Citations

Abstract More Americans die every year of lung cancer than any other cancer. While the environmental risks for lung cancer are well understood, the genetic risk factors for this disease are not, even though it has been shown that lung cancer risk aggregates in families. Segregation analyses have confirmed the likelihood of rare, highly penetrant variants affecting lung cancer. Family studies offer a unique opportunity to identify such rare risk variants. We have previously identified a genome-wide significant risk locus for lung cancer using multipoint linkage analysis in highly aggregated lung cancer families. In this study, we performed targeted sequencing on this 6q23-6q27 region on 75 individuals from the 9 most strongly linked families. Parametric two-point linkage analysis using an autosomal dominant model with 10% penetrance for carriers and a 1% phenocopy rate and disease allele frequency of 1% was performed for each family. While we did not find any genome-wide significant results in any of the individual families, we did observe several interesting potential rare risk variants. First, we observed that the significant signal previously observed on 6q is recapitulated in these data but the location of the peak LOD is highly heterogeneous across families and it is likely that each family has a different risk gene. While most of the highest LOD scores were in noncoding variants, we did observe exonic variants with the highest LOD scores in two families (44 and 42). Both variants were rare, with a minor allele frequency (MAF) of approximately 1% and were in LPA and GPR126 respectively. Both these genes have been implicated somatically in lung cancer, however this is the first time that they have been implicated in the germline. While the other families have their highest LOD scores in noncoding variants, some of these genes are also good potential candidate genes including PARK2 (family 30), GRM1 (family 47), and PDE10A (family 102). All three genes have been implicated in lung cancer in some capacity, and this is the first time that GRM1 and PDE10A have been implicated as germline mutations. Again, all these variants are rare (MAF ⇐ 0.01) in the general population, which makes sense for a potential highly penetrant risk variant. In this study, we have elucidated that a previously identified risk locus on 6q25 is heterogeneous in the nine most strongly linked families, with different families appearing to be carrying different risk variants. Many of the top variants in each family are rare variants that are in good potential causal genes that have been identified for the first time here as germline risk variants for lung cancer. Further functional annotation is underway for these variants and some additional linkage analyses using other penetrance matrices may also be performed. Citation Format: Anthony M. Musolf, Claire L. Simpson, Bilal A. Moiz, Mariza de Andrade, Diptasri Mandal, Colette Gaba, Ping Yang, Ming You, Elena Y. Kupert, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos, Joan E. Bailey-Wilson. Highly aggregated lung cancer families reveal a heterogeneous cause for a previous linkage signal on 6q [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 37.

Abstract Background and Aims: For hepatocellular carcinoma (HCC) with vascular invasion, systemic treatment is recommended but transarterial radioembolization (TARE) is often used in clinical practice. The aim of this study was to investigate the current usage of TARE vs. systemic therapy as a first-line treatment for HCC with vascular invasion in the United States (US). Method: We performed a retrospective cohort study using the National Cancer Database (NCDB), which represents more than 70 percent of newly diagnosed cancer cases nationwide. All HCC patients diagnosed between 2010 and 2015 with the tumor stage of T3BN0M0 according to the 7th edition of the American Joint Committee on Cancer TNM staging system (tumor involving a major branch of a large vein of the liver without lymph nodes or extrahepatic metastasis) and received TARE or systemic treatment as a first-line treatment were included. Multivariable logistic regression was used to estimate factors associated with the utilization of TARE vs. systemic therapy. Results: A total of 1979 patients who received systemic treatment and 524 patients who received TARE were included. The proportion of patients receiving TARE increased from 15.7% in 2010 to 31.4% in 2015 (P<0.01). The median tumor size of the largest lesion was comparable (7.0cm for TARE vs. 7.1 cm for systemic treatment, P=0.43). Factors independently associated with increased likelihood of receiving TARE over systemic treatment were: advanced age (Odds Ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01 - 1.03, p=0.005), insurance status: private (OR: 3.06, 95% CI: 1.61 - 5.65, p<0.001), Medicaid/Medicare (OR: 2.91, 95% CI: 1.52 - 5.31, p<0.001), others (OR: 4.85, 95% CI: 1.90 - 11.62, p<0.001) vs. no insurance, and receiving care in the Midwest vs. Northeast region of the US (OR: 1.89, 95% CI: 1.38 - 2.53, p<0.001). Patients were significantly less likely to receive TARE if receiving treatment at community cancer program (OR: 0.24, 95% CI: 0.098 - 0.49, p<0.001) or comprehensive community cancer program (OR: 0.62, 95% CI: 0.48 - 0.82, p<0.001) vs. academic cancer program. Larger tumor size (OR per 1cm: 0.97, 95% CI: 0.95 - 1.00, p=0.03) and higher Charlson comorbidity index of ≥3 vs. 0 (OR: 0.53, 95% CI: 0.38 - 0.73, p<0.001) were inversely associated with receiving TARE. Recent HCC diagnosis year was associated with an increased likelihood of receiving TARE (OR: 1.23, 95% CI:1.16 - 1.32, p<0.001). Conclusion: The proportion of patients receiving TARE as a first-line treatment for HCC with macrovascular invasion has been increasing in the US. Age, comorbidities, insurance status, tumor size, and the type and location of cancer centers are associated with the usage of TARE vs. systemic treatment in HCC patients with vascular invasion. Citation Format: Joseph C. Ahn, Michael Luu, Walid Ayoub, Alexander Kuo, Andrew Hendifar, Jun Gong, Kambiz Kosari, Shelly Lu, Nicholas Nissen, Ju Dong Yang. Transarterial radioembolization versus systemic treatment for the management of hepatocellular carcinoma with vascular invasion: Analysis of the US National Cancer Database [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2350.

Abstract BackgroundThe effect of angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (ACEI/ARB) on the COVID-19 remains controversial from clinic evidence. MethodsThis is a retrospective, two-center case series of 198 consecutive COVID-19 patients with a history of hypertension. ResultsAmong 198 patients, 58 (29.3%) and 16 (8.1%) were on were on ARB and ACEI, respectively. Patients who were on ARB or ACEI/ARB had a significantly lower rate of severe illness and ARDS when compared with patients treated with ACEI alone or not receiving and RAAS blocker (P＜0.05). The Kaplan-Meier survival curve showed that patients with ARB in their antihypertensive regimen had a trend towards a higher survival rate when compared with individuals without ARB (adjusted hazard ratio, 0.27; 95% CI, 0.07-1.02; P = 0.054). The Cox-regression analysis to compared ACEI vs. ARB groups showed a significantly lower mortality rate in the ARB group (adjusted hazard ratio, 0.03; 95% CI, 0.00-0.58; P = 0.02). ConclusionsUsing of ARB was associated with a reduced rate of severe illness and ARDS, indicating their potential protective impact in COVID-19.

Abstract Background Hypothyroidism is known to be associated with adverse clinical outcomes in heart failure. The association between hypothyroidism and cardiac resynchronization therapy outcomes in patients with severe heart failure is not clear.Methods The study included 1,316 patients who received cardiac resynchronization therapy between 2002 and 2015. Baseline demographics and cardiac resynchronization therapy outcomes, including left ventricular ejection fraction, New York Heart Association class, appropriate implantable cardioverter-defibrillator therapy, and all-cause mortality, were collected from the electronic health record. Results Of the study cohort, 350 patients (26.6%) were classified as the hypothyroidism group. The median duration of follow-up was 3.6 years (interquartile range, 1.7-6.2). Hypothyroidism was not associated with a higher risk of all-cause mortality in patients receiving CRT for heart failure. The risk of appropriate implantable cardioverter-defibrillator therapy significantly increased in association with increased baseline thyroid-stimulating hormone level in the entire cohort (hazard ratio, 1.23 per 5mIU/L increase; 95% CI, 1.01-1.5; P=0.04) as well as in the hypothyroid group (hazard ratio, 1.44 per 5mIU/L increase; 95% CI, 1.13-1.84; P=0.004). Conclusions CRT improves cardiac function in hypothyroid patients. The ventricular arrhythmic events requiring ICD therapies are associated with baseline TSH level, which might be considered as an important biomarker to stratify the risk of sudden death for patients with heart failure and hypothyroidism.

9609 Background: Patients undergoing treatment for cancer often report problems with their cognitive function (CF), which is an essential component in maintaining Quality of Life (QoL). We conducted a longitudinal study of lung cancer (LC) patients to systematically evaluate changes in QOL including changes in CF, over time. Methods: Between 2005–2008, we followed 1757 primary LC patients who responded to CF questions at least once within 8 years of diagnosis. Overall QoL measured by LCSS and LASA (scores 0–100 from worst to best) were assessed among 1,604 of 1,757 (91%) who completed the questionnaire at one or both of two time periods: short-term (T1-within 3 years of diagnosis) and long-term follow-up (T2-beyond 5 years of diagnosis). Questions rated overall CF and problems in thinking clearly. Results: The median age at the time of LC diagnosis was 68 years in men (n=834) and 65 years in women (n=770), p<0.0001. At T1, the mean score of patients reporting problems with CF was 63.2 (±22.45) vs 74.4 (±20.38) who reported no problems (p<0.0001). At T2, the mean score was 62.2 (±24.18) for patients who reported CF problems and 78.1 (±18.28) who reported no changes with their CF (p<0.0001). At T1, the mean score of patients reporting problems thinking clearly was 66.1 (±21.65) vs 75.6 (±20.21) reporting no problems with their thinking (p<0.0001). At T2, the mean score was 70.4 (±20.95) for patients reporting problems thinking clearly vs 82.6 (±17.76) who reported no problems (p<0.0001). Conclusions: Self-reported QoL of lung cancer survivors showed substantial deficits with their cognitive function. Prospective and objective assessments are needed to determine if cancer treatments are positively associated with cognitive decline, to identify the patients at risk, and to test appropriate interventions. Funding Source: NIH grants: CA 115857, CA 84354, CA 80127 and CA 77118. No significant financial relationships to disclose.

e19031 Background: Useful predictors of survival in cancer patients have been found including such as gender, race, age, marital status, state of disease and tumor location. We set to explore the prognostic value of baseline QOL assessments on overall survival in lung cancer patients. Methods: A total of 1,319 lung cancer patients were followed at Mayo Clinic between 1997 and 2007. Overall QOL was assessed by either Lung Cancer Symptom Scale (LCSS) or a single-item Linear Analogue Self Assessment (LASA) with comparable wording. QOL scores were transformed to a 0–100 scale with higher scores representing better status. Patients QOL scores assessed within the first 6 months of follow-up were dichotomized using a priori definition for clinically deficiency score (CDS, ≤50 vs. >50). The Kaplan-Meier method was used to estimate the distribution of survival times by QOL clinical deficient categorization. Cox Proportional Hazards Models were used to evaluate the prognostic importance of QOL on OS alone and in the presence of age, smoking category, gender, treatment, stage of disease, smoking cessation and years of consuming a pack every day. Results: Baseline QOL was significantly associated with OS univariately (HR=0.46 with p<0.0001 based on the CDS categorization). After controlling for all these other factors, the indication of a clinically deficient baseline QOL contributed significantly to the prediction of patient survival (p=0.0002; HR=0.67). Age, treatment, disease stage, smoking cessation and smoking category were also significant predictors of OS multivariately. The median survival for patients that had an overall QOL score less than the CDS (≤50) was 1.6 versus 4.6 years for patients with QOL >50. Conclusions: Baseline overall QOL measured by LCSS or LASA is a significant and independent prognostic factor for OS in lung cancer patients. A meaningful next step in this research is to investigate interventions to improve lung cancer patient QOL and thereby increase their likelihood of survival as well. No significant financial relationships to disclose.

6518 Background: Several studies have demonstrated the importance of pessimism in cardiovascular disease. However, this construct has not been well explored in oncology. Methods: This study examined the survival time of 534 adult who were diagnosed with lung cancer. These patients had completed the Minnesota Multiphasic Personality Inventory (MMPI) approximately 18.2 years prior to their lung cancer diagnosis. MMPI Optimism-Pessimism (PSM) scores were divided into high (60 or more) and low scores (less than 60), and log-rank tests and Kaplan-Meier curves were used to determine survival differences. Multivariate Cox models were used for assessing prognostic values of pessimism along with other known predictors for survival outcome. Results: At the time of diagnosis, patients were on average 67 years old, 48% were female, 85% had non-small cell lung cancer (NSCLC), 15% had small cell lung cancer (SCLC), 30% were stage I, 4% were stage II, 31% were stage III/Limited, and 35% were stage IV/Extensive. Patients who exhibited a non-pessimistic explanatory style survived approximately six months longer than patients classified as pessimists. Pessimists have significantly worse survival rates even after adjusting for other known prognostic variables. Conclusions: Among lung cancer patients, having a pessimistic explanatory style was related to surviving on average six months less compared to patients with a non-pessimistic explanatory style. [Table: see text] No significant financial relationships to disclose.

Background Sorbs2b (sorbin and SH3 domain‐containing 2b) was recently identified as a cardiomyopathy gene from a zebrafish mutagenesis screen. However, cardiac functions of its mammalian ortholog remain elusive. Methods and Results We conducted a detailed expression and subcellular localization analysis of Sorbs2 ortholog in mice and a phenotypic characterization in Sorbs2 knockout mice. Sorbs2 is highly expressed in the mouse heart and encodes an adhesion junction/desmosome protein that is mainly localized to the intercalated disc. A mutation with near complete depletion of the Sorbs2 protein in mice results in phenotypes characteristic of human arrhythmogenic cardiomyopathy (ACM), including right ventricular dilation, right ventricular dysfunction, spontaneous ventricular tachycardia, and premature death. Sorbs2 is required to maintain the structural integrity of intercalated disc. Its absence resulted in profound cardiac electrical remodeling with impaired impulse conduction and action potential derangements. Targeted sequencing of human patients with ACM identified 2 rare splicing variants classified as likely pathogenic were in 2 unrelated individuals with ACM from a cohort of 59 patients with ACM. Conclusions The Sorbs2 knockout mouse manifests several key features reminiscent of human ACM. Although the candidacy of SORBS2 as a new ACM‐susceptibility gene is supported by preliminary human genetics study, future validation in larger cohorts with ACM is needed.

Coronavirus disease (COVID-19) has expanded around the world, resulting in a pandemic with high morbidity and mortality. To date, no specific treatment or vaccine is available to treat or prevent this sudden and potentially deadly disease. Economic restructuring brings opportunities and challenges to integrative medicine treatment. In such complex situations, integrative medicine treatments are to be provided cautiously, and the shift from in-person visits to remote medical services might play an important role in how such services are delivered.

Abstract Background Hypothyroidism is known to be associated with adverse clinical outcomes in heart failure. The association between hypothyroidism and cardiac resynchronization therapy outcomes in patients with severe heart failure is not clear. Methods The study included 1,316 patients who received cardiac resynchronization therapy between 2002 and 2015. Baseline demographics and cardiac resynchronization therapy outcomes, including left ventricular ejection fraction, New York Heart Association class, appropriate implantable cardioverter-defibrillator therapy, and all-cause mortality, were collected from the electronic health record. Results Of the study cohort, 350 patients (26.6%) were classified as the hypothyroidism group. The median duration of follow-up was 3.6 years (interquartile range, 1.7-6.2). Hypothyroidism was not associated with a higher risk of all-cause mortality in patients receiving CRT for heart failure. The risk of appropriate implantable cardioverter-defibrillator therapy significantly increased in association with increased baseline thyroid -stimulating hormone level in the entire cohort (hazard ratio, 1.23 per 5mIU/L increase; 95% CI, 1.01-1.5; P=0.04) as well as in the hypothyroid group (hazard ratio, 1.44 per 5mIU/L increase; 95% CI, 1.13-1.84; P=0.004). Conclusions CRT improves cardiac function in hypothyroid patients. The ventricular arrhythmic events requiring ICD therapies are associated with baseline TSH level, which might be considered as an important biomarker to stratify the risk of sudden death for patients with heart failure and hypothyroidism.