cox regression analysis was used for multivariable analysis. All analyses were conducted using SPSS version 19.0 software. Results: We identified 743 MDS patients evaluated at MCC with known tobacco smoking history (Data on tobacco use was only missing in 24 patients in the MDS database). Two hundred and fifty six patients never smoked (never-smoker group) and 487 patients were current or former smokers (ever smoker group). Tobacco use included current cigarettes smokers (n=70), former tobacco use (n=399), Cigar/pipe (n=16), Snuff/chew (n=2). The baseline characteristics compared between the 2 groups included age, WHO subtype, International Prognostic system (IPSS), MD Anderson risk model, karyotype, RBC transfusion dependence (RBC TD), serum ferritin, and treatment with hypomethylating agents. No statistically significant differences were observed between the 2 groups. (Table-1) In low and int-1 risk IPSS, a significantly greater proportion of poor risk karyotypes was observed in ever smokers (8.8%) versus never smokers (2.4%) (p=0.003). With a median duration of follow up of 55 months (95%CI 50.5–59.6), median OS for never smokers was 48 months (95%CI=36.9–59.1) compared to 35 months (95%CI =28.7–41.3) in ever smokers (p=0.01). The adverse effect of smoking was greatest in low and intermediate-1 IPSS risk groups where median OS was 69 months (95%CI= 42–96) in never smokers compared to 48 months (95%CI= 41–55) in smokers (p=0.006). The median OS was 69 mo (95%CI =42–96), 50 mo (95%CI= 43–57), and 38 mo (95%CI= 23–53) respectively in never-smoker, former-smoker, and current smoker groups in lower risk MDS (p=0.01). No difference was observed in int-2 and high risk IPSS groups with a median OS of 22 months (95%CI =11.75–32.2) in never smokers and 18 months (95%CI =14.3–21.7) in the ever smoker group. (p=0.89). An adverse impact of smoking was observed in good and intermediate risk karyotypes but not in poor risk karyotypes. Among low/int-1 risk IPSS, the rate of AML transformation was 18.2% in ever smokers compared to 9.5% in non-smokers (p=0.04) while no difference in rate of AML transformation was observed in int-2/high risk IPSS MDS between the 2 groups. In Cox regression analysis tobacco use in lower risk MDS predicted inferior OS (Hazard ratio (HR) 1.52 (95%CI 1.06–2.2) after adjustment for age >60, MD Anderson risk group, serum ferritin, RBC-TD, and use of hypomethylating agents. Conclusions: Our study confirms a negative impact of tobacco use on disease natural history and OS in a large cohort of MDS patients. The higher frequency of poor risk karyotype and AML progression among smoking, lower risk patients suggests that tobacco exposure influences disease biologic potential and behavioral modification to discontinue tobacco use may improve outcome. Disclosures: No relevant conflicts of interest to declare.

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Distinct Pattern Of Genomic Changes Associated With Smoking In Patients With Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v122.21.660.660 ◽

2013 ◽

Vol 122 (21) ◽

pp. 660-660 ◽

Cited By ~ 1

Author(s):

David J. Seastone ◽

Sudipto Mukherjee ◽

Zaher K. Otrock ◽

Paul Elson ◽

Michael K. Keng ◽

...

Keyword(s):

Risk Factor ◽

Histone Modification ◽

Conflicts Of Interest ◽

Multivariable Analysis ◽

Smoking History ◽

Common Mutation ◽

Single Mutation ◽

Molecular Abnormalities ◽

Smoking Exposure ◽

Never Smokers

Abstract Background Smoking is a risk factor for development of MDS and for overall survival. The pathogenesis of MDS is a multi-step process with both environmental and genetic influences. The link between smoking and MDS is thought to be mediated by organic solvents in tobacco. We identified specific molecular abnormalities associated with smoking exposure in MDS patients (pts). Methods 151 MDS pts seen from 2000-2012 with complete smoking and molecular data were included. Correlations and univariable comparisons were performed using Fisher’s Exact, Chi-square, Kruskal-Wallis, or Wilcoxon rank sum tests. Poisson regression models were used to assess associations between the number of mutations present and demographic and clinical factors. Analysis was performed using next-generation targeted deep gene sequencing with 22 common gene mutations, selected based on the frequency observed in a cohort of MDS patients analyzed by whole exome sequencing. Mutations were considered individually and in functional groups: methylation (TET2, IDH1, IDH2), histone modification (ASXL1, EZH2), and gene splicing (SRSF2, U2AF1, SF3B1). Paired DNA (tumor vs. CD3+ lymphocytes) produced raw sequence reads aligned using Burrows-Wheeler Aligner (BWA). Variants were detected using the Broad Institute's Best Practice Variant Detection GATK toolkit. Results Median age at MDS diagnosis was 68 years (range 20-85); 42% were female; and 77% had de novo MDS. IPSS (low, Int-1, Int-2, high) and IPSS-R (very low, low, int, high, very high) categories were: 26%, 44%, 22%, 7% and 10%, 40%, 19%, 18%, 13%, respectively; IPSS-R cytogenetic categories were: very good (<1%), good (60%), int (14%), poor (12%), very poor (14%). Median survival was 42.6 months (95% C.I. 34.5-56.0). 54% of pts (81) were former (42%) or current (11%) smokers; median tobacco exposure was similar for both groups: 26 pack years (range 1.5-150) for former and 30 (10-60) for current smokers, p=0.22. More men than women ever smoked (p=0.03); all other clinical characteristics among never, ex-, and current smokers were similar. Overall 68% of pts (100) had at least one mutation of the 22 screened mutations: 32% (48) had a single mutation, 22% (33) had 2, and 13% (19) had 3 (n=10) to 6 (n=1) mutations. The most common mutations were in TET2 (19%), SF3B1 (15%), ASXL1 (14%), DNMT3A (11%), and U2AF1 (10%); 32% of pts had one or more mutation in genes involved in methylation, 19% in histone modification, and 32% with splicing. In univariable analyses, current/ex-smokers were more likely to have at least one of the common mutation than never smokers (75% vs. 52%, respectively, p=0.05). This was particularly true for genes involved in histone modification (25% vs. 11%, respectively, p=0.06). The number of mutations increased with smoking exposure (p=0.02, Figure 1), particularly with genes involved with histone modification, p=0.01. Certain mutations increased in prevalence with age, e.g.: pts<60 had fewer mutations overall than pts >60 (p=0.003), and in particular fewer mutations in methylation-associated genes (p=0.0001). In multivariable analysis that adjusted for IPSS-R cytogenetics, older age (p=0.0005) and greater smoking history/exposure (p=0.002) were both associated with more mutations. Current and ex-smokers and heavier smoking exposure (>20 pack years) were also associated with worse survival (p=.03 and .01, respectively), though current or ex-smokers with <20 pack years had similar survival to never smokers. Multivariable analyses confirmed smoking as a risk factor for survival (HR 1.63 (1.1-2.42); p=0.02). Conclusion Smoking is associated with a greater number of molecular abnormalities in MDS pts, and may generate a distinct mutational signature pattern, particularly along histone acetylation pathways. This study identifies specific environmentally-mediated pathways in the multistep pathogenesis of MDS. Disclosures: No relevant conflicts of interest to declare.

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Smoking history and frequency of somatic KRAS mutations in adenocarcinoma of the lung

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.7573 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 7573-7573

Author(s):

V. A. Miller ◽

G. J. Riely ◽

M. G. Kris ◽

D. Rosenbaum ◽

J. Marks ◽

...

Keyword(s):

Cigarette Smoking ◽

Mutational Analysis ◽

Smoking History ◽

Egfr Mutations ◽

Molecular Testing ◽

Kras Mutations ◽

Exon 2 ◽

Significant Difference ◽

Never Smokers ◽

Lung Adenocarcinomas

7573 Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are more common in patients with adenocarcinoma, especially those who smoked < 15 pack years (py). KRAS mutations are found in ∼25% of lung adenocarcinomas, most commonly in codons 12 and 13 of exon 2 (∼85%) and have been associated with poor prognosis in resected disease [Winton NEJM 2005] and resistance to EGFR tyrosine kinase inhibitors [Pao PLoS Med 2005]. KRAS mutations are uncommon in non-small cell lung cancer histologies other than adenocarcinoma. We sought to determine the association between quantitative measures of cigarette smoking and presence of KRAS mutations in lung adenocarcinomas. Methods: Standard direct sequencing techniques were used to identify KRAS codon 12 and 13 mutations in lung adenocarcinoma specimens from surgical resections between 2001 and 2006 and tumor specimens sent for KRAS molecular analysis in 2006. Surgical specimens were obtained from an institutional tumor bank. Detailed smoking history (age at first cigarette, packs per day, years smoked, years since quitting smoking) was obtained from the medical record and a patient-completed smoking questionnaire. Results: KRAS mutational analysis was performed on 408 lung adenocarcinomas from 242 women and 166 men. Median age was 68 (range 33–89). KRAS mutations were present in 19% (78/408, 95% CI 15 to 23%). The frequency of KRAS mutation was not associated with age or gender. The presence of KRAS mutations was not related to smoking history with 15% (9/61) of never smokers having KRAS mutations compared with 19% (51/275) of former smokers. When compared with never smokers, there was no significant difference in frequency of KRAS mutations for tumors from patients with 1–5 py (5%, p=0.44), 6- 10 py (12%, p=0.99), 11–15 py (25%, p=0.45), 16–25 py (16%, p=0.99), 26–50 py (25%, p=0.129), 51–75 py (20%, p=0.48), >75 py (20%, p=0.47) history of cigarette smoking. Conclusions: While the incidence of EGFR mutations has a strong inverse relationship with the amount of cigarettes smoked, allowing the selective molecular testing for EGFR mutations, the frequency of KRAS mutations cannot be predicted by age, gender, or smoking history. KRAS mutational analysis of all adenocarcinomas is required to reliably identify patients with KRAS mutations. No significant financial relationships to disclose.

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Tumor mutation status of Hodgkin lymphoma survivors with secondary lung adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.9600 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 9600-9600

Author(s):

David Alan Bond ◽

Gregory Alan Otterson ◽

Neil Dunavin

Keyword(s):

Lung Cancer ◽

Radiation Therapy ◽

Lung Adenocarcinoma ◽

Age At Diagnosis ◽

Smoking History ◽

Second Primary ◽

Genomic Alterations ◽

Number Of Patients ◽

Never Smokers ◽

Diagnosis Of Lung Cancer

9600 Background: In a multi-institutional, retrospective study of 1976 patients treated for Hodgkin's lymphoma (HL) from 1969-2007, 55 patients developed second primary lung cancers a median of 19.5 years after treatment. Of these 55 cases, 32 were identified as lung adenocarcinoma (ACA). The development of targeted therapies in recent years has made the detection of specific genomic alterations important for disease prognosis and treatment in lung ACA. The prevalence of certain genomic alterations (EGFR, ALK, and KRAS) is highly correlated with smoking history. We hypothesize that the prevalence of genomic alterations also may differ in patients with a significant exposure to radiation. Methods: This observational retrospective case series includes 6 patients treated with mediastinal radiation for HL who subsequently developed lung ACA. All patients were treated at Ohio State University Wexner Medical Center. Patients were identified by searching billing diagnosis codes in the electronic medical record and by query of the physicians in the department of thoracic oncology at our institution. IRB approval was obtained. Results: The average age at diagnosis of HL was 25 years (range 18-46) and the average age at diagnosis of lung cancer was 58 (range 52-73). All patients were treated with radiation therapy; two patients were treated additionally with chemotherapy. None of the patients received HDT-ASCT. The average time from diagnosis of HL to diagnosis of lung cancer was 33 years. Of our six cases, 2 were positive for EGFR mutations and the other four were triple negative (-EGFR, -ALK, -KRAS). Three were never smokers, one had a 1.5 pack year history, and two had 10 pack year histories. Lung cancer stages at diagnosis were 1B (n=2), 2B (n=1), 3A (n=2), 4 (n=1). Conclusions: To our knowledge, this is the first report of mutational status of second primary lung ACA following radiation therapy for Hodgkin disease. Although the number of patients is small, the higher prevalence of the EGFR mutation in this sample suggests that ACA related to radiation therapy may have a similar mutational profile to that of never smokers. Further investigation is needed to define the disease characteristics of lung ACA in HL survivors.

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Effect of smoking on the efficacy of immune checkpoint inhibitors in advanced cancers: A systematic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14109 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14109-e14109

Author(s):

Chia Ching Lee ◽

Ivan Weng Keong Tham ◽

Yu Yang Soon ◽

Jeremy Chee Seong Tey

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Smoking Status ◽

Meta Analysis ◽

Random Effect ◽

Standard Of Care ◽

Smoking History ◽

P Value ◽

Never Smokers

e14109 Background: The association between smoking history and benefit from treatment with immune checkpoint inhibitors (ICIs) was unclear. We performed a meta-analysis to assess the efficacy of ICIs in advanced cancers according to smoking status (never-smokers vs ever-smokers). Methods: We searched MEDLINE and EMBASE for randomized controlled trials (RCTs) comparing immunotherapy with standard-of-care in the treatment of advanced cancers which reported overall survival (OS) as the outcome, stratified by smoking status. We calculated pooled hazard ratios (HRs) and 95% confidence interval (CIs) for OS using random-effect models and assessed the differences in OS between the two estimates (never smoker (vs) ever smoker). using a test of heterogeneity. We also performed prespecified subgroup analyses based on disease site, line of therapy, proportion of never-smokers in the trials and trial conclusion to assess the potential association of oncologic and methodologic factors in effect modification of smoking status with the efficacy of ICIs. Results: We identified ten RCTs on non-small cell lung cancer, head and neck, and urothelial cancers, including 4,245 ever-smokers and 972 never-smokers. The difference in the effects of ICIs on OS between ever-smokers (HR, 0.74; 95% CI, 0.66-0.84) and never-smokers (HR, 0.79; 95% CI, 0.61-1.02) was not statistically significant (interaction P-value = 0.69). There were no significant differences in the effects of ICIs on OS between ever-smokers and never smokers in the pre-specified subgroups. Conclusions: There was no significant association between smoking status and improved survival outcome with ICIs in the treatment of advanced cancers. Smoking status should not be used as a biomarker for guiding treatment with immunotherapy.

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