Evaluating Molecular Biomarkers for the Early Detection of Lung Cancer: When Is a Biomarker Ready for Clinical Use? An Official American Thoracic Society Policy Statement.

BACKGROUND: Molecular biomarkers have the potential to improve the current state of early lung cancer detection. The goal of this project was to develop a policy statement that provides guidance about the level of evidence required to determine that a molecular biomarker, used to support early lung cancer detection, is appropriate for clinical use. METHODS: An ad hoc project steering committee was formed, to include individuals with expertise in the early detection of lung cancer and molecular biomarker development, from inside and outside of the Assembly on Thoracic Oncology. Key questions, generated from the results of a survey of the project steering committee, were discussed at an in-person meeting. Results of the discussion were summarized in a policy statement that was circulated to the steering committee and revised multiple times to achieve consensus. RESULTS: With a focus on the clinical applications of lung cancer screening and lung nodule evaluation, the policy statement outlines categories of results that should be reported in the early phases of molecular biomarker development, discusses the level of evidence that would support study of the clinical utility, describes the outcomes that should be proven to consider a molecular biomarker clinically useful, and suggests study designs capable of assessing these outcomes. CONCLUSIONS: The application of molecular biomarkers to assist with the early detection of lung cancer has the potential to substantially improve our ability to select patients for lung cancer screening, and to assist with the characterization of indeterminate lung nodules. We have described relevant considerations and have suggested standards to apply when determining whether a molecular biomarker for the early detection of lung cancer is ready for clinical use.

Indeterminate Pulmonary Nodules: How to Minimize Harm.

Each year, more than 1 million persons worldwide are found to have a lung nodule that carries a risk of being malignant. In reality, the vast majority of lung nodules are benign, whether identified by screening or incidentally. The consequences of delaying or missing the diagnosis of lung cancer can be substantial, as can be the consequences of invasive procedures on patients with benign lung nodules. The challenge for the clinician caring for these patients is to differentiate between benign and malignant nodules with the least harm possible. In this review, we will discuss management strategies of the indeterminate pulmonary nodule and will review recent advances and harm-reduction strategies.

Changes in global function and regional ventilation and perfusion on SPECT during the course of radiotherapy in patients with non-small-cell lung cancer.

PURPOSE: This study aimed to (1) examine changes in dyspnea, global pulmonary function test (PFT) results, and functional activity on ventilation (V)/perfusion (Q) single-photon emission computerized tomography (SPECT) scans during the course of radiation (RT), and (2) factors associated with the changes in patients with non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Fifty-six stage I to III NSCLC patients treated with definitive RT with or without chemotherapy were enrolled prospectively. Dyspnea was graded according to Common Terminology Criteria for Adverse Events version 3.0 prior to and weekly during RT. V/Q SPECT-computed tomography (CT) and PFTs were performed prior to and during RT at approximately 45 Gy. Functions of V and Q activities were assessed using a semiquantitative scoring of SPECT images. RESULTS: Breathing improved significantly at the third week (mean dyspnea grade, 0.8 vs. 0.6; paired t-test p = 0.011) and worsened during the later course of RT (p > 0.05). Global PFT results did not change significantly, while regional lung function on V/Q SPECT improved significantly after ∼45 Gy. The V defect score (DS) was 4.9 pre-RT versus 4.3 during RT (p = 0.01); Q DS was 4.3 pre-RT versus 4.0 during RT (p < 0.01). Improvements in V and Q functions were seen primarily in the ipsilateral lung (V DS, 1.9 pre-RT versus 1.4 during RT, p < 0.01; Q DS, 1.7 pre-RT versus 1.5 during RT, p < 0.01). Baseline primary tumor volume was significantly correlated with pre-RT V/Q DS (p < 0.01). Patients with central lung tumors had greater interval changes in V and Q than those with more peripheral tumors (p <0.05 for both V and Q DS). CONCLUSIONS: Regional ventilation and perfusion improved during RT at 45 Gy. This suggests that adaptive planning based on V/Q SPECT during RT may allow sparing of functionally recoverable lung tissue.

The application of molecular diagnostic studies interrogating EGFR and KRAS mutations to stained cytologic smears of lung carcinoma.

EGFR and KRAS mutation analyses are of increasing importance for guiding the treatment of non-small cell lung carcinomas. Insufficient cellularity of cell blocks can represent an impediment to the performance of these tests. We investigated the usefulness of cytologic direct smears as an alternative specimen source for mutation testing. Tumor cell-enriched areas from freshly prepared and archived rapid Romanowsky-stained direct smears in 33 cases of lung carcinoma were microdissected for DNA isolation and evaluated for EGFR and KRAS mutations. EGFR mutations were detected in 3 adenocarcinomas; 2 tumors had the L858R substitution and 1 an exon 19 deletion. KRAS mutations affecting codon 12, 13, or 61 were detected in 11 cases (8 adenocarcinomas and 3 non-small cell carcinomas). EGFR and KRAS mutations were mutually exclusive. Hence, archived and freshly prepared direct smears represent a robust and valuable specimen source for molecular studies, especially when cell blocks exhibit insufficient cellularity.

Semiquantification and classification of local pulmonary function by V/Q single photon emission computed tomography in patients with non-small cell lung cancer: potential indication for radiotherapy planning.

INTRODUCTION: Perfusion (Q) single photon emission computed tomography (SPECT) has been used to divert dose away from higher-functioning lung during radiation therapy (RT) planning. This study aimed to (1) study regional lung function through coregistered pulmonary ventilation/perfusion (V/Q)-SPECT-CT and (2) classify these defects for its potential value in radiation planning in patients with non-small cell lung cancer (NSCLC). METHODS: Patients with stages I to III NSCLC requiring radiation-based therapy were eligible for this prospective study. V/Q-SPECT performed within 2 weeks before the start of radiation was interpreted by nuclear medicine physicians and then measured by a semiquantitative score. The potential mechanism of V and Q defects was analyzed; the potential impact of V/Q-SPECT over Q-SPECT alone was completed through classified applications (high-dose RT versus RT avoidance) during planning. RESULTS: Images of 51 consecutive patients were analyzed. The V and Q defects were matched, reverse mismatched (V defect > Q defect), and mismatched (Q defect > V defect) in 61, 31, and 8% of patients, respectively. Tumor was the leading cause of the defects of ipsilateral lung in 73% of patients. The defect scores of the ipsilateral lung were greater in patients with central primaries than those with peripheral primaries for both V-SPECT (2.3 ± 1.1 versus 1.5 ± 0.8, p = 0.017) and Q-SPECT (2.2 ± 0.8 versus 1.4 ± 0.6, p = 0.000). The patients with chronic obstructive pulmonary disease had greater defect scores in contralateral lung for both V-SPECT (1.5 ± 0.7 versus 1.0 ± 0.8, p = 0.006) and Q-SPECT (1.4 ± 0.6 versus 1.0 ± 0.4, p = 0.010). On assessing the potential value of SPECT on RT plan, 39% of patients could have their RT plan when applying V/Q-SPECT rather than Q-SPECT alone. CONCLUSIONS: V/Q-SPECT provides a more comprehensive functional assessment, may provide additional value over Q-SPECT alone in assessing local pulmonary function, and guide RT plan decisions in patients with NSCLC.

Time to treatment in patients with stage III non-small cell lung cancer.

PURPOSE: To determine whether time to treatment (TTT) has an effect on overall survival (OS) in patients with unresectable or medically inoperable Stage III non-small cell lung cancer (NSCLC) and whether patient or treatment factors are associated with TTT. METHODS AND MATERIALS: Included in the study were 237 consecutive patients with Stage III NSCLC treated at University of Michigan Hospital (UM) or the Veterans Affairs Ann Arbor Healthcare System (VA). Patients were treated with either palliative or definitive radiotherapy and radiotherapy alone (n = 106) or either sequential (n = 69) or concurrent chemoradiation (n = 62). The primary endpoint was OS. RESULTS: Median follow-up was 69 months, and median TTT was 57 days. On univariate analysis, the risk of death did not increase significantly with longer TTT (p = 0.093). However, subset analysis showed that there was a higher risk of death with longer TTT in patients who survived >or= 5 years (p = 0.029). Younger age (p = 0.027), male sex (p = 0.013), lower Karnofsky Performance Score (KPS) (p = 0.002), and treatment at the VA (p = 0.001) were significantly associated with longer TTT. However, on multivariate analysis, only lower KPS remained significantly associated with longer TTT (p = 0.003). CONCLUSION: Time to treatment is significantly associated with OS in patients with Stage III NSCLC who lived longer than 5 years, although it is not a significant factor in Stage III patients as a whole. Lower KPS is associated with longer TTT.

The predictive role of plasma TGF-beta1 during radiation therapy for radiation-induced lung toxicity deserves further study in patients with non-small cell lung cancer.

BACKGROUND: This study aimed to further investigate the role of circulating TGF-beta1 during radiation therapy (RT) in predicting radiation-induced lung toxicity (RILT). METHODS AND MATERIALS: Patients with stages I-III non-small cell lung cancer treated with RT based therapy were included in this study. Platelet poor plasma was obtained pre-RT, at 2 and 4 weeks during-RT, and at the end of RT. TGF-beta1 was measured using an enzyme-linked immunosorbent assay. The primary endpoint for RILT was >or=grade 2 radiation pneumonitis or fibrosis. RESULTS: Twenty-six patients with a minimum follow-up of 12 months were included. Six patients (23.1%) experienced >or=grade 2 RILT. There was no significant difference in absolute TGF-beta1 levels pre-RT, at 2 and 4 weeks during-RT, or at the end of RT between patients with and without RILT. The TGF-beta1 ratios (over the pre-RT levels) for patients with and without RILT at 2, 4 weeks during-, and the end of RT were 2.8+/-2.2 and 1.0+/-0.6 (P=0.123), 2.3+/-1.3 and 0.8+/-0.5 (P=0.001), 1.5+/-0.9 and 0.8+/-0.5 (P=0.098), respectively. Using 2.0 as a cut-off, the TGF-beta1 ratio at 4 weeks during-RT predicted RILT with a sensitivity and specificity of 66.7% and 95.0%, respectively. CONCLUSION: Elevation of plasma TGF-beta1 level 4 weeks during-RT is significantly predictive of RILT. The role of plasma TGF-beta1 in predicting RILT deserves further study.