Faculty Bibliography

OBJECTIVES:Efficient use of nivolumab in non-small-cell lung cancer (NSCLC) has been limited by the lack of a definitive predictive biomarker. In patients with metastatic melanoma treated with ipilimumab, a pretreatment neutrophil-to-lymphocyte ratio (NLR)<5 has been associated with improved survival. This retrospective cohort study aimed to determine whether the pretreatment NLR was associated with outcomes in NSCLC patients treated with nivolumab. METHODS:We reviewed the medical records of all patients with previously treated advanced NSCLC who received nivolumab between March 2015 and March 2016 outside of a clinical trial at the University of Pennsylvania. Patients were dichotomized according to pretreatment NLR<5 vs. ≥5. Multivariable logistic regression and Cox proportional hazards models were used to assess the impact of pretreatment NLR on overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS:175 patients were treated. Median age was 68 (range, 33-88); 54% were female. Twenty-five percent of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2; 46% had received ≥2 prior systemic therapies. In multivariate analyses, pretreatment neutrophil-to-lymphocyte ratio (NLR) ≥5 was independently associated with inferior OS (median 5.5 vs. 8.4 months; HR 2.07, 95% CI 1.3-3.3; p=0.002) and inferior PFS (median 1.9 vs. 2.8 months; HR 1.43, 95% CI 1.02-2.0; p=0.04). CONCLUSIONS:In a cohort of patients with NSCLC treated with nivolumab in routine practice, pretreatment NLR≥5 was associated with inferior outcomes. It is unclear whether this marker is predictive or prognostic. Prospective studies are warranted to determine the utility of NLR in the context of other biomarkers of programmed death-1 (PD-1) therapy.

INTRODUCTION:Pemetrexed inhibits folate-dependent enzymes involved in pyrimidine and purine synthesis. Previous studies of genetic variation in these enzymes as predictors of pemetrexed efficacy have yielded inconsistent results. We investigated whether red blood cell (RBC) total folate, a phenotypic rather than genotypic, marker of cellular folate status was associated with the response to pemetrexed-based chemotherapy in advanced nonsquamous non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS:We conducted a prospective cohort study of patients with stage IV nonsquamous NSCLC receiving first-line chemotherapy containing pemetrexed. The pretreatment RBC total folate level was quantified using liquid chromatography mass spectrometry. We then compared the objective response rate (ORR) between patients with RBC total folate concentrations greater than and less than an optimal cutoff value determined from the receiver operating characteristic curve. A logistic regression model was used to adjust for age, sex, and the use of bevacizumab. RESULTS:The ORR was 62% (32 of 52 patients). Receiver operating characteristic analysis was used to establish that a RBC total folate cutoff value of 364.6 nM optimally discriminated between pemetrexed responders and nonresponders. Patients with RBC total folate < 364.5 nM had an ORR of 27% compared with 71% for patients with RBC total folate > 364.5 nM (P = .01). This difference persisted after adjusting for age, sex, and the use of bevacizumab (odds ratio, 0.07; 95% confidence interval, 0.01-0.57; P = .01). CONCLUSION:A low pretreatment RBC total folate was associated with an inferior response to pemetrexed-based chemotherapy in stage IV nonsquamous NSCLC. Larger, multicenter studies are needed to validate RBC total folate as a predictive marker of pemetrexed response.

At least seven studies have suggested that microRNA levels in whole blood can be diagnostic for lung cancer. We conducted a large bi-institutional study to validate this. Qiagen® PAXgene™ Blood miRNA System was used to collect blood and extract RNA from it for 85 pathologic stage I-IV non-small cell lung cancer (NSCLC) cases and 76 clinically-relevant controls who had a benign pulmonary mass, or a high risk of developing lung cancer because of a history of cigarette smoking or age >60 years. Cases and controls were similar for age, gender, race, and blood hemoglobin and leukocyte but not platelet levels (0.23 and 0.26 million/μl, respectively; t test P = 0.01). Exiqon® MiRCURY™ microarrays were used to quantify microRNAs in RNA isolates. Quantification was also performed using Taqman™ microRNA reverse transcription (RT)-PCR assays for five microRNAs whose lung cancer-diagnostic potential had been suggested in seven published studies. Of the 1,941 human mature microRNAs detectable with the microarray platform, 598 (31%) were identified as expressed and reliably quantified among the study's subjects. However, none of the microRNAs was differentially expressed between cases and controls (P >0.05 at false discovery rate <5% in test using empirical Bayes-moderated t statistics). In classification analyses with leave-one-out internal cross-validation, cases and controls could be identified by microRNA expression with 47% and 50% accuracy with support vector machines and top-scoring pair methods, respectively. Cases and controls did not differ for RT-PCR-based measurements of any of the five microRNAs whose biomarker potential had been suggested by seven previous studies. Additionally, no difference for microRNA expression was noticed in microarray-based microRNA profiles of whole blood of 12 stage IA-IIIB NSCLC cases before and three-four weeks after tumor resection. These findings show that whole blood microRNA expression profiles lack diagnostic value for high-risk screening of NSCLC, though such value may exist for selective sub-groups of NSCLC and control populations.

A multiplexed quantitative method for the analysis of three major unconjugated steroids in human serum by stable isotope dilution liquid chromatography-high resolution mass spectrometry (LC-HRMS) was developed and validated on a Q Exactive Plus hybrid quadrupole/Orbitrap mass spectrometer. This quantification utilized isotope dilution and Girard P derivatization on the keto-groups of testosterone (T), androstenedione (AD) and dehydroepiandrosterone (DHEA) to improve ionization efficiency using electrospray ionization. Major isomeric compounds to T and DHEA; the inactive epimer of testosterone (epiT), and the metabolite of AD, 5α-androstanedione (5α-AD) were completely resolved on a biphenyl column within an 18min method. Inter- and intra-day method validation using LC-HRMS with qualifying product ions was performed and acceptable analytical performance was achieved. The method was further validated by comparing steroid levels from 100μL of serum from young vs older subjects. Since this approach provides high-dimensional HRMS data, untargeted analysis by age group was performed. DHEA and T were detected among the top analytes most significantly different across the two groups after untargeted LC-HRMS analysis, as well as a number of other still unknown metabolites, indicating the potential for combined targeted/untargeted analysis in steroid analysis.

RATIONALE:Radiographic lung cancer screening guidelines and coverage requirements warrant a shared decision-making process. Guidance is needed regarding how to conduct shared decision making effectively. A useful organizing theme should include consideration of a patient's response to and tolerance of uncertainty associated with lung cancer screening. OBJECTIVES:The objectives of this study are to: (1) describe how patients respond to specific categories of uncertainty in the context of lung cancer screening, and (2) inform strategies for addressing concerns about uncertainty as part of the shared decision making. METHODS:We performed two series of structured interviews on participants in a convenience sample of current or former cigarette smokers recruited from primary care and pulmonary practices in Philadelphia. An interview guide included prompts related to benefits, harms, and responses to general and specific types of uncertainty (stochastic, statistical, and evidentiary) associated with lung cancer screening. Interviews were audio-recorded, transcribed, and independently coded by two investigators. An inductive analysis was conducted, and major themes were identified. MEASUREMENTS AND MAIN RESULTS:Twenty-two adults participated in the study. Sixty-eight percent were men, 72% were black or African American, and 50% met U.S. Preventive Services Task Force criteria for lung cancer screening. The primary themes to emerge from our study were: (1) the desire to decrease uncertainty may motivate lung cancer screening decisions; (2) uncertainty is an attribute of health states that impacts how patients weigh benefits and harms of lung cancer screening; (3) patient understanding and tolerance of uncertainty varies across stochastic, statistical, and evidentiary uncertainty; and (4) provider-patient communication may mitigate intolerance of uncertainty in the context of lung cancer screening. CONCLUSIONS:A systematic approach to understanding and addressing patients' concerns about uncertainty in the context of lung cancer screening can guide a patient-centered approach to shared decision making. The results of this study can inform provider-patient communication strategies regarding the decision to perform radiographic lung cancer screening.

The lung cancer epidemic of the twentieth century grew out of increasing tobacco consumption in the first half of that century. Tobacco control policies have been instituted in many high-income countries since the mid-1960s. Since then smoking rates have declined in these countries, particularly in men where lung cancer rates have stabilized. Tobacco control measures are not strong enough in many countries around the world, particularly low and middle income countries in Eastern Europe and Asia. In these countries, smoking rates and lung cancer rates remain high. Tobacco cessation is more successful in countries with stronger tobacco control and confers quality of life and survival benefits in smokers including lung cancer patients. A significant degree of stigma surrounds the diagnosis of lung cancer which is often considered "self-inflicted" even though the tobacco industry promotes smoking uptake and maintenance. Sustained, effective tobacco control and cessation may improve lung cancer outcomes and are key considerations in modern care of lung cancer patients.

OBJECTIVES:Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping. MATERIALS AND METHODS:We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p<1.51×10(-5)) in an independent set of 866 cases and 796 controls in stage 2. RESULTS AND CONCLUSION:In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p=1.3×10(-9); OR=1.32; 95% CI=1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p=2.8×10(-9); OR=1.28; 95% CI=1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p=1.3×10(-8); OR=1.37; 95% CI=1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans.

BACKGROUND:Bronchoscopy is often the initial diagnostic procedure performed in patients with pulmonary lesions suggestive of lung cancer. A bronchial genomic classifier was previously validated to identify patients at low risk for lung cancer after an inconclusive bronchoscopy. In this study, we evaluated the potential of the classifier to reduce invasive procedure utilization in patients with suspected lung cancer. METHODS:In two multicenter trials of patients undergoing bronchoscopy for suspected lung cancer, the classifier was measured in normal-appearing bronchial epithelial cells from a mainstem bronchus. Among patients with low and intermediate pretest probability of cancer (n = 222), subsequent invasive procedures after an inconclusive bronchoscopy were identified. Estimates of the ability of the classifier to reduce unnecessary procedures were calculated. RESULTS:Of the 222 patients, 188 (85%) had an inconclusive bronchoscopy and follow-up procedure data available for analysis. Seventy-seven (41%) patients underwent an additional 99 invasive procedures, which included surgical lung biopsy in 40 (52%) patients. Benign and malignant diseases were ultimately diagnosed in 62 (81%) and 15 (19%) patients, respectively. Among those undergoing surgical biopsy, 20 (50%) were performed in patients with benign disease. If the classifier had been used to guide decision making, procedures could have been avoided in 50% (21 of 42) of patients undergoing further invasive testing. Further, among 35 patients with an inconclusive index bronchoscopy who were diagnosed with lung cancer, the sensitivity of the classifier was 89%, with 4 (11%) patients having a false-negative classifier result. CONCLUSIONS:Invasive procedures after an inconclusive bronchoscopy occur frequently, and most are performed in patients ultimately diagnosed with benign disease. Using the genomic classifier as an adjunct to bronchoscopy may reduce the frequency and associated morbidity of these invasive procedures. TRIAL REGISTRY/BACKGROUND:ClinicalTrials.gov; Nos. NCT01309087 and NCT00746759; URL: www.clinicaltrials.gov.

PURPOSE/OBJECTIVE:Surveillance PET after curative-intent treatment of non-small-cell lung cancer (NSCLC) or colorectal cancer (CRC) is not clearly supported by available evidence or the Choosing Wisely campaign. However, the frequency of PET imaging during the surveillance period is relatively unknown. METHODS:Using Surveillance, Epidemiology, and End Results-Medicare data, 65,748 patients aged 66 years or older who were diagnosed with stage I to IIIA NSCLC or stage I to III CRC from 2001 through 2009 and who underwent surgical resection were identified. Trends in "any PET" or "PET-only" use 6 to 18 months postoperatively were assessed. RESULTS:Any PET use more than doubled over the study period. Eleven percent of patients with NSCLC and 4% of those with CRC diagnosed in 2001 received any PET, compared with 25% of patients with NSCLC and 13% of those with CRC in 2009 (P < .001 for both). Higher stage disease was correlated with higher PET utilization and faster growth in use over the study period. PET-only use also increased over the study period, especially in higher stage disease. Fewer than 2% of patients diagnosed with stage IIIA NSCLC in 2001 received PET only, compared with 15% of patients diagnosed in 2009 (P = .014). Similarly, 1% of patients diagnosed with stage III CRC in 2001 received PET only, compared with 8% of patients diagnosed in 2009 (P < .001). CONCLUSIONS:PET utilization during the surveillance period increased between 2001 and 2009. Further research is needed to determine the factors driving use of surveillance PET and to examine relationships between PET and patient outcomes.