tbuckley/cabot-search huggingface dataset:
Impact of a breast cancer (BC) polygenic risk score (PRS) on the decision to take preventive endocrine therapy (ET): The Genetic Risk Estimate (GENRE) trial.
Authors: Julian Oliver Kim, Daniel J. Schaid, Andrew Cooke, Christina Kim, Benjamin Adam Goldenberg, W Edward Highsmith, Debjani Grenier, Jason P. Sinnwell, Amy C. Degnim, Fergus Couch, Celine M Vachon, Sandhya Pruthi
Journal: Journal of Clinical Oncology (2019)

1501 Background: Despite BC risk reduction of 50-65% by preventive endocrine therapy (ET), very few at-risk women choose to take them. A woman’s perceived BC risk correlates with uptake of ET. A PRS comprised of 77 BC genetic susceptibility loci (Single Nucleotide Polymorphisms (SNP) improves the accuracy of risk prediction for BC. We examined the impact of the addition of individualized PRS BC risk prediction to standard risk calculator estimates on intent to take BC prevention medication. Methods: Eligible women had ≥5% 10 yr BC Tyrer-Cuzick risk (IBIS) or 5 year Gail score ≥3%, with no history of BC or hereditary BC syndrome. Standard BC risk estimates (IBIS or Gail) were incorporated into the counselling on BC preventive ET. A self-reported questionnaire at baseline quantified intention to take ET and explored factors associated with this decision. Blood samples were obtained and genotyped for 77 SNPs, individualized PRS were calculated then incorporated into IBIS and Gail predictions for 5 yr, 10 yr, &amp; lifetime BC risk. At a second visit, PRS risk &amp; prevention recommendations were revisited. Post visit questionnaires assessed change in intent to take ET. Multivariable linear regression was performed to assess impact of baseline variables on change in intent to take medication. Results: From 2016 to 2017, 151 women in Canada &amp; USA were enrolled, median age: 56.1 (range 36-76.4), 35.6% were premenopausal, 98.7% were Caucasian. Median 5yr, 10yr, &amp; lifetime IBIS risk estimates were 3.8% (2.0-11.5), 7.9% (5.0-23.1), and 25.3% (5.5 to 92.2). PRS increased BC risk estimates in 84 (55.6%) and reduced BC risk estimates in 67 (44%) women. After PRS risk counselling, intention to take ET significantly changed (p&lt;0.001): 41.9% of those with increased PRS were more inclined, and 46.7% of women with decreased PRS were less inclined to take ET. On multivariable regression, increase in PRS (p&lt;0.0001) and less concern about ET side effects (p&lt;0.0001) were associated with greater intent to take ET. Conclusions: In high risk women, PRS significantly changed BC risk estimates &amp; intent to take preventive ET. Further assessments of the impact of PRS scores on compliance with ET are warranted. Clinical trial information: NCT02517593.
Outcomes of Hispanic/Latino women with triple-negative breast cancer who achieve a complete pathologic response after neoadjuvant chemotherapy.
Authors: Alexander Philipovskiy, Javier Chavez Corral, Rosalinda Heydarian, Alok Kumar Dwivedi, Gong Xiaoming, Sajid Leelani, Sumit Gaur
Journal: Journal of Clinical Oncology (2019)

e12081 Background: The aim of this study was to determine the efficacy of neoadjuvant chemotherapy (NACT) versus adjuvant chemotherapy (ACT) in Hispanic/Latino (H/L) women with triple negative breast cancer (TNBC). Methods: We retrospectively reviewed 104 records of female patients diagnosed with TNBC, stages I–III, treated at Texas Tech Breast Care Center from 2006 to 2016. Pathological complete response (pCR), overall survival (OS) and progression-free survival (PFS) were estimated and compared between two treatment groups. Kaplan Meier survival curve and Cox proportional hazards regression analyses were conducted to determine unadjusted and adjusted effects of NACT compared to ACT. Results: Of 104 TNBC patients with median duration of follow up of 6 (range 2-11) years, 30 (29%) received NACT and 74 (71%) received ACT. Women undergoing NACT were mostly younger, with a mean age of 50.8 (range 40-67) years, compared with those in the ACT group, mean age of 53 (range 32-80) years. Additionally, women in the NACT group had more advanced cancer, stage III (61%) and stage II (33%), in contrast to the ACT group, who had stage III (23%) and stage II (55%). Of 30 patients received NACT,twelve (40%) had pCR. The (median 6 years/range 2-11 years Women who achieved pCR had better PFS and OS compared with patients who received ACT. On the other hand, women with residual cancer after NACT had worse survival outcomes compared with women who received ACT (Hazards Ratio-HR = 0.1, p = 0.001). Conclusions: In our study, we observed that the patients in the NACT group with residual cancer had statistically significantly worse survival outcomes compared with ACT group. Patients who received NACT and had pCR had no relapse over the observation period. Our study suggests that there is a need of a prospective study to better understand the biology of TNBC among H/L women in order to individualized NACT to population of patients with “chemosensitive” subtype of TNBC.
Abstract MP80: Genome-wide Meta-analysis of SNP-by-antihypertensive Treatment Class Effect on Serum Potassium in Cohorts of European and African Ancestry From Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium
Authors: Marguerite R Irvin, Degui Zhi, Colleen Sitlani, Nita Limdi, Joshua A Bis, James Floyd, Christy Avery, Eric Whitsel, Leslie Lange, Albert Smith, Raymond Noordam, Donna Arnett, Bruce Psaty
Journal: Circulation (2016)

Thiazide diuretics (TD) lead to hypokalemia and angiotensin-converting enzyme inhibitors (ACE) and angiotensin receptor blockers (ARB) lead to hyperkalemia more frequently than other antihypertensives. Inter-individual variation in serum potassium on antihypertensive treatments exist and we hypothesized genetic markers may modify the association of treatment class with serum potassium levels. We separately evaluated interactions of SNP-by-TD as well as SNP-by-ACE /ARB on serum potassium levels among users of antihypertensive medication (anti-HTN). Our study included 7 European-ancestry cohorts (EA, N = 1673 TD exposed; N=1262 ACE /ARB exposed; N=1998 reference, users of other anti-HTN) and 4 African-American ancestry cohorts (AA, N = 482 TD exposed; N =411 ACE/ARB exposed; N=1182 users of other anti-HTN). Models were adjusted for age, sex, BMI, potassium supplementation, and ancestry at the cohort level. We filtered results based on an estimated degrees of freedom filter that incorporated SNP imputation quality, minor allele frequency (MAF), and the number of exposed participants. We performed race-stratified fixed effects inverse variance weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates. ACE /ARB data uncovered eleven significant (P&lt;5x10-8, Figure top line) SNPs (smallest P=1.1х10-8; MAF 0.37-0.40) at a single locus among EAs with consistent direction of effect across the 7 cohorts. The SNPs are located between the genes for NR2F1 antisense RNA 1 (NR2F1-AS1) and arrestin domain containing 3 antisense RNA 1 (ARRDC3-AS1) on chromosome 5 (Figure). The ACE /ARB interaction meta-analysis in AAs highlighted a SNP in insulin-like growth factor 1 receptor (IGF1R). The TD interaction analysis did not yield significant results in either race group. In conclusion, genome-wide SNP-by-ACE /ARB interaction analyses for serum potassium uncovered loci that could have future implications for the prevention of arrhythmias due to high potassium levels on a common antihypertensive treatment.
Association between breast cancer mortality-to-incidence ratios and state health disparities in the United States.
Authors: Yu-Che Lee, Ko-Yun Chang, Judith Hurley
Journal: Journal of Clinical Oncology (2019)

1548 Background: Breast cancer is the most commonly diagnosed cancer and second leading cause of cancer deaths among women in the United States. The cancer mortality-to-incidence ratio (MIR) provides a population-based indicator of cancer survival and has been established previously to evaluate healthcare variations among different countries. We aim to evaluate the association, which has not been investigated before, between MIR of breast cancer and state-level health disparities in the United States. Methods: We used United States Cancer Statistics (USCS) database to calculate 6-year average of MIRs for breast cancer from 2010 to 2015. America’s Health Rankings (AHR) is a platform using weighted measures in 5 different categories (Behaviors, Community &amp; Environment, Policy, Clinical Care and Outcomes) to determine annual state health rankings. Six-year average (2010-2015) of health uninsured rate by state was obtained from the U.S. Census Bureau and 5-year average (2010-2014) of health spending per capita by state was obtained from Centers for Medicare &amp; Medicaid Services. The correlations between breast cancer MIRs and state health variables were calculated by linear regression analyses. Results: From 2010 through 2015, 1,390,357 females were diagnosed with breast cancer and 246,671 females died from breast cancer in the United States. The 6-year average of age-adjusted incidence rate, mortality rate and MIRs were 124.2 ± 1.3 per 100,000 population, 21.1 ± 0.6 per 100,000 and 0.170 ± 0.007, respectively. Among fifty states we included for analyses, Hawaii had the lowest MIR (0.116 ± 0.014) and Nevada had the highest MIR (0.204 ± 0.004). AHR showed Hawaii had the highest health ranking (No. 1) whereas Louisiana had the lowest health ranking (No. 50) in 2015. In our analysis, states with better health rankings, lower health uninsured rates and higher health spending per capita were significantly correlated with lower MIRs (R 2 = 0.695, 0.453 and 0.253, respectively; all P &lt; 0.001). Conclusions: The difference of MIRs for breast cancer was strongly associated with state health diversities. These findings suggest that MIR of breast cancer can be an applicable measure to evaluate and reflect the state-level health disparities in the United States. [Table: see text]
The impact of a digital solution on tumor board preparation time for nurse navigators.
Authors: Donna Fowler, Lincoln R Sheets, Matthew S Prime, Athanasios Siadimas, Yariv Z Levy, Richard D Hammer
Journal: Journal of Clinical Oncology (2019)

e18020 Background: A multidisciplinary tumor board (MTB) provides an interdisciplinary approach for decision-making in cancer care. Oncology nurse navigators (NN) have been introduced to facilitate patient access to services and resources, and to improve continuity and coordination of care. Little is known about how digital technologies support this role. Methods: A prospective IRB approved cohort study was undertaken to evaluate NN time preparation for MTBs before and after the implementation of the NAVIFY Tumor Board (NTB) solution at University of Missouri Health Care (MU). Data was collected using a digital time-tracking application. The NTB manual version was implemented via a phased roll-out (Hematology – Apr 9, 2018; Breast May 18, 2018; Gastrointestinal Jul 11, 2018). Subsequently, the integrated version was introduced (Oct 4, 2018). Results: Time preparation for 101 MTBs (828 cases) were evaluated throughout 2018 (35 Breast; 213 cases / 32 GI; 302 cases / 34 Hematology; 313 cases). Data showed NN meeting preparation time decreased for each MTB after the introduction of NTB; further time saving was achieved with NTB integrated version (Table 1). For the Breast MTB there was statistical significance between time preparation pre- &amp; post-NTB (p-value = 0.011) but not between the manual and integrated versions (p-value = 0.118). For the Gastrointestinal MTB, there was no statistical significance between pre- &amp; post-NTB (p-value = 0.214). For Hematology MTB there was statistical significance between the change from the NTB manual version vs. integration (p-value = 0.004). Note before NTB implementation Hematology MTB was not supported by NN. Conclusions: Introduction of the NTB reduced time spent by NNs preparing for 3 different MTBs, EMR integration delivered further time-savings. No discernable learning curve was observed suggesting user-training was sufficient and NTB was easy to learn. A reduction in variance (SD &amp; IQR) for time preparation across all MTBs was seen. This suggests the NTB solution standardized the process for MTB preparation. Less time spent preparing for MTBs gives NNs more time to support patients.
The relationship between response and dose in published, contemporary phase 1 oncology trials.
Authors: Antonious Ziad Hazim, Emerson Yu-sheng Chen, Gordon B. Mills, Vinay Prasad
Journal: Journal of Clinical Oncology (2019)

e14583 Background: Traditional dose-escalation trial designs have changed little even as diverse classes of oncology drugs have been developed. We aimed to examine whether the association of drug dose to preliminary clinical efficacy previously established in cytotoxic chemotherapies remains true in contemporary phase I dose-escalation oncology trials. Methods: We conducted a systematic review of recent early-phase, dose-finding clinical trials of oncology drugs from November 15, 2015 to November 15, 2018 to examine the relationship between the dose of the investigational drug and objective response rate. We searched PubMed using “cancer” or “oncology” search terms and selected studies that enrolled adults with advanced cancer, determined maximum tolerated dose (MTD) and/or recommended phase II dose, and reported efficacy results by drug dose level. Trials testing combination therapies, single dose level, and non-pharmacologic therapies were excluded. Information related to the study drug, study design, cancer type, dose levels, MTD, and recommended phase II dose were all collected. Treatment response for every dose level was categorized into: complete response, partial response, stable disease, and progressive disease. Dose level was categorized into four categories: &lt; = 40%, 41-80%, 81-120%, and &gt; 120% of the recommended phase II dose. Results: We identified 93 trials with 2506 participants having both dose and treatment response data. Of these trials, 71 (76%) were testing targeted agents, 7 (8%) were immunotherapy, and 6 (7%) were cytotoxic chemotherapy. Median response rate across trials was 5% (range 0-83%). Among the dose range of &lt; = 40%, the response rate was 12% (57 of 491), 41-80% was 17% (95 of 562), 81-120% was 23% (272 of 1206), and &gt; 120% was 29% (71 of 247). Conclusions: Observed treatment response across dose levels in recent phase I trials should cause us to re-examine the toxicity-benefit ratio and influence how we design phase I trials testing novel classes of oncology drugs.
Predictive Value of Fasting Glucose, Postload Glucose, and Hemoglobin A1c on Risk of Diabetes and Complications in Chinese Adults
Authors: Jieli Lu, Jiang He, Mian Li, Xulei Tang, Ruying Hu, Lixin Shi, Qing Su, Kui Peng, Min Xu, Yu Xu, Yuhong Chen, Xuefeng Yu, Li Yan, Tiange Wang, Zhiyun Zhao, Guijun Qin, Qin Wan, Gang Chen, Meng Dai, Di Zhang, Zhengnan Gao, Guixia Wang, Feixia Shen, Zuojie Luo, Yingfen Qin, Li Chen, Yanan Huo, Qiang Li, Zhen Ye, Yinfei Zhang, Rui Du, Di Cheng, Chao Liu, Youmin Wang, Shengli Wu, Tao Yang, Huacong Deng, Donghui Li, Shenghan Lai, Zachary T. Bloomgarden, Lulu Chen, Jiajun Zhao, Yiming Mu, Guang Ning, Weiqing Wang, Yufang Bi
Journal: Diabetes Care (2019)

OBJECTIVE Uncertainty remains regarding the predictive value of various glycemic measures as they relate to the risk of diabetes and its complications. Using the cutoffs recommended by the American Diabetes Association’s 2010 criteria, we determined the associations of fasting plasma glucose (FPG), 2-h postload glucose (2h-PG), and HbA1c with the outcomes. RESEARCH DESIGN AND METHODS Baseline medical history, FPG, 2h-PG, and HbA1c were obtained from a population-based cohort of 193,846 adults aged ≥40 years in China during 2011–2012. A follow-up visit was conducted during 2014–2016 in order to assess incident diabetes, cardiovascular disease (CVD), cancer, and mortality. RESULTS We documented 8,063 cases of diabetes, 3,014 CVD-related events, 1,624 cases of cancer, and 2,409 deaths during up to 5 years of follow-up. Multivariable-adjusted risk ratios (95% CIs) of diabetes associated with prediabetes based on FPG of 100–125 mg/dL, 2h-PG of 140–199 mg/dL, or HbA1c of 5.7–6.4% (39–47 mmol/mol) were 1.60 (1.43–1.79), 2.72 (2.43–3.04), and 1.49 (1.36–1.62), respectively. Restricted cubic spline analyses suggested J-shaped associations of FPG, 2h-PG, and HbA1c levels with CVD, cancer, and mortality. Multivariable-adjusted hazard ratios (95% CIs) associated with untreated diabetes based on FPG ≥126 mg/dL, 2h-PG ≥200 mg/dL, or HbA1c ≥6.5% (48 mmol/mol) were 1.18 (1.05–1.33), 1.31 (1.18–1.45), and 1.20 (1.07–1.34) for CVD; 1.10 (0.92–1.32), 1.44 (1.25–1.67), and 1.08 (0.92–1.28) for cancer; and 1.37 (1.20–1.57), 1.57 (1.41–1.76), and 1.33 (1.17–1.52) for mortality, respectively. 2h-PG remained significantly associated with outcomes in models including FPG and HbA1c as spline terms. Furthermore, 2h-PG significantly improved the ability of the C statistic to predict diabetes, CVD, and mortality. CONCLUSIONS 2h-PG remains independently predictive of outcomes in models including FPG and HbA1c. Therefore, in addition to FPG and HbA1c, routine testing of 2h-PG should be considered in order to better assess the risks of outcomes.
Learning from every patient: Real-world clinical outcomes of patients with metastatic triple-negative breast cancer treated in the community oncology setting.
Authors: Anchit Khanna, Elani Bowers, Amin Haiderali, Michael Marian Slancar, Natalie Heather Rainey, Lee Na Teo, Ian M. Collins, Ali Tafreshi, Khageshwor Pokharel, Ream Sabbah, Megan Bohensky
Journal: Journal of Clinical Oncology (2019)

e12554 Background: Triple-negative breast cancer is a biologically aggressive disease that accounts for 15% of all breast cancers, of which around 4-5% are metastatic (mTNBC) at diagnosis. Notably, there is no standard of care for mTNBC in the first line (1L) setting. This, in addition to higher relapse rates and poor long-term survival, warrants evaluation of real-world treatment patterns, especially in the 1L setting, to better inform on clinical outcomes. Methods: This observational, retrospective, chart review study included a cohort of twenty-six mTNBC patients from six different sites Australia, who commenced 1L treatment between July 1, 2012 and June 30, 2015. Medical records of eligible patients were abstracted using electronic case report forms after gaining relevant ethics approvals. Data on treatment patterns and clinical outcomes in the 1L setting were then collected from the index date until the end of data abstraction or death. The index date is defined as the date of initiation of 1L systemic therapy for mTNBC. Results: In the 1L setting, patients that received combination (52%) chemotherapy was slightly higher than single-agent (48%) chemotherapy. The commonest combination used was Carboplatin-Gemcitabine (12%), and the most common monotherapy was Nab-Paclitaxel (24%). The overall response rate and disease control rate were estimated to be 32% and 60% in the 1L setting. The median duration of treatment and the median time to next line of therapy were calculated to be 98 days and 12.45 (95% CI 2.79, 20.30) months respectively. Importantly, the median progression free survival (sensitivity analysis) and the median overall survival were estimated to be 3.17 (95% CI 1.91, 5.09) and 10.41 (95% CI 5.36, 16.53) months respectively. Conclusions: Chemotherapy is currently the mainstay of treatment for mTNBC. However, disease progression and chemo-related toxicities warrant stratified use of more efficacious and tolerable treatment options, especially in the 1L setting. Results from this study could be useful in comparing the efficacy and cost effectiveness of these emerging targeted and immuno-therapies outside the clinical trial setting.
CD8+ T cells in tumor parenchyma and stroma by image analysis (IA) and gene expression profiling (GEP): Potential biomarkers for immuno-oncology (I-O) therapy.
Authors: Peter M Szabo, George Lee, Scott Ely, Vipul Baxi, Harsha Pokkalla, Hunter Elliott, Dayong Wang, Benjamin Glass, Jennifer K Kerner, Ilan Wapinski, Cyrus Hedvat, Darren Locke, Dimple Pandya, Neeraj Adya, Zhenhao Qi, Alex Greenfield, Robin Edwards, Michael Montalto
Journal: Journal of Clinical Oncology (2019)

2594 Background: Distribution patterns of CD8+ T cells within the tumor microenvironment (TME) can be assessed by IA, which may reflect underlying tumor biology and serve as a potential biomarker to assess the utility of I-O therapy. These patterns are variable and may be classified as immune desert (minimal infiltrate), excluded (T cells confined to tumor stroma or to the invasive margin), or inflamed (T cells diffusely infiltrating tumor parenchyma and stroma). We hypothesized that association of a GEP signature with abundance of parenchymal and stromal T-cell infiltrates may identify biomarkers of response or resistance to I-O therapy. To test this, we applied an AI-powered IA platform to quantify CD8+ T cells by geographical location and used GEP to define both CD8 abundance and associated geographic localization to tumor parenchyma and stroma. Methods: We performed an analysis using a tumor inflammatory GEP assay and CD8 immunohistochemistry on procured specimens (335 melanoma, 391 SCCHN). Digitized slides were used to train a convolutional neural network to quantify the number of CD8+ T cells in stroma, tumor parenchyma, parenchyma-stromal interface, and invasive margin. Generalized constrained regression models were used to predict GEP signatures specifically for stromal and parenchymal CD8+ T cells. Results: Parenchymal and stromal GEP scores were highly concordant with CD8+ infiltrate geography (adj- r 2 : 0.67, 0.65, respectively; P ≤ 0.01). Little overlap existed between gene sets associated with parenchymal and stromal CD8 T-cell geographies. CSF1R and NECTIN2 gene expression was observed to correlate inversely with parenchymal localization and directly with stromal CD8+ T-cell abundance. Conclusions: GEP signatures can be identified that are concordant with various CD8+ T-cell localization patterns in melanoma and SCCHN, demonstrating that GEP-IA can be developed to identify the immune status of interest in the TME. The specific genes identified have potential to elucidate mechanisms of resistance and/or inform I-O targets that can be further evaluated in relation to clinical significance in future studies.
Hypersensitivity Pneumonitis: Current Concepts of Pathogenesis and Potential Targets for Treatment
Authors: Martina Vasakova, Moises Selman, Ferran Morell, Martina Sterclova, Maria Molina-Molina, Ganesh Raghu
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Hypersensitivity pneumonitis (HP) is a disease triggered by different inducers in susceptible individuals. The inhaled inducing particles can be of both organic and less frequently inorganic origin...