Cost of screening for lung cancer in Australia.

BACKGROUND: Lung cancer screening can reduce lung cancer mortality. Australian cost estimates are important to inform policy but remain uncertain. AIM: To describe the first direct medical costs associated with lung cancer screening in Australia. METHODS: Single-centre prospective screening cohort. Healthy volunteers (age 60-74 years, current or former smokers quit <15 years prior to enrolment, ≥30 pack-years exposure) underwent baseline and two annual incidence computed tomography (CT) screening scans. Health status and healthcare usage data were collated for 5 years. The main outcome measures were: rates of lung cancer; individual healthcare resource use derived from multiple data sources adjusted to 2018 Australian Medicare Benefits Schedule values. RESULTS: A total of 256, 239, 233 participants was screened at each round respectively; 12 participants were diagnosed with lung cancer during screening and 2 during follow-up: 9 underwent surgery, 4 received concurrent chemoradiation, 1 received palliative chemotherapy. One surgical case died from lymphoma 1407 days after diagnosis, all other surgical cases survived >5 years. Non-surgical median survival post-diagnosis was 654 days. Gross trial cost was Australian dollar (AU$) 965 665 (AU$397 396 CT scans; AU$29 303 false-positive scan work-up; AU$96 340 true-positive scan workup; AU$336 914 lung cancer treatment; AU$104 712 lung cancer follow-up post-treatment). Average total direct medical cost per participant was AU$3 768. Average direct cost of surgery was AU$22 659; average non-surgical cost was AU$47 395 (radiotherapy, chemotherapy, palliative care). CONCLUSIONS: Advanced cancer cost more to treat and had worse survival than early cancer. Screening costs are similar to international studies and suggest that lung cancer early detection could limit treatment costs and improve outcomes.

The effect of different radiological models on diagnostic accuracy and lung cancer screening performance.

High false-positive (FP) scan rates associated with low-dose computed tomography (LDCT) lung cancer screening result in unnecessary follow-up tests and exposure to harm. The definition of a 'positive' scan can impact FP rates and screening performance. We explored the effect of Lung Imaging Reporting and Data System (Lung-RADS) criteria, PanCan Nodule Malignancy Probability Model and varying nodule size thresholds (≥4 mm, ≥6 mm, ≥8 mm) on diagnostic accuracy and screening performance compared with original trial definitions (National Lung Screening Trial (NLST) criteria) in a secondary analysis of a lung cancer screening cohort. We found Lung-RADS criteria and the PanCan Nodule Malignancy Probability Model could substantially improve screening performance and reduce FP scan rates compared with NLST definitions of positivity but that this needs to be balanced against possible risk of false-negative results. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry, ACTRN12610000007033.

Brief Tailored Smoking Cessation Counseling in a Lung Cancer Screening Population is Feasible: A Pilot Randomized Controlled Trial.

INTRODUCTION: Maximizing smoking abstinence in lung cancer screening participants is important to reduce individual risk of disease and improve screening cost-effectiveness; however, the optimal strategy remains undefined. We hypothesized that a single session of tailored face-to-face counseling on the day of screening CT scan, coupled with audio and printed cessation information would be feasible to deliver in a CT screening trial. METHODS: We randomized volunteer smokers in the Queensland Lung Cancer Screening Study to intervention (counseling session, audio quit materials, printed quit materials, Quitline contact details) or control group (printed quit materials, Quitline contact details). Participants self-reported point prevalence quit rates at 1 year. RESULTS: Fifty-five smokers were enrolled; 28 randomized to intervention and 27 controls. Median cigarette consumption was 25/day; 54/55 smoked at least 15 cigarettes per day. Median smoking duration was 46 years. Median Fagerström dependence score was 6. In total 58% did not report any quit attempt in the prior 12 months. Mean duration of counseling was 26.5 minutes. After 1 year, four participants (14.3%) in the intervention group and five participants (18.5%) in the control group had quit (P = .74). Combined annual point prevalence quit rate was 16.4%. CONCLUSIONS: Although feasible to deliver a single session of tailored counseling on the day of screening this intervention had no discernible impact on cessation over and above printed materials and Quitline access. As participants exhibited hardcore smoking characteristics, more intensive strategies, in larger cohorts, should be explored. IMPLICATIONS: The optimal smoking cessation strategy within a lung cancer screening program is not known. This study demonstrates that a single session of counseling can be feasibly delivered on the day of screening but may not have been intensive enough for long-term, hard-core smokers.

Genetic influences on right ventricular systolic pressure (RVSP) in chronic obstructive pulmonary disease (COPD).

BACKGROUND: Pulmonary hypertension (PH) is a complication of chronic obstructive pulmonary disease (COPD). This study examined genetic variations in mediators of vascular remodelling and their association with PH in patients with COPD. In patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia. METHODS: In patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia. RESULTS: 580 COPD patients were recruited, 341 patients had a transthoracic echocardiogram, with RVSP measurable in 278 patients (mean age 69 years, mean FEV1 50% predicted, mean RVSP 44 mmHg, median history of 50 pack-years). Of the 7 tested SNPs, the NOS3-VNTR polymorphism was significantly associated with RVSP in a dose-dependent fashion for the risk allele: mean RVSP for a/a and a/b genotypes were 52.0 and 46.6 mmHg respectively, compared to 43.2 mmHg for b/b genotypes (P = 0.032). No associations were found between RVSP and other polymorphisms. ACE II or ID genotypes were associated with a lower FEV1% predicted than the ACE DD genotype (P = 0.028). The NOS3-298 TT genotype was associated with lower KCO % predicted than the NOS3-298 GG or GT genotype (P = 0.031). CONCLUSIONS: The NOS3-VNTR polymorphism was associated with RVSP in patients with COPD, supporting its involvement in the pathogenesis of PH in COPD. ACE and NOS3 genotypes were associated with COPD disease severity, but not with the presence of PH. Further study of these genes could lead to the development of prognostic and screening tools for PH in COPD.

MicroRNA-218 is deleted and downregulated in lung squamous cell carcinoma.

MicroRNAs (miRNAs) are a family of small, non-coding RNA species functioning as negative regulators of multiple target genes including tumour suppressor genes and oncogenes. Many miRNA gene loci are located within cancer-associated genomic regions. To identify potential new amplified oncogenic and/or deleted tumour suppressing miRNAs in lung cancer, we inferred miRNA gene dosage from high dimensional arrayCGH data. From miRBase v9.0 (http://microrna.sanger.ac.uk), 474 human miRNA genes were physically mapped to regions of chromosomal loss or gain identified from a high-resolution genome-wide arrayCGH study of 132 primary non-small cell lung cancers (NSCLCs) (a training set of 60 squamous cell carcinomas and 72 adenocarcinomas). MiRNAs were selected as candidates if their immediately flanking probes or host gene were deleted or amplified in at least 25% of primary tumours using both Analysis of Copy Errors algorithm and fold change (≥ ± 1.2) analyses. Using these criteria, 97 miRNAs mapped to regions of aberrant copy number. Analysis of three independent published lung cancer arrayCGH datasets confirmed that 22 of these miRNA loci showed directionally concordant copy number variation. MiR-218, encoded on 4p15.31 and 5q35.1 within two host genes (SLIT2 and SLIT3), in a region of copy number loss, was selected as a priority candidate for follow-up as it is reported as underexpressed in lung cancer. We confirmed decreased expression of mature miR-218 and its host genes by qRT-PCR in 39 NSCLCs relative to normal lung tissue. This downregulation of miR-218 was found to be associated with a history of cigarette smoking, but not human papilloma virus. Thus, we show for the first time that putative lung cancer-associated miRNAs can be identified from genome-wide arrayCGH datasets using a bioinformatics mapping approach, and report that miR-218 is a strong candidate tumour suppressing miRNA potentially involved in lung cancer.

ADAM28: a potential oncogene involved in asbestos-related lung adenocarcinomas.

Asbestos-related lung cancer accounts for 4-12% of all lung cancers worldwide. Since putative mechanisms of carcinogenesis differ between asbestos and tobacco induced lung cancers, tumors induced by the two agents may be genetically distinct. To identify gene expression biomarkers associated with asbestos-related lung tumorigenicity we performed gene expression array analysis on tumors of 36 patients with primary lung adenocarcinoma, comparing 12 patients with lung asbestos body counts above levels associated with urban dwelling (ARLC-AC: asbestos-related lung cancer-adenocarcinoma) with 24 patients with no asbestos bodies (NARLC-AC: non-asbestos related lung cancer-adenocarcinoma). Genes differentially expressed between ARLC-AC and NARLC-AC were identified on fold change and P value, and then prioritized using gene ontology. Candidates included ZNRF3, ADAM28, PPP1CA, IRF6, RAB3D, and PRDX1. Expression of these six genes was technically and biologically replicated by qRT-PCR in the training set and biologically validated in three independent test sets. ADAM28, encoding a disintegrin and metalloproteinase domain protein that interacts with integrins, was consistently upregulated in ARLC across all four datasets. Further studies are being designed to investigate the possible role of this gene in asbestos lung tumorigenicity, its potential utility as a marker of asbestos related lung cancer for purposes of causal attribution, and its potential as a treatment target for lung cancers arising in asbestos exposed persons.

Lung asbestos content in lungs resected for primary lung cancer.

INTRODUCTION: The majority of Australia's burden of lung cancer occurs in current or former tobacco smokers. To determine the possible contribution of asbestos exposure in Australians presenting with primary lung cancer, we measured lung asbestos content in cases resected consecutively at a single cardio-thoracic hospital. METHODS: Asbestos bodies were quantified by lung tissue digestion, filtration, and light microscopy, and were correlated with exposure questionnaires and clinicopathological features. RESULTS: We demonstrate high intrarater reproducibility and interrater reliability using these methods. In 463 patients with resected primary lung cancers, asbestos content ranged from 0 to 749 asbestos bodies per gram wet weight (AB/gww). Forty-eight percent of patients had no asbestos bodies identified. One-third had less than or equal to 20 AB/gww (a level previously found to be consistent with urban dwelling). Nineteen percent had lung content in excess of this level. Only 20 cases had AB >100/gww, approximately equivalent to the Helsinki threshold for attribution of lung cancer to asbestos. Median asbestos body counts were higher in patients who reported previous asbestos exposure than in those who reported no exposure. A subgroup of cases gave detailed exposure histories that did not predict presence or absence of asbestos bodies in men or women. In cases with cumulative tobacco exposure less than 20 pack-years, asbestos body counts exceeding 20 AB/gww were overrepresented. CONCLUSIONS: We found that the majority of patients with primary lung cancer at a single Australian center have detectable asbestos in resected lung tissue, but fiber burdens are generally low. The contributory role of this low-level asbestos exposure in causing lung cancer remains uncertain.

Gene expression signature predicts recurrence in lung adenocarcinoma.

PURPOSE: Improving outcomes for early-stage lung cancer is a major research focus at present because a significant proportion of stage I patients develop recurrent disease within 5 years of curative-intent lung resection. Within tumor stage groups, conventional prognostic indicators currently fail to predict relapse accurately. EXPERIMENTAL DESIGN: To identify a gene signature predictive of recurrence in primary lung adenocarcinoma, we analyzed gene expression profiles in a training set of 48 node-negative tumors (stage I-II), comparing tumors from cases who remained disease-free for a minimum of 36 months with those from cases whose disease recurred within 18 months of complete resection. RESULTS: Cox proportional hazards modeling with leave-one-out cross-validation identified a 54-gene signature capable of predicting risk of recurrence in two independent validation cohorts of 55 adenocarcinomas [log-rank P=0.039; hazard ratio (HR), 2.2; 95% confidence interval (95% CI), 1.1-4.7] and 40 adenocarcinomas (log-rank P=0.044; HR, 3.3; 95% CI, 1.4-7.9). Kaplan-Meier log-rank analysis found that predicted poor-outcome groups had significantly shorter survival, and furthermore, the signature predicted outcome independently of conventional indicators of tumor stage and node stage. In a subset of earliest stage adenocarcinomas, generally expected to have good outcome, the signature predicted samples with significantly poorer survival. CONCLUSIONS: We describe a 54-gene signature that predicts the risk of recurrent disease independently of tumor stage and which therefore has potential to refine clinical prognosis for patients undergoing resection for primary adenocarcinoma of the lung.