Yang, Ping

PURPOSEDrug development is becoming increasingly expensive and time consuming. Drug repurposing is one potential solution to accelerate drug discovery. However, limited research exists on the use of electronic health record (EHR) data for drug repurposing, and most published studies have been conducted in a hypothesis-driven manner that requires a predefined hypothesis about drugs and new indications. Whether EHRs can be used to detect drug repurposing signals is not clear. We want to demonstrate the feasibility of mining large, longitudinal EHRs for drug repurposing by detecting candidate noncancer drugs that can potentially be used for the treatment of cancer.PATIENTS AND METHODSBy linking cancer registry data to EHRs, we identified 43,310 patients with cancer treated at Vanderbilt University Medical Center (VUMC) and 98,366 treated at the Mayo Clinic. We assessed the effect of 146 noncancer drugs on cancer survival using VUMC EHR data and sought to replicate significant associations (false discovery rate < .1) using the identical approach with Mayo Clinic EHR data. To evaluate replicated signals further, we reviewed the biomedical literature and clinical trials on cancers for corroborating evidence.RESULTSWe identified 22 drugs from six drug classes (statins, proton pump inhibitors, angiotensin-converting enzyme inhibitors, β-blockers, nonsteroidal anti-inflammatory drugs, and α-1 blockers) associated with improved overall cancer survival (false discovery rate < .1) from VUMC; nine of the 22 drug associations were replicated at the Mayo Clinic. Literature and cancer clinical trial evaluations also showed very strong evidence to support the repurposing signals from EHRs.CONCLUSIONMining of EHRs for drug exposure–mediated survival signals is feasible and identifies potential candidates for antineoplastic repurposing. This study sets up a new model of mining EHRs for drug repurposing signals.

1562 Background: In Caucasian-predominant populations, overweight or obese NSCLC pts (BMI≥25-kg/m2) have better prognosis while underweight (BMI≤18.5-kg/m2) pts have a worse prognosis. A large pooled sample allowed us to evaluate the role of ethnicity in this BMI-NSCLC OS relationship. Methods: Using individual data, survival analysis was performed on 15 ILCCO studies, assessing the interactions between ethnicity and BMI on overall survival (OS). Adjusted Hazard Ratios (aHR) from Cox models and adjusted penalized smoothing spline plots were generated. Results: Among 13416 (77%) Caucasian, 2975 (17%) Asian, and 935 (5%) Black NSCLC pts analyzed, we confirmed that for all pts, being underweight at NSCLC diagnosis was associated with worse OS (aHR=1.68, CI 1.5-1.8, p<0.001), while overweight/obese pts had improved survival (aHR 0.89, CI 0.8-0.9, p<0.001), when compared to pts with normal BMI. In general, Black pts had poorer OS than Caucasian pts (aHR 1.26 CI 1.1-1.4, p<0.001). However, the BMI-OS relationship differed according to ethnicity (BMI-ethnicity interaction, p=0.009): Caucasian underweight pts had poorer OS (aHR 1.67, CI 1.5-1.8, P<0.001) while overweight/obese pts had improved OS (aHR 0.89, CI 0.8-0.9, P<0.001). In Asian pts, these two associations were aHR 1.15, CI 0.8-1.5, P=0.33, and aHR 0.91, CI 0.7-1.1, P=0.32, respectively. In Black pts, these two associations were aHR 1.06, CI 0.7-1.5, p=0.73 and 0.75, CI 0.6-0.8 p<0.001, respectively. For overweight/obese patients, as BMI rises from 25-kg/m2 through 45-kg/m2, the prognosis worsens for Caucasian pts, remains stable for Asian pts, but improves for Black pts. Conclusions: InCaucasian pts, being underweight had a greater negative impact on OS than for Asian or Black pts, while being obese had a greater beneficial impact in Blacks than in other ethnic groups. These ethnic differences likely reflect genetically-informed muscle/adipose tissue distributions, where Black pts may have less sarcopenic obesity than other ethnicities. In future prognostic studies, BMI relationships must account for ethnic differences.

Abstract An ultimate goal of precision medicine in lung cancer treatment is to restore patient health with maximized quality of life (QOL). Results from Mayo Clinic studies show that a significant improvement in fatigue, dyspnea, and pain scales could lead to better overall QOL. Although treatments and guidelines for clinical implementation to alleviate these key symptoms are available, few cancer patients receive adequate therapy, mostly because of limitations in current care delivery systems and unclear clinicians’ roles. For optimal care of lung cancer survivors in different subpopulations, three barriers must be overcome: physicians’ lack of knowledge, unwarranted practice variation, and uncertainty regarding care provider roles. Appropriate culturally adapted, tested and validated tools for QOL measures must be developed, rather than directly translating existing tools between different languages and across cultures or diverse subpopulations. Finally, lack of sensitive, adequate, and relevant tools in measuring health-related QOL (HRQOL) has long been an issue for effective data collection, demanding a global consensus on a set of core components that reflect the needs of all critical parties for the best cure and care, supporting patients to achieve optimal HRQOL.

Abstract Rationale Chronic obstructive pulmonary disease is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that lung stromal cells activate pathological gene expression programs that support oncogenesis. Objectives To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer. Methods The study included subjects with and without lung cancer across a spectrum of lung-function values. We conducted a multiomics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome. Measurements and Main Results Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation modulating protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms that drove these cancer-associated translation programs differed based on lung function. In subjects with normal to mildly impaired lung function, the mammalian target of rapamycin (mTOR) pathway served as an upstream driver, whereas in subjects with severe airflow obstruction, pathways downstream of pathological extracellular matrix emerged. Consistent with a role during cancer initiation, both the mTOR and extracellular matrix gene expression programs paralleled the activation of previously identified procancer secretomes. Furthermore, an in situ examination of lung tissue showed that stromal fibroblasts expressed cancer-associated proteins from two procancer secretomes: one that included IL-6 (in cases of mild or no airflow obstruction), and one that included BMP1 (in cases of severe airflow obstruction). Conclusions Two distinct stromal gene expression programs that promote cancer initiation are activated in patients with lung cancer depending on lung function. Our work has implications both for screening strategies and for personalized approaches to cancer treatment.

Abstract Rationale Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that stromal cells comprising the COPD lung contain pathological gene expression programs supporting oncogenesis. Objectives To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer. Methods Study subjects included patients with COPD with (n = 30) or without (n = 30) lung cancer across a spectrum of COPD severity. We conducted multi-omics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome. Results Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation impacting protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms driving these procancer translation programs differed on the basis of COPD severity. In mild or no COPD, the mammalian target of rapamycin pathway served as an upstream driver; whereas in advanced COPD, pathways downstream of pathological extracellular matrix emerged. Both the mammalian target of rapamycin and extracellular matrix gene expression programs paralleled activation of previously identified secretomes that can be independently induced and promote cancer initiation in mouse models. These included the senescence secretome in mild to no COPD and the ETS2 (erythroblast transformation-specific 2) secretome in moderate to severe COPD. Furthermore, in situ examination of COPD lung tissue documented stromal fibroblasts expressing key cancer-associated proteins from procancer secretomes including IL-6 (senescence secretome) in mild COPD and bone morphogenetic protein-1 (ETS2 secretome) in advanced COPD. Conclusions Two distinct stromal gene expression programs promoting cancer initiation are activated in patients with lung cancer depending on the severity of COPD as measured by lung function. Our work has implications both for screening strategies and personalized approaches to prevent cancer in COPD.

e20092 Background: More than 5,000 premenopausal women are diagnosed (dx’d) with lung cancer annually in the United States. Improvements in treatment are contributing to a growing population of young survivors. Limited data exist regarding the risk of treatment-related amenorrhea, a surrogate for infertility and early menopause, after systemic therapies for lung cancer. Methods: Since 1997, we mailed annual surveys to patients seen at Mayo Clinic for lung cancer who consented to join a research cohort. Surveys queried menopausal status and age of menopause. Those who were dx’d under age 50, who were treated with curative intent, and who reported that they were premenopausal at the time of the cancer dx were included in this analysis. “Immediate” treatment-related menopause was defined as reporting age of menopause as the same as the age at diagnosis or 1 year (yr) older. Results: Of 182 survey respondents to date (mean time from dx to 1st survey: 26 mos, SD 24 mos, range 12-202 mos), 85 (mean age 44 yrs, SD 5, range 34-48) received chemo during the yr after diagnosis, 26 of whom also received targeted therapy during that yr. Lung cancer dx occurred 1958-2016. Platinum drugs, taxanes, and etoposide were the most common chemotherapies. 46% of chemo recipients (mean age 47, SD 2, range 41-49) experienced immediate menopause, 9% (mean age 43 yrs, SD 5, range 35-48) experienced menopause at least 2 yrs after the age of dx, and 45% (mean age 40 yrs, SD 5, range 25-48) remained pre- or peri-menopausal at their final survey (on average 3 years after dx, SD 2, range 1-10). Only 3 patients received targeted therapy alone, and the remaining 94 (mean age 42 yrs, SD 6 years) received no systemic therapy within a year of diagnosis. 15% of these 94 (mean age 45 yrs, SD 3, range 41-49) experienced immediate menopause, 16% (mean age 43 yrs, SD 4, range 36-49) experienced menopause 2+ yrs after the age of diagnosis, and 69% (mean age 41 yrs, SD 7, range 20-49) remained pre- or perimenopausal at their final survey (on average 4 yrs after dx, SD 3, range 1-10). Conclusions: Chemotherapy for lung cancer causes amenorrhea in a substantial proportion of women dx’d with lung cancer while premenopausal. Further research on fertility and menopausal symptoms after lung cancer treatment, and on differences between regimens, is warranted.

Abstract Objective: More than 5,000 premenopausal women are diagnosed with lung cancer annually in the United States. Limited data exist regarding the risk of treatment-related amenorrhea, a surrogate for infertility and early menopause, after systemic therapies for lung cancer. Methods: Premenopausal women diagnosed with lung cancer under age 50 were surveyed at diagnosis and annually thereafter about their menstrual status as a part of the Mayo Clinic Epidemiology and Genetics of Lung Cancer Research Program. Types of lung cancer-directed treatments were recorded, and frequencies of self-reported menopause at each survey were calculated. Results: A cohort of 182 premenopausal women were included in this study, with average age at lung cancer diagnosis 43 years (SD 6). Among the 85 patients who received chemotherapy, 64% self-reported that they had become menopausal within a year of diagnosis. Platinum salts were universally included in these chemotherapy regimens, and the majority of these women also received taxanes within 1 year of diagnosis. Only 15% of the 94 patients who did not receive systemic therapy within 1 year of diagnosis experienced self-reported menopause. Three patients received targeted therapy alone, two of whom remained premenopausal at the final qualifying survey, completed a median of 3 years after diagnosis. Conclusions: Chemotherapy for lung cancer patients appears to increase risk of early loss of menses in survivors.