Lung Cancer In Never-smokers Research Articles

P2.10-01 Analysis of Human Papilloma Viruses (HPV) and Human Polyoma Viruses (HPyV) in Lung Cancer from Swedish Never-Smokers

A possible role for oncogenic infections in the etiology of lung cancer has been investigated in a large number of studies, with contradictory results. High-risk mucosal human papillomaviruses (HPV), recognized as being associated with cervical cancer and oropharyngeal cancer, has been suggested as a causative factor also in lung cancer [1,2], whereas other studies found no, or at most very limited, involvement of HPV in lung cancer [3,4]. To investigate human papillomaviruses (HPV) and human polyomaviruses (HPyV) as possible causative factors behind lung cancer in never-smokers, we analyzed the presence of these viruses in a subset of tumors within a larger Swedish cohort of never-smoking lung cancer patients [Swedish Molecular Initiative against Lung cancer, SMIL; Salomonsson et al. Abstract WCLC 2019]. Eighty-seven surgically resected lung cancer samples from never-smokers, diagnosed 2005-2014 in Stockholm, Sweden, were analyzed by Luminex assays for the presence of 27 HPV types (including all HPV types currently regarded as high-risk types) and for 10 HPyV species (BKPyV, JCPyV, KIPyV, WUPyV, TSPyV, MWPyV, HPyV6, 7, 9, and 10). All samples were positive for the β-globin gene, confirming the presence, amplification and detection of cellular DNA. All samples were negative for the HPV types included in the assay. The only viral DNA detected in the tumors were low amounts of Merkel cell polyomavirus (MCPyV) DNA, of unknown significance, in 15 samples. Our study shows no evidence for neither HPV nor HPyV in the etiology of lung cancer in Swedish never-smokers.

P1.01-35 Real World Characterization of Advanced Non-Small Cell Lung Cancer in Never Smokers

NSCLC in never smokers is vastly different from those with a history of smoking in terms of etiology, driver-mutations and response to immunotherapy. We have previously demonstrated a hereditary contribution in never smokers which is not identified in smokers1. This study compares the real-world survival of NSCLC in never smokers to those with a smoking history by mutation status. The study included patients in the Flatiron Health nationwide electronic health record-derived database who were diagnosed with NSCLC, received biomarker testing results (EGFR, BRAF, ALK, and ROS1), and initiated therapy between 2011-2017 with follow-up through June 2018. Overall survival (OS) of patients by smoking and driver mutation groups was summarized via Kaplan-Meier survival estimates and compared in the context of a multivariate Cox proportional hazard model adjusted by age at stage IV diagnosis, gender, state of residence, histology, smoking status, and race/ethnicity, stratified by categories of advanced diagnosis date within practices. The study included 30,310 patients with median age of 68.8 years, 46.7% female, 76.8% non-Hispanic white, and 12.6% never smokers. Actionable mutations were reported in 9.0%, differentially as 34.2% in non-smokers and 5.5% in smokers. OS differed by smoking and driver-mutation categories (adjusted and stratified p<0.001). The median OS for patients with wild-type mutation status and history of smoking was 9.6 months, for mutated smokers was 19.4 months (adjusted and stratified hazard ratio [HR] relative to WT smokers 0.65 (95% CI 0.60-0.71)) , for wild-type never-smokers was 15.1 months (0.78 (0.73-0.83) relative to WT smokers), and for mutated never-smokers was 25.5 months (0.52 (0.48-0.58) relative to WT smokers). Never-smokers with NSCLC survived longer than those with smoking history, in both groups of wild-type and mutation-positive patients. Findings highlight that in patients with NSCLC, a smoking history may have similar effect on hazard of death as actionable mutation status.

S02.04 Dr. Gazdar as a Mentor

It was September in 1989 when I joined the NCI-Navy Medical Oncology Branch as a postdoctoral fellow. At that time, I was in my 10th year as a surgeon. The reason why I wanted to join the NCI-Navy was that I was greatly fascinated by the book entitled “The Biology of Lung Cancer” published by Marcel Dekker authored by many of the NCI-Navy MOB investigators. Especially, I was attracted by experimental works that used many lung cancer cell lines established by Adi’s group. When I first met Adi, my impression was that he was a calm and quiet person. My first project was to characterize peripheral airway cell phenotype in the adenocarcinoma cell lines by examining the expression of surfactant proteins as well as class II MHC. But I did not like this project and after 2 months or so, he agreed to change my theme to KRAS or TP53 mutations in lung cancer cell lines. He never pushed me to do or not to do something and never became emotional. I was deeply immersed in the research to look for the clinical and pathologic significance of those genetic abnormalities in lung cancer. This was what is called “translational research” today. I thought I could find what I should pursue throughout my life as a lung cancer doctor. It is obvious that without this experience and Adi, my life would have been so different. In addition, human network owing to Adi has been a precious treasure for me. One day in 1990, he gave me a paraffin block of bronchial biopsy sample and told me to search for TP53 mutation. It is currently a routine diagnostic workup to examine genetic alterations in the biopsy samples when you see lung cancer patients. It was as if he had known what would be the future diagnostic workup before 30 years. During this fruitful time of my life, I am so proud that I was able to co-authored 18 papers with Adi. After coming back to Japan, I saw Adi occasionally but periodically at various meetings such as the AACR, ASCO, ELCC and especially WCLC. Every time, he encouraged me to pursue my goal and gave some suggestions on my experiments. When Adi was to edit a special issue on Lung Cancer in Never Smokers in Translational Lung Cancer Research in 2018, he invited me to write about GGO lesions in never smokers. It was the last homework that he assigned to me. I am going to organize the Annual meeting of the Japanese Lung Cancer Society in December 2019. When I talked to him and his wife Celia at the Toronto WCLC meeting in 2018, Adi promised me to come to Japan to give a lecture. That was our last conversation. The promise has been broken and I really miss him. Adi. Please rest in peace. There are many of your children all over the world who have inherited your spirit as a lung cancer researcher. Translational research, mentor

Identification of Recurrent Activating HER2 Mutations in Primary Canine Pulmonary Adenocarcinoma.

Naturally occurring primary canine lung cancers share clinicopathologic features with human lung cancers in never-smokers, but the genetic underpinnings of canine lung cancer are unknown. We have charted the genomic landscape of canine lung cancer and performed functional characterization of novel, recurrent HER2 (ERBB2) mutations occurring in canine pulmonary adenocarcinoma (cPAC). We performed multiplatform genomic sequencing of 88 primary canine lung tumors or cell lines. Additionally, in cPAC cell lines, we performed functional characterization of HER2 signaling and evaluated mutation-dependent HER2 inhibitor drug dose-response. We discovered somatic, coding HER2 point mutations in 38% of cPACs (28/74), but none in adenosquamous (cPASC, 0/11) or squamous cell (cPSCC, 0/3) carcinomas. The majority (93%) of HER2 mutations were hotspot V659E transmembrane domain (TMD) mutations comparable to activating mutations at this same site in human cancer. Other HER2 mutations were located in the extracellular domain and TMD. HER2 V659E was detected in the plasma of 33% (2/6) of dogs with localized HER2 V659E tumors. HER2 V659E cPAC cell lines displayed constitutive phosphorylation of AKT and significantly higher sensitivity to the HER2 inhibitors lapatinib and neratinib relative to HER2-wild-type cell lines (IC50 < 200 nmol/L in HER2 V659E vs. IC50 > 2,500 nmol/L in HER2 WT). This study creates a foundation for molecular understanding of and drug development for canine lung cancer. These data also establish molecular contexts for comparative studies in dogs and humans of low mutation burden, never-smoker lung cancer, and mutant HER2 function and inhibition.

P2.10-05 Indoor Radon and Lung Cancer Risk. A Pooling Study on the Second Risk Factor for Lung Cancer

Residential radon is the second risk factor of lung cancer following tobacco consumption, according to WHO (World Health Organization) and United States EPA statements. It is recognized as the first cause of lung cancer in never-smokers by both organizations. Nevertheless, case-control studies performed in radon prone areas are still scarce and with limited sample sizes. We aim to know the relationship between residential radon and lung cancer risk in a study performed in a radon-prone area, and where inhabitants live for a long time in the same dwelling. We have pooled results from 5 different case-control studies performed in the same geographical area to assess the relationship between indoor radon and lung cancer. One of these studies was focused specifically in never smokers and other in Small Cell Lung Cancer. All cases and controls were older than 30 and cases had a confirmed diagnosis of lung cancer. Controls were selected for attending hospital for trivial surgery. Controls were selected through a frequency-based sampling based on age and gender distribution of cases. The information and questionnaires collected was the same in all studies, with special focus on tobacco consumption. Radon devices of an alpha track type were placed at the participants’ homes for at least three months. Odds Ratios of lung cancer due to radon exposure have been calculated adjusted by age, gender, and tobacco consumption. We included 1691 cases and 1698 controls. Median age was 63 and 67, respectively, and females comprised 33% of both cases and controls. Adenocarcinoma was the most frequent histology (43%) and participants lived a median of 30 years in the same dwelling. The table show the risk of lung cancer due to radon exposure. Residential radon is a relevant risk factor for lung cancer, even below concentrations established as safe by USEPA and WHO.

P1.14-37 Lung Cancer in Never-Smokers: A Nationwide Population Based Mapping of Targetable Alterations

P1.14-37 Lung Cancer in Never-Smokers: A Nationwide Population Based Mapping of Targetable Alterations

P2.14-10 Identification of Frequent, Activating HER2 Mutations and HER2 Inhibitor Response and Resistance in Canine Lung Cancer

Naturally occurring primary canine lung cancers share clinical and pathologic features with human never-smoker lung cancer, but their genetic and biologic underpinnings have been unknown. We mapped the genomic landscape of canine lung cancer, discovering somatic HER2 (ERBB2) mutations in ∼38% of canine pulmonary adenocarcinomas (cPACs). We describe our genomic findings, effects of HER2 mutations on cell signaling and HER2 inhibitor response/resistance, and results of pharmacokinetic (PK) studies of the HER2 inhibitor neratinib in healthy dogs. We performed multi-platform genomic analysis of 92 primary canine lung tumors or cell lines. We evaluated HER2 signaling by Western blot. Neratinib and lapatinib responses were assessed in HER2-mutant and wild-type cPAC cell lines in vitro. HER2-mutant cell lines were continuously treated with IC50 neratinib doses to select for drug resistance, then evaluated for resistance mutations. Neratinib tolerability and PK were evaluated in healthy, mixed-breed, middle-aged dogs given a single 6 mg/kg oral neratinib dose with or without maropitant citrate or loperamide. Plasma samples for PK were collected pre-dose and timepoints from 0.5-24h after dosing. Canine lung cancers exhibited low tumor mutation burden. HER2 was the most commonly mutated gene in cPACs, occurring in ∼38%, but was absent from canine adenosquamous or squamous cell carcinomas. HER2 hotspot V659E transmembrane domain (TMD) mutations were most common and comparable to activating TMD mutations in human cancer. HER2 V659E correlated with constitutive phosphorylation of Akt in cPAC cell lines. HER2 V659E lines displayed hypersensitivity to neratinib and lapatinib relative to wild-type lines. Continuous treatment of HER2-mutant cell lines led to rapid development of resistance. Characterization of resistance-driving alterations is ongoing, as are efficacy studies in mouse xenografts. A dose of 6 mg/kg neratinib in healthy dogs showed that neratinib was tolerable and achieved therapeutic levels from IC50 studies. Evaluation of neratinib tolerability and efficacy in dogs bearing HER2-mutant lung cancer is ongoing. HER2 TMD mutations are common in otherwise low-mutation-burden primary canine lung cancers. They confer constitutive HER2 signaling and HER2 inhibitor response in cell lines. Dosing and tolerability studies in healthy dogs have shown that therapeutically relevant doses are achievable. Study of HER2 inhibitor response/resistance in cell lines and mouse xenografts is ongoing as is clinical evaluation of neratinib activity in dogs with spontaneous lung cancer. These data offer immediate diagnostic and therapeutic opportunities for pet dogs and bear implications for comparative understanding of human never-smoker lung cancers and other HER2-mutant cancers.

Landscape on CT screening for lung cancer in Asia.

Lung cancer remains the leading cause of cancer incidence and mortality worldwide. Approximately 60% of the world’s new cases of lung cancer and deaths from it are expected in Asia in 2018. Currently, lung cancer screening using low-dose computed tomography (LDCT) is recommended for heavy smokers in North America, Europe and some countries in Asia. Tobacco smoking being the major risk factor for lung cancer, but in Asia, lung cancer in never-smokers (LCINS) is also a concern. This paper reviews on lung cancer incidence, mortality, etiology, smoking in Asia, and systematic reviews on LDCT lung cancer screening studies, including ongoing projects and recommendation on lung cancer screening in Asia. Some of the earliest studies of LDCT lung cancer screening worldwide were in Asia. Many countries in Asia have developed LDCT screening studies in various high-risk participants. Currently, there are several ongoing large-scale lung cancer screening trials to evaluate the efficacy of LDCT screening for never-smokers and light smokers, as well as heavy smokers, and to evaluate the feasibility of population-based LDCT lung cancer screening.

Ambient fine particulate matter inhibits 15-lipoxygenases to promote lung carcinogenesis

BackgroundEpidemiological observations have demonstrated that ambient fine particulate matter with dp < 2.5 μm (PM2.5) as the major factor responsible for the increasing incidence of lung cancer in never-smokers. However, there are very limited experimental data to support the association of PM2.5 with lung carcinogenesis and to compare PM2.5 with smoking carcinogens.MethodsTo study whether PM2.5 can contribute to lung tumorigenesis in a way similar to smoking carcinogen 4-methylnitrosamino-l-3-pyridyl-butanone (NNK) via 15-lipoxygenases (15-LOXs) reduction, normal lung epithelial cells and cancer cells were treated with NNK or PM2.5 and then epigenetically and post-translationally examined the cellular and molecular profiles of the cells. The data were verified in lung cancer samples and a mouse lung tumor model.ResultsWe found that similar to smoking carcinogen NNK, PM2.5 significantly enhanced cell proliferation, migration and invasion, but reduced the levels of 15-lipoxygenases-1 (15-LOX1) and 15-lipoxygenases-2 (15-LOX2), both of which were also obviously decreased in lung cancer tissues. 15-LOX1/15-LOX2 overexpression inhibited the oncogenic cell functions induced by PM2.5/NNK. The tumor formation and growth were significantly higher/faster in mice implanted with PM2.5- or NNK-treated NCI-H23 cells, accompanied with a reduction of 15-LOX1/15-LOX2. Moreover, 15-LOX1 expression was epigenetically regulated at methylation level by PM2.5/NNK, while both 15-LOX1 and 15-LOX2 could be significantly inhibited by a set of PM2.5/NNK-mediated microRNAs.ConclusionCollectively, PM2.5 can function as the smoking carcinogen NNK to induce lung tumorigenesis by inhibiting 15-LOX1/15-LOX2.

Clinical characteristics and survival in non-small cell lung cancer patients by smoking history: a population-based cohort study

Introduction: Approximately, 10–15% of lung cancer patients have never smoked. Previous epidemiological studies on non-tobacco associated lung cancer have been hampered by selected data from a small number of hospitals or limited numbers of patients. By use of data from large population-based registers with national coverage, this study aims to compare characteristics and survival of patients with non-small cell lung cancer (NSCLC) with different smoking histories.Methods: Swedish national population-based registers were used to retrieve data on patients diagnosed with primary NSCLC between 2002 and 2016. The Kaplan–Meier method and Cox proportional hazard models were used to estimate overall survival and lung cancer-specific survival by smoking history.Results: In total, 41,262 patients with NSCLC were included. Of those, 4624 (11%) had never smoked. Never-smokers were more often women and older compared to ever smokers (current and former). Adenocarcinoma was proportionally more common in never-smokers (77%) compared to current (52%) and former smokers (57%). Stage IV disease was more common in never-smokers (57%) than in current (48%) and former smokers (48%). Epidermal growth factor receptor mutation was observed more in never-smokers (37%) compared to current (5%) and former smokers (9%). Both lung cancer-specific and overall survival were higher for never-smokers compared to current smokers.Conclusions: The observed differences in characteristics between never-smokers and smokers, and the higher survival in never-smokers compared to smokers from this large population-based study provide further evidence that lung cancer in never-smokers is clinically different to tobacco-associated lung cancer. The findings from this study emphasise the need for an improved understanding of genetics, pathogenesis, mechanisms and progression of non-tobacco associated lung cancer that may help prevent lung cancer or identify individually targeted treatments.

The clinical impact of family history of cancer in female never-smoker lung adenocarcinoma

ObjectivesAccumulating evidence reveals the association between the risk of never-smoker lung cancer and family history of cancer. However, the clinicogenomic effect of family history of cancer in never-smoker lung cancer remains unknown. Material and methodsWe screened 3,241 lung cancer patients who (a) underwent curative resection at National Cancer Center (Goyang, Korea) between 2001–2014, and (b) completed a pre-designed interview about family/smoking history at the time of diagnosis and identified 604 female never smoker lung adenocarcinoma. A positive family history of cancer [categorized as pulmonary cancer (FH-PC) or non-pulmonary cancer (FH-NPC)] was defined as a self-reported history of cancer in first-degree relatives. Survival data were followed up until January 2017. Multiplexed targeted next-generation sequencing was performed for genetic profiling. ResultsOf 604 patients, 29.1% (n = 176) had a FH, including 132 (21.9%) with FH-NPC and 44 (7.3%) with FH-PC. Patients with the FH-NPC had a higher proportion of young patients (≤45 years) than those without the FH-NPC (FH-NPC, FH-PC, and no FH; 13.6%, 2.3%, and 8.2%, respectively; P = 0.032). Patients with the FH-NPC had an increased risk of recurrence (hazard ratio [HR]: 1.90; 95% confidence interval [CI]: 1.40–2.56; P<0.001) and death (HR: 1.67; 95% CI: 1.18–2.37; P=0.004). In contrast, the FH-PC had no prognostic effect on recurrence (HR: 1.23; 95% CI: 0.71–2.15; P = 0.456) and death (HR: 0.93; 95% CI: 0.45–1.91; P=0.838). Among three driver oncogene alterations, EGFR mutation was significantly associated with the FH-PC (53.8%, 84.1%, and 65.8%, respectively; P = 0.016), ALK/ROS1/RET fusions was significantly associated with the FH-NPC (13.7%, 0.0%, and 5.0%, respectively; P = 0.004), but KRAS mutation was not associated with any type of the FH (13.8% vs. 6.0% vs. 7.8%, respectively; P = 0.288). ConclusionThe type of family history of cancer was associated with distinct clinocogenomic subtypes and prognosis of never-smoker lung adenocarcinoma.

Residential radon, genetic polymorphisms in DNA damage and repair-related

ObjectivesTo analyze the relationship of GSTT1, GSTM1, XRCC1 (rs25487), ERCC1 (rs11615, rs3212986), ERCC2 (rs13181), XRCC3 (rs861539), OGG1 (rs1052133), and Alpha-1-Antitrypsin mutations (AAT) with the risk of lung cancer in never-smokers, and ascertain if there is an effect modification between these polymorphisms and residential radon exposure. Material and methodsWe designed a multicenter hospital-based case-control study in a radon-prone area. 322 cases and 338 controls, all never-smokers, were included. They were selected using a frequency sampling based on sex and age distribution of the cases. Participants donated 3 ml. of whole blood used to determine genotype for polymorphisms. They placed a radon detector to measure residential radon exposure in their dwelling. ResultsThe OR for deleted GSTM1 patients was 3.46 (95% CI = 1.52–7.89) at residential radon exposures above 200 Bq/m3. The ERCC1 rs3212986 polymorphism was the most associated with the risk of developing lung cancer, both for low and high radon exposures. The ERCC1 rs321986 GT and TT genotypes (at radon concentrations >200 Bq/m3) were more significantly associated with higher lung cancer risk (OR = 2.40, 95% CI = 1.29–4.45; OR = 4.45, 95% CI = 1.26–15.7, respectively). ConclusionsThese findings support the hypothesis that certain polymorphisms in genes involved in DNA-repair and carriers of GSTM1 deletion have an increased risk of lung cancer in never-smokers exposed to residential radon.

Abstract SY26-02: Sherlock-Lung: Tracing lung cancer mutational processes in never smokers

Abstract Globally, about 2 million people are diagnosed with lung cancer annually, making it the most common type of cancer in the world. In addition, lung cancer is the leading cause of cancer death among both men and women, accounting for ~25% of all cancer deaths in the United States and ~19% of cancer deaths worldwide. Although tobacco smoking is the most common cause of lung cancer, it is estimated that 10-25% of all patients diagnosed with lung cancer worldwide are never smokers, with higher proportions in Asians and women. Compared to former and current smokers with lung cancer, lung cancers in never smokers tend to present at an earlier age and more frequently have adenocarcinoma histology. Although a few risk factors are known to contribute to the etiology of lung cancer in never smokers, a large fraction of cancer cases cannot be explained by established environmental and genetic risk factors, highlighting the need for research in this area. One promising approach to identify the etiological factors involved in lung tumorigenesis in never smokers is based on the study of the “mutational signatures” that the exogenous and endogenous processes leave on the tumor tissue and surrounding areas. Somatic mutations accumulate throughout individuals’ lifetime, as a result of the balance between DNA damage and DNA repair. Mutational sources can change over time and mutational signatures can provide information on the tumor evolutionary trajectory, tracking activities of mutational processes. We designed “Sherlock-Lung” to identify mutational signatures in lung cancers from never smokers and order them based on their clonal and subclonal localization to have an insight on the factors involved in the initiation of the tumors. Prevention and treatment strategies are likely to be more effective when targeting the tumor initiating factors rather than those responsible for the tumor progression. Here, we present the Sherlock-Lung study design, which includes a combination of lung cancer cases from populations highly exposed to lung cancer risk factors and populations with unknown exposures. We also present preliminary data from this study and what we have learned from whole genome sequencing analysis of the mutational landscape of lung cancers from smokers and nonsmokers and from different histological subtypes. For example, although the mutational signature associated with tobacco smoking is largely clonal in all lung cancers from smokers, consistent with an initiating role of tobacco smoking in lung tumorigenesis, the mutational signatures distribution varies across histological subtypes. Moreover, the frequency of mutations in major cancer driver genes varies dramatically between smokers and never smokers, and mutational signatures distribution appears to differ between tumors with and without specific driver genes. In never smokers, without the dominant mutational source of tobacco smoking, other signatures emerged, e.g., that associated with reactive oxygen species. Although this approach has already revealed important information on the etiological processes involved in tumorigenesis of lung cancer and other cancer types, there is a growing list of open questions and challenges that need to be addressed. In population studies, careful exposure assessment to identify and validate new mutational signatures and the inclusion of study subjects from different geographical locations and ethnicities are critical. Citation Format: Maria Teresa Landi, Tongwu Zhang, Montserrat Garcia-Closas, Yohan Bossé, Jianxin Shi, Bin Zhu, Qing Lan, Nathaniel Rothman, Jiyeon Choi, Neil E. Caporaso, Wei Zhao, Chongyi Chen, Eytan Ruppin, Jennifer Rosenbaum, Dmitry Gordenin, Sai Yendamuri, Chris Amos, Paul Brennan, David C. Christiani, Geoff Liu, Bonnie Gould Rothberg, Matthew Schabath, Han Liang, Ludmil Alexandrov, David Wedge, Stephen Chanock. Sherlock-Lung: Tracing lung cancer mutational processes in never smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY26-02.

Abstract 631: High BMI in relation to low risk of lung cancer among never smokers

Abstract Background. Lean smokers have increased oxidative DNA damage relative to their non-lean counterparts, indicating their heightened susceptibility to tobacco carcinogens-induced DNA damage. Epidemiological association between body mass index (BMI) and lung cancer is inconclusive. We have reported that BMI is a protective factor for smoking-related lung cancer and so did a recent meta-analysis. Knowledge about the association between BMI and non-smoking related lung cancer is limited as this is rare in Western population. We therefore sought to investigate the association between BMI and the risk of never-smoking related lung cancer in an on-going prospective cohort study, the Singapore Chinese Health Study. Methods. The current analysis used data from the Singapore Chinese Health Study, a cohort of 63,257 middle-aged and older Chinese men and women enrolled between 1993 and 1998. As of December 31, 2015, 2,001 study participants who were free of lung cancer at baseline developed lung cancer of whom 621 were never smokers. Cox proportional hazard regression method was used to calculate hazard ratio (HR) and the corresponding 95% confidence interval (CI) for lung cancer associated with BMI in never-smokers. Results. Our results shown that increasing BMI was a protective factor for never-smoking related lung cancer and there is no interaction by gender. The respective HRs and 95% CIs were 0.66 (0.45-0.95) for overall and 0.60 (0.39-0.93) in female for those with BMI&amp;gt;27.5 compared to those with BMI&amp;lt;18.5. Even after eliminating those with exposure to any second-hand smoke in childhood or adulthood, the inverse association between BMI and the risk of never-smoking related lung cancer was stronger and significant (HR=0.31, 95% CI: 0.13-0.75; Ptrend=0.01). There was no difference by histologic subtypes (i.e., adenocarcinomas vs. squamous cell). Conclusion. There was an inverse association between BMI and the risk of never-smoking related lung cancer and there is no interaction by gender for this association. This association was also not different by histologic subtypes. Citation Format: Hung N. Luu, Renwei Wang, Jennifer Adams-Haduch, Aizhen Jin, Woon-Puay Koh, Jian-Min Yuan. High BMI in relation to low risk of lung cancer among never smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 631.

Multiple Molecular Targets Associated with Genomic Instability in Lung Cancer

Lung cancer (LC) is the first cause of cancer-related deaths worldwide. Elucidating the pathogenesis of LC will give information on key elements of tumor initiation and development while helping to design novel targeted therapies. LC is an heterogeneous disease that has the second highest mutation rate surpassed only by melanoma, since 90% of LC occurs in tobacco smokers. However, only a small percent of smokers develops LC, indicating an inherent genomic instability. Additionally, LC in never smokers suggests other molecular mechanisms not causally linked to tobacco carcinogens. This review presents a current outlook of the connection between LC and genomic instability at the molecular and clinical level summarizing its implications for diagnosis, therapy, and prognosis. The genomic landscape of LC shows widespread alterations such as DNA methylation, point mutations, copy number variation, chromosomal translocations, and aneuploidy. Genome maintenance mechanisms including cell cycle control, DNA repair, and mitotic checkpoints open a window to translational research for finding novel diagnostic biomarkers and targeted therapies in LC.

Abstract 3705: Identification of frequent HER2 activating mutations in canine primary pulmonary adenocarcinoma

Abstract Spontaneous primary canine lung cancers are aggressive malignancies that are increasingly common in dogs. They share clinicopathologic features with human lung cancers in never-smokers, but their genetic underpinnings are unknown. As never-smoker lung cancer incidence increases in humans, a need exists for improved biologic understanding and development of new models to fuel translational research. Here, we describe for the first time the detailed clinical and genetic features of primary canine lung cancers through case review and multi-platform sequencing of 90 primary canine lung tumors and cell lines. We performed multi-platform genomic profiling including whole exome sequencing (WES), amplicon panel-based sequencing of 250 regions of 51 cancer genes, and single nucleotide polymorphism (SNP) array-based analysis of tumors and matched constitutional DNA. We profiled 76 cPAC, 11 canine pulmonary adenosquamous carcinomas (cPASC) and three canine pulmonary squamous cell carcinomas (cPSCC). The median age at the time of diagnosis was 11 year old. The most common affected pure breed was the Labrador retriever (19%). Five cPACs assessed by WES displayed low mutation burden with a median of 64 somatic single nucleotide variants (SNVs), 19 somatic copy number variants (CNVs), and 1 structural variant (SV), and frequent C&amp;gt;T substitutions (80%) at NpCpG trinucleotides, a common mutation signature seen across human and canine cancers. Based on WES and amplicon sequencing, we discovered somatic, coding HER2 (ERRB2) point mutations in 37% of cPAC, but none in cPASC or cPSCC. Additional recurrently mutated genes in cPAC included CDKN2A/B (~40%), TP53 (~12%), K/HRAS (~7%), SMAD4 (~5%), and PTEN (~5%). In cPASC, KRAS and TP53 were the most frequently mutated genes (18% each). In cPSCC, no recurrently mutated genes were identified, but individual somatic coding mutations were found in BRAF and PTPN11. The majority (93%) of HER2 mutations were hotspot V659E, located on the transmembrane domain (TMD), and comparable to activating mutations at this same site in human cancer. We were able to detect this mutation not only in biopsied tumors, but also in the plasma of 33% (2/6) of dogs with localized V659E-positive tumors. Other somatic HER2 mutations identified were similarly located in the HER2 juxtamembrane domain and TMD including A664T and K676E. HER2 point mutations occurred in the absence of significant focal amplification (assessed by WES and SNP array) or overexpression (assessed by qRT-PCR and IHC). We also showed that HER2 mutation correlated with constitutive phosphorylation of Akt in cPAC cell lines. Furthermore, HER2 V659E-mutant lines displayed hypersensitivity to the HER2 kinase inhibitors neratinib (IC50, 23nM) and lapatinib (IC50, 168nM) relative to HER2 wild-type cell lines (IC50, &amp;gt;2500nM). These data bear implications for comparative understanding of HER2-mutant lung cancer across species. Citation Format: Gwendolen Lorch, Karthigayini Sivaprakasam, Victoria Zissman, Nieves Perdigones, Tania Contente-Cuomo, Alexandra Nazareno, Salvatore Facista, ShukMei Wong, Winnie Liang, Joseph M. Amann, Sara L. Sinicropi-Yao, Michael J. Koenig, Krista La Perle, Timothy G. Whitsett, Muhammed Murtaza, Jeffrey Trent, David P. Carbone, William P. Hendricks. Identification of frequent HER2 activating mutations in canine primary pulmonary adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3705.

Abstract 632: Associations of coffee and tea consumption with lung cancer risk: A pooled analysis of 17 cohort studies involving over 1.2 million participants

Abstract Background Epidemiological studies investigating the associations of coffee and tea intake with lung cancer risk have yielded inconsistent results. These previous studies included mostly lung cancer patients diagnosed among smokers. Because coffee and tea consumption are closely related to smoking behavior, these previous studies could suffer from biases due to residual confounding of smoking. To better characterize the relationship, a large study with a large number of lung cancer cases diagnosed among never smokers and detailed information on tea and coffee consumption, is needed. Using data from a large-scale pooled analysis that consists of over 1.2 million participants in the U.S. and Asia, we carried out a comprehensive evaluation on the association of coffee and tea intake with lung cancer risk. Methods Individual-level data from seven prospective cohort studies conducted in the U.S., and ten studies conducted in Asia, were included. Demographic, lifestyle, coffee and tea intake data were collected at the baseline survey for each study. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The first 2 years of follow-up time was excluded to minimize potential influence of reverse causality on study results. Subgroup analyses by smoking status, sex, race, histologic subtype and coffee type (caffeinated or decaffeinated) were also conducted to assess potential effect modification, as well as heterogeneity of the association. Results After a median follow-up of 8.6 years, 20,519 incident lung cancer cases were identified. Both coffee and tea consumption were associated with an increased risk of lung cancer. Comparing non-coffee and non-tea consumption, HRs for lung cancer associated with exclusive coffee drinkers (≥2 cups/day) among current, former and never smokers were 1.30 (95% CI, 1.15-1.47), 1.49 (1.27-1.74) and 1.41 (95% CI, 1.21-1.63), respectively. Similar positive associations were observed for caffeinated and decaffeinated coffee. The HRs associated with exclusive tea drinkers (&amp;gt;2 cups/day) were 1.16 (95% CI, 1.02-1.32), 1.10 (0.92, 1.32) and 1.37 (95% CI, 1.17-1.60) for current, former and never smokers, respectively. These associations did not differ significantly by sex, race or histologic subtypes. Conclusion A high consumption of coffee or tea was both associated with an increased risk of lung cancer regardless of race or smoking status. Our study included a large number of never-smoker lung cancer patients, which minimized potential confounding effects due to smoking. The positive association observed for both caffeinated and decaffeinated coffee suggests that compounds other than caffeine may play a role in the etiology of lung cancer. Citation Format: Jingjing Zhu, Wei Zheng, Rashimi Sinha, Stephanie A. Smith-Warner, Yong-Bing Xiang, Yikyung Park, Shoichiro Tsugane, Emily White, Woon-Puay Koh, Sue K. Park, Norie Sawada, Seiki Kanemura, Yumi Sugawara, Ichiro Tsuji, Kim Robien, Yasutake Tomata, Keun-Young Yoo, Jeongseon Kim, Jian-Min Yuan, Yu-Tang Gao, Yumie Takata, Eiko Saito, William Blot, Xiao-Ou Shu. Associations of coffee and tea consumption with lung cancer risk: A pooled analysis of 17 cohort studies involving over 1.2 million participants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 632.

Lung cancer in never-smokers: a hidden disease.

Lung cancer in never-smokers: a hidden disease.

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region

IntroductionInherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. MethodsWe conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. ResultsWe detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722–0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723–0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730–0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. ConclusionsWe found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.

Multigene Mutation Profiling and Clinical Characteristics of Small-Cell Lung Cancer in Never-Smokers vs. Heavy Smokers (Geno1.3-CLICaP)

Objectives: Lung cancer is a heterogeneous disease. Presentation and prognosis are known to vary according to several factors, such as genetic and demographic characteristics. Small-cell lung cancer incidence is increasing in never-smokers. However, the disease phenotype in this population is different compared with patients who have a smoking history.Material and Methods: To further investigate the clinical and genetic characteristics of this patient subgroup, a cohort of small cell lung cancer patients was divided into smokers (n = 10) and never/ever-smokers (n = 10). A somatic mutation profile was obtained using a comprehensive NGS assay. Clinical outcomes were compared using the Kaplan-Meier method and Cox proportional models.Results: Median age was 63 years (46–81), 40% were men, and 90% had extended disease. Smoker patients had significantly more cerebral metastases (p = 0.04) and were older (p = 0.03) compared to their non-smoker counterparts. For never/ever smokers, the main genetic mutations were TP53 (80%), RB1 (40%), CYLD (30%), and EGFR (30%). Smoker patients had more RB1 (80%, p = 0.04), CDKN2A (30%, p = 0.05), and CEBPA (30%, p = 0.05) mutations. Response rates to first-line therapy with etoposide plus cisplatin/carboplatin were 50% in smokers and 90% in never/ever smokers (p = 0.141). Median overall survival was significantly longer in never smokers compared with smokers (29.1 months [23.5–34.6] vs. 17.3 months [4.8–29.7]; p = 0.0054). Never/ever smoking history (HR 0.543, 95% CI 0.41–0.80), limited-stage disease (HR 0.56, 95% CI 0.40–0.91) and response to first-line platinum-based chemotherapy (HR 0.63, 95% CI 0.60–0.92) were independently associated with good prognosis.Conclusion: Our data supports that never/ever smoker patients with small-cell lung cancer have better prognosis compared to their smoker counterparts. Further, patients with never/ever smoking history who present with small-cell lung cancer have a different mutation profile compared with smokers, including a high frequency of EGFR, MET, and SMAD4 mutations. Further studies are required to assess whether the differential mutation profile is a consequence of a diverse pathological mechanism for disease onset.