Citations

AbstractIntroductionPatients with small‐cell lung cancer (SCLC) have a very poor prognosis. However, a subset of SCLC achieves long‐term survival. The objective of this study was to investigate factors and pattern of long‐term survival in patients with limited‐stage small cell lung cancer (LS‐SCLC) who achieved a complete response (CR) after chemoradiotherapy.Patient and MethodsThis was a single‐center retrospective study. The analysis of hazard ratio (HR) and 95% confidence interval (CI) was performed using Cox proportional hazards model. For pattern analysis, the date of recurrence was used as the endpoint. The nominal categorical variables were analyzed by the χ2 test. Survival was estimated using the Kaplan–Meier model, and the results were reported as the median and interquartile range.ResultsWe identified 162 patients, median age was 64.7 (56.2–70.2) years, and 94 (58%) were females. Eighty‐one patients (50%) had recurrence during follow‐up. Gastroesophageal reflux disease (GERD) (HR, 0.65; 95% CI, 0.45–0.93; p = 0.016) and neurological paraneoplastic syndrome (PNS) (HR, 0.46; 95% CI, 0.29–0.72; p < 0.001) were independent factors associated with improved overall survival (OS). Patients with GERD had prolonged recurrence free survival (RFS) compared to patients without GERD (median, 29.1 months vs. 13.9 months, p < 0.001), whereas patients with neurological PNS had a reduced recurrence rate compared to those patients without neurological PNS (No. [%], 8 [20.5] vs. 73 [59.3], p < 0.001).ConclusionsPatients with LS‐SCLC achieving a CR after chemoradiotherapy, GERD, and neurological PNS were associated with improved OS. GERD and neurological PNS were associated with longer RFS and lower recurrence rate, respectively.

Abstract Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene–sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency &lt; 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10−8); rs79942605 (OR = 2.17, P = 2.81×10−8) and rs208908 (OR = 0.70, P = 4.54×10−8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Abstract Background: Somatic EGFR mutations define a subset of non–small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74–0.77) in the training and 0.77 (95% CI, 0.74–0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

Abstract Objective The study sought to test the feasibility of conducting a phenome-wide association study to characterize phenotypic abnormalities associated with individuals at high risk for lung cancer using electronic health records. Materials and Methods We used the beta release of the All of Us Researcher Workbench with clinical and survey data from a population of 225 000 subjects. We identified 3 cohorts of individuals at high risk to develop lung cancer based on (1) the 2013 U.S. Preventive Services Task Force criteria, (2) the long-term quitters of cigarette smoking criteria, and (3) the younger age of onset criteria. We applied the logistic regression analysis to identify the significant associations between individuals’ phenotypes and their risk categories. We validated our findings against a lung cancer cohort from the same population and conducted an expert review to understand whether these associations are known or potentially novel. Results We found a total of 214 statistically significant associations (P &lt; .05 with a Bonferroni correction and odds ratio &gt; 1.5) enriched in the high-risk individuals from 3 cohorts, and 15 enriched in the low-risk individuals. Forty significant associations enriched in the high-risk individuals and 13 enriched in the low-risk individuals were validated in the cancer cohort. Expert review identified 15 potentially new associations enriched in the high-risk individuals. Conclusions It is feasible to conduct a phenome-wide association study to characterize phenotypic abnormalities associated in high-risk individuals developing lung cancer using electronic health records. The All of Us Research Workbench is a promising resource for the research studies to evaluate and optimize lung cancer screening criteria.

Abstract There is growing evidence showing that sex disparity in lung cancer risk cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotype from a lung cancer cohort including ~ 47,000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 (OR=0.71, p=4.29x10-8); rs79942605 (OR=2.17, p=2.81x10-8); and rs208908 (OR=0.70, p=4.54x10-8), were identified with different risk effect of lung cancer between men and women. Further eQTL and functional annotation analysis suggested rs208908 affect lung cancer risk through differential regulation of CXADR (Coxsackie Virus And Adenovirus Receptor) gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

8569 Background: Immune checkpoint inhibitor (atezolizumab or durvalumab) combined with platinum-etoposide is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). The phase III clinical trials that led to the approval of chemoimmunotherapy in ES-SCLC, excluded patients with an Eastern Cooperative Group (ECOG) Performance Status (PS) of Two or Greater. Therefore, data on efficacy of this combination in this subgroup of ES-SCLC patients whose performance status two or greater is limited. Methods: A retrospective analysis was performed of patients diagnosed with ES-SCLC who received chemoimmunotherapy (atezolizumab or durvalumab) within the Mayo Clinic Health System between January 2016 and January 2021. Cases were identified from clinical databases at Mayo Clinic. Data on demographics, ECOG-PS, date of diagnosis, date of progression, whole brain radiation, CNS involvement, liver involvement, stereotactic body radiation, chest consolidation, platinum sensitivity, lines of therapy and last follow up date were extracted. Overall Survival (OS) and progression free survival (PFS) for ECOG-PS 2-3 were compared to patients with an ECOG-PS 0-1. Results: A total of 84 patients were identified with a median age of 68.2 (48-88) years old. Of these, 54 patients were identified with an ECOG-PS 0-1 and 30 patients with an ECOG-PS 2-3. The median PFS for the ECOG PS 0-1 cohort was 5.2 months (95% CI 4.6-6.1) while the median PFS for the ECOG-PS 2-3 cohort was 6.0 months (95% CI 4.2-7.7; logrank p = 0.93). The median OS for the ECOG-PS 0-1 cohort was 10.8 months (95% CI 8.5-12.9) while the median OS for the ECOG-PS 2-3 cohort was 10.3 months (95% CI 6.0-14.1; logrank p = 0.39). Hazard ratios of ECOG-PS 0-1 versus 2-3 showed no tendency of increased PFS or OS for either group within cox proportional hazards models. Forty-three percent of ECOG-PS 0-1 achieved a partial response (PR) and 57% of patients who had ECOG-PS 2-3 also achieved a PR (Fisher’s exact p = 0.23). A complete response was found in 4% of ECOG-PS 0-1 compared to 3% in the ECOG-PS 2-3 cohort. For patients who responded to initial therapy, 46% of ECOG-PS 2-3 patients had a platinum sensitive relapse while only 33% of ECOG-PS 0-1 were still platinum sensitive at the time of relapse. Five ECOG-PS 2-3 patients were able to receive a second-line therapy. Conclusions: To our knowledge, this is the first study to evaluate chemoimmunotherapy in the subgroup of ES-SCLC patients with an ECOG-PS 2 or greater. This retrospective study demonstrated no significant difference in PFS, OS, and ability to achieve a least a PR in ECOG-PS 2-3 cohort when compared to ECOG-PS 0-1. Therefore, chemoimmunotherapy should not be reserved for only an ECOG-PS of 0-1 but should be considered for all treatment eligible patients.

Abstract Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap: ARID1B at 6q25.3, MAP3K4 at 6q26, and UTRN (6q24.1) and PHACTR2 (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work. Significance: This study identifies four genes associated with lung cancer risk, which could help guide future lung cancer prevention and treatment approaches.