Knowledge and Practice Patterns Among Pulmonologists for Molecular Biomarker Testing in Advanced Non-small Cell Lung Cancer.

BACKGROUND: Targeted therapies for advanced non-small cell lung cancer (NSCLC) with oncogenic drivers have caused a paradigm shift in care. Biomarker testing is needed to assess eligibility for these therapies. Pulmonologists often perform bronchoscopy, providing tissue for both pathologic diagnosis and biomarker analysis. We performed this survey to define the existing knowledge and practices regarding the pulmonologists' role in biomarker testing for advanced NSCLC. RESEARCH QUESTION: What is the current knowledge and practice of pulmonologists regarding biomarker testing and targeted therapies in advanced NSCLC? STUDY DESIGN AND METHODS: This cross-sectional study was performed using an electronic survey of a random sample of 7,238 pulmonologists. Questions focused on diagnostic steps and biomarker analyses for NSCLC. RESULTS: A total of 453 pulmonologists responded. Respondents vary by reported lung cancer patient volume, ranging from 51% evaluating one to four new cases per month to 19% evaluating > 10 cases per month. Interventional training, academic practice setting, and higher volume of endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) were associated with increased knowledge of practice guidelines for the number of recommended passes during EBUS-TBNA (P < .05). Academic pulmonologists more commonly performed or referred for EBUS-TBNA than community pulmonologists (96% and 83%, respectively; P < .0005). Higher testing rates were associated with interventional training, academic setting, and the presence of an institutional policy, whereas lower testing rates were associated with general pulmonologists, practice in community settings, and lack of a guiding institutional policy (P < .05). INTERPRETATION: Substantial differences among pulmonologists' evaluation of advanced NSCLC, variation in knowledge of available biomarkers and the importance of targeted therapies, and differences in institutional coordination likely lead to underutilization of biomarker testing. Interventional training appears to drive improved knowledge and practice for biomarker testing more than practice setting. Improvements are needed in tissue acquisition and interdisciplinary coordination to ensure universal and comprehensive testing for eligible patients.

Effect of a Rule-in Biomarker Test on Pulmonary Nodule Management: A Survey of Pulmonologists and Thoracic Surgeons.

INTRODUCTION: The field of biomarker development is evolving to assist in determining benign from malignant pulmonary nodules. Although a prospective clinical utility would best to show how a biomarker affects patient treatment and outcomes, we sought to begin to understand how the results might alter management by determining how physicians would use the results of a rule-in blood test to manage pulmonary nodules. MATERIALS AND METHODS: Pulmonologists and thoracic surgeons in the American College of Chest Physicians clinician database were invited to participate in an online survey. The participant demographic data were collected. Four hypothetical clinical vignettes were presented. The participants accessed the pretest probability (probability of cancer [pCA]) for malignancy and chose the management strategies as the case progressed. The management strategies chosen before and after the result of a rule-in biomarker test were compared and assessed for guideline concordance. RESULTS: Of the 455 eligible participants who had opened the survey, 416 (92%) completed it: 332 pulmonologists and 84 thoracic surgeons. Although 91% of the participants were very comfortable managing nodules, depending on the case, 30% to 62% incorrectly assessed the pCA, with 22% to 62% overestimating the risk and 8% to 51% underestimating the risk. After a rule-in blood test result, the clinician change in management moved in the right direction in some cases but, in others, the physicians used the results incorrectly. Pulmonologists and thoracic surgeons differed in the management strategies, with surgeons recommending surgery more often. CONCLUSIONS: Although the use of biomarker testing for pulmonary nodule evaluation is promising, without proper physician education, the potential for harm exists. Clinical utility studies are needed to appropriately inform the effect of biomarker use.

Comparison of Programmed Death Ligand-1 Immunohistochemical Staining Between Endobronchial Ultrasound Transbronchial Needle Aspiration and Resected Lung Cancer Specimens.

BACKGROUND: In advanced non-small cell lung cancer (NSCLC), small biopsy specimens from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are often the only available material from cancer tissue for the analysis of programmed death ligand-1 (PD-L1) expression. We aim to assess the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PD-L1 expression at ≥ 1% and ≥ 50% on EBUS-TBNA samples compared with their corresponding surgically resected tumor. METHODS: We retrospectively reviewed all patients who underwent EBUS-TBNA followed by surgical resection of NSCLC between July 2006 and September 2016. Demographic information and periprocedural/surgical data were collected. The archived specimens were retrieved and assessed for PD-L1. A positive PD-L1 stain was defined using two separate cutoff points: ≥ 1% and ≥ 50% of tumor cell positivity. EBUS-TBNA aspirates were compared with the surgically resected specimen to calculate the sensitivity, specificity, PPV, and NPV. RESULTS: Sixty-one patients were included. For PD-L1 ≥ 1%, the sensitivity, specificity, PPV, and NPV were 72%, 100%, 100%, and 80%, respectively. For PD-L1 ≥ 50%, the sensitivity, specificity, PPV, and NPV were 47%, 93%, 70%, and 84%, respectively. The concordance rates for PD-L1 ≥ 1% and ≥ 50% were 87% and 82%, respectively. CONCLUSIONS: A PD-L1 cutoff of ≥ 1% on EBUS-TBNA has a strong correlation with resected tumor specimen. For PD-L1 ≥ 50%, there is a significant decrease in the sensitivity and PPV of EBUS-TBNA specimen when compared with resected tumor. When analyzing for PD-L1 expression using a cutoff of ≥ 50%, EBUS-TBNA specimens may misclassify the status of PD-L1.

Cost-effectiveness of an autoantibody test (EarlyCDT-Lung) as an aid to early diagnosis of lung cancer in patients with incidentally detected pulmonary nodules.

OBJECTIVE: Patients who have incidentally detected pulmonary nodules and an estimated intermediate risk (5-60%) of lung cancer frequently are followed via computed tomography (CT) surveillance to detect nodule growth, despite guidelines for a more aggressive diagnostic strategy. We examined the cost-effectiveness of an autoantibody test (AABT)-Early Cancer Detection Test-Lung (EarlyCDT-LungTM)-as an aid to early diagnosis of lung cancer among such patients. METHODS: We developed a decision-analytic model to evaluate use of the AABT versus CT surveillance alone. In the model, patients with a positive AABT-because they are at substantially enhanced risk of lung cancer-are assumed to go directly to biopsy, resulting in diagnosis of lung cancer in earlier stages than under current guidelines (a beneficial stage shift). Patients with a negative AABT, and those scheduled for CT surveillance alone, are assumed to have periodic CT screenings to detect rapid growth and thus to have their lung cancers diagnosed-on average-at more advanced stages. RESULTS: Among 1,000 patients who have incidentally detected nodules 8-30 mm, have an intermediate-risk of lung cancer, and are evaluated by CT surveillance alone, 95 (9.5%) are assumed to have lung cancer (local, 73.6%; regional, 22.0%; distant, 4.4%). With use of the AABT set at a sensitivity/specificity of 41%/93% (stage shift = 10.8%), although expected costs would be higher by $949,442 ($949 per person), life years would be higher by 53 (0.05 per person), resulting in a cost per life-year gained of $18,029 and a cost per quality-adjusted life year (QALY) gained of $24,330. With use of the AABT set at a sensitivity/specificity of 28%/98% (stage shift = 7.4%), corresponding cost-effectiveness ratios would be $18,454 and $24,833. CONCLUSIONS: Under our base-case assumptions, and reasonable variations thereof, using AABT as an aid in the early diagnosis of lung cancer in patients with incidentally detected pulmonary nodules who are estimated to be at intermediate risk of lung cancer and are scheduled for CT surveillance alone is likely to be a cost-effective use of healthcare resources.

Molecular and Immune Biomarker Testing in Squamous-Cell Lung Cancer: Effect of Current and Future Therapies and Technologies.

Patients with non-small-cell lung cancer, including squamous-cell lung cancer (SqCLC), typically present at an advanced stage. The current treatment landscape, which includes chemotherapy, radiotherapy, surgery, immunotherapy, and targeted agents, is rapidly evolving, including for patients with SqCLC. Prompt molecular and immune biomarker testing can serve to guide optimal treatment choices, and immune biomarker testing is becoming more important for this patient population. In this review we provide an overview of current and emerging practices and technologies for molecular and immune biomarker testing in advanced non-small-cell lung cancer, with a focus on SqCLC.

Cannabis Use, Lung Cancer, and Related Issues.

The cannabis plant and its derivatives have been exploited for centuries for recreational and medicinal purposes, with millions of regular users around the world. The recreational use of cannabis is reflective of its neuropsychiatric effects, such as anxiolysis and euphoria. However, cannabis appears to have an emerging therapeutic role, especially in chronic disease and as an adjunct to cancer treatment. Increasing evidence supports cannabis in the management of chemotherapy-induced nausea and vomiting (CINV) and for pain management; however, studies are limited, particularly by difficulties associated with standardized dosing estimates and inability to accurately assess biologic activities of compounds in cannabis and derivative products. Smoking cannabis has not been proved to be a risk factor in the development of lung cancer, but the data are limited by small studies, misclassification due to self-reporting of use, small numbers of heavy cannabis smokers, and confounding of the risk associated with known causative agents for lung cancer (such as parallel chronic tobacco use). Cannabis and its biologically effective derivatives warrant additional research, ideally, controlled trials in which the cannabidiol and the delta-9-tetrahydrocabinol strength and use are controlled and documented.

Extent of Resection and Lymph Node Assessment for Clinical Stage T1aN0M0 Typical Carcinoid Tumors.

BACKGROUND: The optimal extent of lung resection and lymph node (LN) assessment for surgical treatment of clinical stage T1aN0M0 typical carcinoid tumors is unclear. Using a cohort including only these patients, we aimed to determine the impact of extent of lung resection and LN assessment on overall survival. METHODS: Patients undergoing lobectomy or sublobar resection for clinical stage T1aN0M0 intraparenchymal typical carcinoid tumor were identified in the National Cancer Data Base from 1998 to 2012. Kaplan-Meier analysis was used to determine overall survival. A multivariable Cox proportional hazards model was used to determine independent predictors of mortality. RESULTS: Of 1,495 patients, 536 (35.9%) had sublobar resection (wedge resection, n = 429; segmentectomy, n = 91) and 959 (64.2%) had lobectomy. There were 366 patients (24.5%) with no LN assessment. As tumor size increased, sublobar resection decreased and LN assessment increased. Overall, 60 patients (4.0%) were upstaged. Fifty-two patients were upstaged because of LN metastases (40 pN1, 11 pN2, and 1 pN3). The 5-year overall survival rate was 87%. It was 88% for lobectomy versus 87% for sublobar resection (p = 0.3), 65% for LN upstaging versus 89% for patients without LN upstaging, and 86% for patients with no LN assessment (p = 0.002). Independent predictors of mortality included LN upstaging, age, male sex, and Charlson comorbidity index. CONCLUSIONS: For patients with clinical stage T1aN0M0 typical carcinoid, sublobar resection results in similar overall survival compared with lobectomy. However, regardless of resection type, LN assessment is important to identify LN upstaging, the strongest independent predictor of overall mortality.

Scientific Advances in Thoracic Oncology 2016.

Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review.

Long-Term Results of a Trial of Concurrent Chemotherapy and Escalating Doses of Radiation for Unresectable Non-Small Cell Lung Cancer: NCCTG N0028 (Alliance).

INTRODUCTION: This phase I/II trial was designed to determine the maximally tolerated dose of thoracic radiotherapy as part of a combined modality approach. This report includes the long-term outcomes of patients treated on this study. The phase II portion was never completed, as RTOG-0617 opened before it was concluded. METHODS: In this study, the maximally tolerated dose was defined as 74 Gy of radiation in 37 fractions. Twenty-five patients with unresectable NSCLC were treated with 2-Gy daily fractions and concurrent weekly carboplatin and paclitaxel. Of these patients, 20 had stage III disease and five had stage I or II disease. RESULTS: Patients were followed until death or for a minimum of 5 years in the case of survivors. The median and 5-year survivals were 42.5 months and 20% for all patients, 52.9 months and 40% in patients with stages I or II disease, and 39.8 months and 15% in patients with stage III disease. CONCLUSIONS: The median survival of the stage III patients was quite favorable. We believe that this may have been due to a robust central review program of radiotherapy plans before treatment, ensuring compliance with protocol guidelines along with very low exposure of the heart to radiotherapy. Further improvements in 5-year survival will likely require research on both systemic therapy and thoracic radiotherapy. Potential therapeutic modalities that may aid in these efforts include immunotherapy, targeted therapy, improved imaging, adaptive radiotherapy, simultaneous integrated boost techniques, novel dose fractionation regimens, and charged particle therapy.

Accuracy of volatile urine biomarkers for the detection and characterization of lung cancer.

BACKGROUND: The mixture of volatile organic compounds in the headspace gas of urine may be able to distinguish lung cancer patients from relevant control populations. METHODS: Subjects with biopsy confirmed untreated lung cancer, and others at risk for developing lung cancer, provided a urine sample. A colorimetric sensor array was exposed to the headspace gas of neat and pre-treated urine samples. Random forest models were trained from the sensor output of 70% of the study subjects and were tested against the remaining 30%. Models were developed to separate cancer and cancer subgroups from control, and to characterize the cancer. An additional model was developed on the largest clinical subgroup. RESULTS: 90 subjects with lung cancer and 55 control subjects participated. The accuracies, reported as C-statistics, for models of cancer or cancer subgroups vs. control ranged from 0.795 - 0.917. A model of lung cancer vs. control built using only subjects from the largest available clinical subgroup (30 subjects) had a C-statistic of 0.970. Models developed and tested to characterize cancer histology, and to compare early to late stage cancer, had C-statistics of 0.849 and 0.922 respectively. CONCLUSIONS: The colorimetric sensor array signature of volatile organic compounds in the urine headspace may be capable of distinguishing lung cancer patients from clinically relevant controls. The incorporation of clinical phenotypes into the development of this biomarker may optimize its accuracy.