bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA methylation profile in unknown cancer origin identification: A multi-class classification model.
Authors: Yu Jianing , Hong Yuanyuan , Zhihua Pei , Han Tiancheng , Xiaofeng Song , Song Xue , Xiaoqing Wang , Zhuo Zhang , Chen Weizhi , He Ji ,   Too
Published: May 2020

e13554

Background: Approximately 3-5% of human cancers are cancer of unknown primary (CUP). Treatment of a cancer patient is largely dependent on the tumor origin. Therefore, identification of the tumor origin can improve the survival of patients with CUP. We developed a multi-class classification model using DNA methylation profile as biomarker to determine the primary site of CUP. Methods: We split 7,082 primary tumor samples of 19 cancers and 679 normal samples of 15 tissues from TCGA into a 75% training set and a 25% testing set to develop the classification model. We started with multiple support vector machine (SVM) models, and then combined them into an optimal multi-class ensemble model. Predictors included tumor-specific markers and tissue-specific markers, which were filtered by comparing between groups. Only the training samples were used for feature selection and model development. A validation dataset consisting of 150 primary tissues, 54 metastasis tissues, 105 plasma samples with known cancer site origins from 12 classes was generated in house by a self-designed panel. Performance was measured by area under the curve (AUC) using the one-vs-all approach. Results: 7,453 tumor-specific and 1,533 tissue-specific markers were selected for model construction. AUCs of all cancer types were high in TCGA training and testing set (AUC≥0.96 for all classes). In our validation tissues, esophageal cancer, pancreatic cancer, colorectal cancer, lung adenocarcinoma, breast cancer and liver cancer achieved high AUC in both primary (0.83, 0.83, 0.82, 0.82, 0.80 and 0.79 respectively) and metastasis (0.74, 0.92, 0.86, 0.61, 0.92 and 0.65 respectively). Lung adenocarcinoma, colorectal cancer, liver cancer, breast cancer and esophageal cancer even achieved high AUC in the plasmas. Conclusions: Performance of our model in tissue and plasma samples indicated the potential clinical application of DNA methylation profile in unknown cancer origin identification.
Early cancer detection using multi-omic approach including epigenetic signal from ultra-small fragments.
Authors: Wu Johnny , Li Xin-Xing , Zhou Huabang , Liu Wendi , Wang Fenfen , Yao Qianqian , Lu Dongsheng , Lu Huiqi , Wang Hongyan , Wittkop Tobias , Tang Paul , Hu Heping , Cheng Xiaodong , Hu Zhiqian , Faham Malek , Weng Li
Published: May 2020

e13561

Background: Genetic and epigenetic signals from plasma cell-free DNA (cfDNA) as well as proteins have been shown to detect cancer early. We have previously developed Circular Ligation and Amplification (CLAmp-seq) to detect mutations very sensitively and demonstrated higher performance than molecular barcode-based methods. The same single strand based technology yielded a much larger proportion of small fragments ( < 100 bp) than traditional methods typically relying on double stranded ligation, allowing us to investigate epigenetic signature of cancer in ultra-short fragments. We sought to measure the performance using a multi-omics approach of these genetic and epigenetic changes as well as proteins in detecting colorectal cancer (CRC), ovarian cancer (OC) and hepatocellular carcinoma (HCC). Methods: A healthy and a late stage cancer sample were assessed by whole genome sequencing (WGS) using CLAmp-seq. Then we analyzed cfDNA from plasma samples of 731 patients, including 69 CRC, 57 HCC, 49 OC patients and 556 age-matched healthy individuals. Out of the diseased samples, the numbers for stages I-IV are 49, 39, 71, and 16, respectively. CLAmp-seq WGS was performed on 58 healthy and 66 cancer samples to discover cancer epigenetic signature. In addition, all the samples were analyzed for a panel of proteins and a CLAmp-seq targeted panel that includes known mutation sites. Results: Using CLAmp-Seq in late stage cancer showed 33% of its fragments as smaller than 100 bp compared to 15% in healthy and < 1% in late stage by double stranded library prep. In addition, the difference in fragment size between late stage cancer and healthy was 29bp using CLAmp-Seq and 12bp using traditional double stranded prep. This focused our attention to detect epigenetic signature specific to cancer on the small fragments using CLAmp-Seq. Using data from whole genome analysis we demonstrated a performance using the epigenetic signature alone of 50% sensitivity at 97% specificity. Combined with mutations and proteins, we obtained at specificity of 97% sensitivities of 50%, 88%, 88%, and 100% in stage I, II, III, and IV, respectively. At the same 97% specificity we obtained the sensitivities of 73%, 100%, and 85% in CRC, OC, and HCC, respectively. Conclusions: We have demonstrated that CLAmp-Seq detects small fragments that are enriched in cancer. We have found predictive epigenetic signature in these small fragments. When combined with mutations and proteins we obtained a performance of 80% sensitivity at 97% specificity.
Mammographic screening and socio-epidemiological profile of Amerindian riverside women in the Amazon forest.
Authors: Chaves Juliana Ramos , Zemero Maria Isabel , dos Reis Matheus Dinelly Ribeiro , Puty Taynah Cascaes , Fernandes Bruno Melo , Martins Junior Rodnei Jose Macambira , Lima Lorena Lira Tavares dos Santos de , Werneck De Carvalho Luis Eduardo
Published: May 2020

e13573

Background: Breast cancer still represents the most common tumor among women in the world and in Brazil. Screening coverage in Brazil is much lower than what is recommended by the World Health Organization (WHO), which makes it difficult to perform an early diagnosis. Thus, the current work aims to carry out mammographic screening and the socio-epidemiological profile of Amerindian riverside women in the Amazon region. Methods: This study is characterized as sectional and the sample consists of 260 female patients, living riverside, from the communities of the Amazon Forest, Xingu and Tapajos rivers, interviewed after the mammography screening in a task force promoted by the Brazilian Navy. Results: The median patients age was 49 years (p25-75: 45-58), menarche was around 13 years (p25-75: 12-14), menopause was 48 years (p25-75: 43-50) and the median of pregnancies was four (p25-75: 2-6). Most patients were classified as BIRADS 1 (41.32%), 4 of the 8 suspected and highly suspected cases were confirmed as breast cancer, and these patients had no complaints (82.98%), did not use therapy hormonal (97.15%), and did not use oral contraceptives (60.57%) and breastfed during pregnancy (97.52%). Conclusions: There is a high prevalence of protective factors against cancer, related to lifestyle and local culture. However, these communities have minimal access to health services, which demonstrates actual need of public policies to assist Amerindian riverside women, in order to promote better health care and, thus, reduce one of the most prevalent diseases in the Amazon region. [Table: see text]
Subsequent pregnancy and long-term safety from breast cancer patients.
Authors: Kim Yunyeong , Kang Minsun , Jung Jaehun , Cho Eun Kyung , Park Heung Kyu , Chun Yong-Soon
Published: May 2020

e13575

Background: Long-term safety of pregnancy after breast cancer still remained controversial, especially according to tumor subtypes. Prior results of other studies have limitations of short follow-up periods or small groups. Methods: We analyzed a population-based retrospective cohort data extracted from a random sample of 50% of women aged between 20 and 60 years who were diagnosed with breast cancer from 2002 to 2017 in the Korean National Health Insurance Service database. Propensity score matching analysis for age and Charlson Comorbidity Index (CCI) variables was performed for pregnant groups and non-pregnant groups with the same type of hormone therapy, chemotherapy and surgery. Study population was categorized to 4 biologic subgroups by the combination of hormone therapy, chemotherapy and target therapy. In this observational study, 1,566 patients with pregnancy after breast cancer were matched (1:2) to 2,462 non-pregnant patients of similar characteristics, adjusting for guaranteed bias. The matched patients were followed up to 7 years, or disease and mortality occurrence after the diagnosis of breast cancer. Survival estimates were calculated using the Kaplan-Meier analysis, groups were compared with the log-rank test. Results: Mean time from diagnosis to pregnancy was 3.4 years in study population. At a follow-up of 7 years after pregnancy, no inferiority in disease-free survival and overall survival was observed in pregnant patients factoring in treatment bias. In sub-analysis according to tumor subtypes, no difference in disease-free survival was observed between pregnant and non-pregnant patients in HR-positive and triple negative subgroup ( p= 0.088, p= 0.048, respectively). Likewise, no overall survival difference was observed in ER-positive patients and triple negative patients ( p= 0.05∼0.73, p= 0.03∼0.09, respectively). Conclusions: Our observational data provides reassuring evidence on long-term safety of pregnancy in young breast cancer patients, regardless of tumor subtypes.
The relationship between leptin, leptin receptor, and FGFR1 in primary human breast tumors.
Authors: Shoemaker Wyatt , Paithankar Shreya , Benham Vanessa , Chen Bin , Bernard Jamie
Published: May 2020

e13578

Background: General/overall obesity and visceral/central obesity are associated with increased breast cancer risk and poorer cancer outcomes; however, the precise etiology of these observations is not fully known. Our previous research suggests that adipose tissue-derived fibroblast growth factor 2 (FGF2) promotes malignant transformation of mammary epithelial cells through the activation of its primary receptor, fibroblast growth factor receptor 1 (FGFR1). Both FGF2 and leptin have been shown to be elevated in the serum in obesity (body mass index (BMI) > 25kg/m2). It is well established that elevated sera leptin promotes breast cancer through multiple mechanisms. Therefore, we hypothesized that tumors that express elevated FGFR1 and leptin receptor (LepR) may have a poorer prognosis in obese patients. Methods: Databases that house gene-sequenced breast cancer tumors and normal breast tissue were analyzed to discern relationships between gene copy number and mRNA levels of leptin, leptin receptor, FGFR1 and janus kinase 2 (Jak2), as Jak2 was shown to be a common downstream mediator of both FGFR1 and leptin receptor activation by Cytoscape network analysis. Furthermore, we tested the efficacy of Jak2 inhibitors for preventing mammary epithelial cell malignant transformation using our well-established models of adipose tissue-stimulated growth in soft agar. The anchorage-independent growth in soft agar is a surrogate marker for malignant transformation. Results: A much stronger significant relationship exists between FGFR1 mRNA and leptin mRNA in primary breast cancer (p = 3.17*10−9) compared with normal breast epithelium (p = 0.0013). In primary breast tumors, gene copy number of FGFR1 positively correlates with leptin copy number (p = 8.956*10−8, r = 0.19). Moreover, two separate Jak2 inhibitors attenuated both leptin+FGF2-stimulated and mouse adipose tissue-stimulated MCF-10A cell transformation. Conclusions: Taken together, these results suggest that elevated sera FGF2 and leptin in obese patients may promote breast tumorigenesis in tumors that express elevated FGFR1 and LepR and that Jak2 inhibitors may be a novel therapeutic option for adiposity-driven breast cancers. Future work will examine the relationship between FGFR1/leptin receptor expression and survival and how these relationships are influenced by BMI status.
Is there an association between air pollution levels and lung cancer incidence?
Authors: Patel Seema , Chagpar Anees B.
Published: May 2020

e13584

Background: PM2.5 particles are an indicator of air pollution levels associated with various respiratory illnesses. We sought to determine the association between air pollution levels and lung cancer incidence across different countries. Methods: Country-specific data for median PM2.5 levels and age-standardized lung cancer incidence rates (ASLCIR) were collected for the year 2016 from the World Health Organization and the Global Cancer Observatory, respectively. Country-specific data for median age and proportion of smokers were collected from the Central Intelligence Agency and Our World in Data, respectively. Statistical analyses were performed using SPSS Version 26.0. Results: Across 105 countries, the median PM2.5 level was 18 ug/m3 (range; 6-94 ug/m3). The WHO has set 10 ug/m3 as the upper limit for PM2.5 levels; 91 (86.7%) of countries had rates higher than this. The ASLCIR was surprisingly higher in countries with PM2.5 ≤ 10 ug/m3 (median 28.7 vs. 13.9 per 100,000 population, Pearson correlation coefficient -0.386, p < 0.001). Countries with PM2.5 levels ≤ 10 ug/m3 tended to have a higher GDP (median $55,709 vs. $5,931, p < 0.001), and an older population (median 41.5 vs. 30.4, p < 0.001); however, the proportion of population who smoked was no different in countries with low vs. high PM2.5 levels (20.3% vs. 22.5%, p = 0.847). Controlling for age, GDP, and proportion of the population who smoke in a multiple linear regression model, ASLCIR were not influenced by median PM2.5 (see linear regression table below, p = 0.888). Removing PM2.5 levels from the model did not significantly affect the model fit (R2= 0.749 in both models). Conclusions: These results demonstrate that air pollution levels do not significantly impact lung cancer incidence rates, which are more related to age, tobacco use, and GDP. [Table: see text]
Epidemiological profile of cancers among adolescent and young adult patients of a Haitian cancer program.
Authors: Bernard Joseph , Constant Pascale , Henderson Rebecca , Alexis Lynn Gabrielle , Gilbert Doukens Patrick , Pierre Lenz Sacha Christyl , DeGennaro Vincent A.
Published: May 2020

e13589

Background: The epidemiology of cancer among adolescents and young adults (AYA) has been a relatively neglected topic, particularly in the developing countries. The main objective of this study was to present the epidemiology of cancer among this subpopulation in Haiti’s largest cancer program. Methods: A retrospective study was conducted on patients aged 15 to 39 years old with pathological and/or clinical diagnosis of cancer at the cancer clinic of Innovating Health International (IHI) in Port-au-Prince, Haiti from January 2016 to December 2019. The chart review collected variables such as age, gender, date of diagnosis, cancer type and outcome to present this epidemiological profile of AYA cancers. Results: Among the two thousand two hundred and ninety-eight (2298) cancer cases managed during this study period, 20.1% (n = 461) were adolescents and young adults. 82% of these patients were female and 18% male. 25.2% (n = 116) were less than 30 years old. Breast cancer was the most common type (n = 222, 48.2%%), followed by gynecological cancers (n = 70, 15.1%) with cervical cancer representing 61.4% of the cases (n = 43), hematological malignancies (n = 44, 9.5%) with lymphomas (n = 31) as the most common type, sarcomas (n = 43, 9.3%), head and neck cancers (n = 24, 5.2%), gastrointestinal cancers (n = 22, 4.8%), cutaneous cancers (n = 10, 2.2%), urological cancers (n = 5, 1.1%), thyroid cancer (n = 5, 1.1%) and CNS tumors (n = 2, 0.4%). 3.0% of the AYA patients (n = 14) presented with a cancer of unknown primary (CUP). In the < 30 y/o subgroup blood cancers, breast cancer, sarcomas, and head and neck malignancies were respectively the most common types, while in the ≥ 30 y/o subgroup, breast and gynecological cancers were the most common, followed by sarcomas, GI and blood cancers. No case of lung cancer was received for the AYA population. The overall mortality rate was 30.6% and 12.8% of the patients were lost to follow-up. Conclusions: Cancers among AYA patients represented 20.1% of the cancer population, with a different epidemiological profile for the < 30 y/o and ≥ 30 y/o subgroups. The CNS tumors, leukemias and urological cancers were most likely under-represented due to low referral, misdiagnosis or early mortality.
Epidemiology and mortality of metastatic castration-resistant prostate cancer (mCRPC) in a managed care population in the United States.
Authors: Wallace Katrine , Landsteiner Adrienne , Bunner Scott , Engel-Nitz Nicole , Luckenbaugh Amy
Published: May 2020

e13592

Background: To date, there has been a paucity of information in the literature describing the epidemiology of mCRPC within the prostate cancer population. We present a real-world data study describing characteristics and mortality of patients with mCRPC within an administrative claims database of an insured population within the United States. Methods: In an administrative claims database of ≈18,000,000 covered lives, adult male patients were included if they had ≥1 claim for prostate cancer (ICD-9: 185 or 233.4; ICD-10: C61 or D075), underwent pharmacologic or surgical castration, and had a code for metastatic disease during the identification period (January 1, 2008–March 31, 2018). The index date was the first metastatic claim; 6 months of continuous enrollment (CE) prior to (baseline period) and after (follow-up period) the index date was required. Patients with metastatic claims in the baseline period were excluded. Patients were followed until the earliest of: death (unless prior to the 6-month CE), end of study period, or disenrollment. A claims-based algorithm was employed to identify locally advanced and distant mCRPC patients in the prostate cancer study population. Mortality data were sourced from the Social Security Administration Medicare data, and a claims algorithm. Results: 343,089 patients were identified with a claim for prostate cancer; of those, 3690 mCRPC cases (1.1%) were identified using the claims-based algorithm and met the study inclusion criteria. Median age was 75 years. Insurance type included commercial plans (27%) and Medicare (73%). Castration type included pharmacologic (99%) and surgical (1%). First claims for metastases were most commonly in the bone (65%) or lymph nodes (15%), with 20% in other sites. The study population averaged a Charlson comorbidity index score of 3.05 at baseline, with 16% of patients receiving a score of ≥5. The most common baseline comorbidities were hypertension (67%), urinary disease (58%), dyslipidemia (52%), and cardiac disease (45%). Median follow-up time among the mCRPC group was 538 days, during which 1834 deaths occurred; 50% of the population experienced mortality during the study period. Conclusions: This study provides valuable insights into the epidemiology, clinical characteristics, prevalence rate, and mortality of patients with mCRPC. Given the high mortality proportion of this disease, the development of novel therapies to prolong life in patients with mCRPC is warranted.
Differential effect of obesity on comorbidity risk in younger and older women with early breast cancer.
Authors: Lorentsen Michael , Deal Allison Mary , Muss Hyman B. , Chen Yi Tang , Brenizer Tucker , Shachar Shlomit S. , Nyrop Kirsten A.
Published: May 2020

e13601

Background: Overall survival in women with early breast cancer (EBC) (Stage I-III) has made great strides over the past several decades, with survivors more likely to die from causes other than breast cancer. This study investigates the differential effect of obesity on pre-treatment comorbidity risk in younger versus older women with EBC. Methods: This is a retrospective chart review of women with EBC, age 21 and older, seen at a single institution. Differences in 18 common comorbidities were assessed by age ( > = 65 vs < 65) and Body Mass Index/BMI ( > = BMI 30 vs < 30), with relative risks (RR) estimated from log-binomial regression. Results: In a sample of 590 women, 24% were age 65+, 32% non-white, and 39% had obesity. Patients age 65+ were more likely to report 2+ comorbidities compared to age < 65 (RR 1.62, 69% v 43%). Obese patients (BMI > = 30) were more likely to report 2+ comorbidities compared to BMI < 30 (RR: 1.73, 66% v 38%). Women with obesity were more likely to have hyperlipidemia (RR: 1.85, 28% v 15%) as well as diabetes (RR: 2.51, 17% v 7%). The impact of BMI on comorbidity risk (2+ v < 2) differed by age group (interaction p < 0.001). In the < 65 group, obese patients were more likely to have 2+ comorbidities compared to non-obese (RR: 2.12, 62% v 29%, p < 0.0001). The difference was not as large in the 65+ group (RR: 1.28, 81% v 63%, p = 0.02). Conclusions: This study demonstrates increased comorbidity burden, including hyperlipidemia and diabetes, in women with obesity and EBC, especially those < 65. Providers should ensure that patients with obesity and EBC are appropriately screened and treated for underlying comorbidities. Future research should assess the impact of weight loss on overall survival in EBC patients.
Pharmacogenetics findings in Brazilian cancer patients.
Authors: Werneck De Carvalho Luis Eduardo , Sarraf Jonathan Souza , Puty Taynah Cascaes , Chaves Juliana Ramos , Câmara Thiago Farias , Yamaguchi Nise Hitomi , Adami Fernando
Published: May 2020

e13607

Background: Pharmacogenetic is the study of genetic modifications influence on drugs action. Recent studies have suggested that some genetic polymorphisms may have an influence on patient outcomes. Thus, the objective of this thesis is to evaluate the frequency of genetic polymorphisms in cancer patients. Methods: Cross-sectional study at the Oncology Center of São Paulo. The reports presented a SNP evaluation (saliva - PCR-Multiplex, PCR-RFLP or capillary sequencing - Genotypic variants: 1 allele, 2 alleles and no allelic alteration). Polymorphs were validated according to the localized gene and its relationship to drugs using PharmGKB, NCBI SNP Database, NCBI Gene Database and DrugBank Database. Results: Sample mean aging was 49.92 years (SD = 22.73), with breast cancer (n = 26 /% = 26.3) and stage IV (n = 51 /% = 51.6). Among the evaluated platinum components, it is possible to verify that the presence of polymorphisms was more frequent. Of these, all had the highest frequency of polymorphisms in only 1 allele (xpc__rs2228001 = 25.4%; ercc1_rs11615 = 21.2%; xrcc3_rs861539 = 22.2%; mthfr_rs1801133 = 44.4%). This was repeated when evaluating the Cyclophosphamide, Fluoropyrimidines, Taxanes, Anastrozole and Epirubicin-related polymorphisms. When we evaluated the Tamoxifen-related genes, the polymorphisms absence was more frequent (cyp2d6_rs3892097 = 26.3%; cyp3a4_rs2740574 = 61.6%). Evaluating all medications the highest frequency was polymorphism in only 1 allele. Consequently, for the irinotecan drug evaluation, two polymorphisms were evaluated and presence of polymorphism (xrcc3_rs861539 = 58%), mostly in only 1 allele (44%). Conclusions: Therefore we can evaluate that the allelic frequency variability of the polymorphs observed, despite the great variability, shows most evaluated individuals present some type of genotypic modification, being the majority in only 1 allele.
All-cause and cancer mortality in a private health plan in Brazil: Ten years retrospective analysis.
Authors: Reis Neto Joao Paulo , Busch Juliana Martinho , Stefani Stephen D.
Published: May 2020

e13610

Background: Cancer is the second leading cause of death worldwide. From 2014 to 2015 Brazil estimated more than 500,000 new cases of cancer, which placed the country among those with the highest cancer incidence. This study evaluates the 10-year evolution of mortality rates due to all causes and cancer and to estimate the potential years of life lost (PYLL) in beneficiaries of health plan, according to sex, age and geographic region. Methods: Retrospective cross-sectional, descriptive study evaluated the causes of death, between 2008 and 2017, by sex and age groups, for all causes (AC) and cancer (CA) data from the health insurance system. The information on the death certificates (DC) was coded according to the ICD-10. Age was stratified into groups: up to 49 years, 50–59 years, 60–69 years, 70–79 years and 80 years or more. Data were analyzed by checking the proportions and mortality rates (MR), grouped into two five-year periods, 2008-2012 (P1) e 2013-2017 (P2). Annual MR per 100,000 population was estimated using the direct method and proportional mortality rates (PMR). To calculate the potential years of life lost (PYLL) the upper limit was 76 years old. The avoidable MR was also analyzed for individuals up to 75 years and cancer. Microsoft Excel v2010 and Qlik Sense v13.21 were used to analyze data and statistics. Results: 5,779 deaths were analyzed, 4,447 in men (77.0%, average 70.1 years) and 1,332 women (33%, 75.9 years). Cancer was the second leading cause of death (n = 953, PMR 16.5%), behind cardiovascular disease (n = 1,662 PMR 28.8%). The major crude death rate per 100,000 was due circulatory system diseases (347), followed by cancer (199) and respiratory system diseases (110). The highest cancer MR were in men, elderly and Brazilian regions with the lowest Human Development Index (HDI). Greatest number of deaths in men at P1 were from cancers of lung (CMP 19.8%), prostate (14.2%) and pancreas (8.0%). At P2, prostate (18.2%), lung (16.8%) and stomach (7.6%). In women, during P1, breast (20.2%), lung (13.1%) and pancreas (83%), and during P2, the same order, 22.5%, 14.6% and 9.3%, respectively. Cancer accounted for a total of 6,335 PYLL and 40.9% of causes of death were classified as avoidable. Conclusions: Cancer was one of the leading causes of mortality during the study. High pancreatic cancer MR differs from national statistics, requiring more analysis that involves possible occupational exposure. Although preventive actions for healthy life habits, early screening and diagnosis, Brazil presents high cancer mortality rates as showed in this analysis.
Comorbidities and survival in breast cancer: A retrospective cohort study from an academic institution in southern Illinois.
Authors: Maini Ruby , Regmi Manjari Rani , Parajuli Priyanka , Lara Garcia Odalys Estefania , Cheema Asad , Sahib Hamsa , Tandan Nitin , Koester Cameron , Mirihagalle Noupama , Abedrabo Sabree , Niaz Zurain , Ibrahim Abdisamad M. , Bhandari Bishal , Johnson Alexander , Delfino Kristin , Robinson Kathy , Kulkarni Abhishek , Desai Meghna R.
Published: May 2020

e13624

Background: Breast cancer is the most common malignancy in females. Early detection and advances in treatment modalities have resulted in decreasing rates of breast cancer related death. While breast cancer survival has improved, risks of death from cardiovascular comorbidities have increased. Our study aims to evaluate survival among breast cancer patients with cardiac comorbidities. Methods: This study was conducted using a retrospective cohort design with use of de-identified hospital electronic patient records. ICD diagnoses codes were used to identify breast cancer patients. Our initial search criteria revealed 1618 patients. Our eligibility criteria included adult patients 18 years and older with newly diagnosed breast cancer from January 1st, 2014 – January 31st, 2017 which yielded 478 patients. All data was collected through retrospective chart review. Analysis was performed with SAS v9.4 software. Qualitative variables were analyzed using Chi-Square Test. Survival curves are estimated using Kaplan-Meier methodology and analyzed with a log rank test. Predictors of survival are assessed with Cox proportional hazards regression analyses. All significance was assumed at the p < 0.05 level and reported as hazard ratios (HR). Results: Of our 478 patients, the following comorbidities were noted: diabetes n = 98 (21.17%), myocardial infarction (MI) n = 14 (2.98%), heart failure (HF) n = 36 (8.38%), coronary artery disease (CAD) n = 26 (5.75%), hypertension (HTN) n = 261 (55.77%), peripheral vascular disease (PVD) n = 9 (1.95%), hyperlipidemia (HLD) n = 230 (49.15%). Survival analysis was completed on patients with CAD (p = 0.49), HLD (p = 0.40), HTN (p = 0.15), MI (p = 0.52), and HF HR = 6.35 (95% CI 2.40-16.7, p = 0.0002). Pre-existing HF had a higher risk of mortality, which was statistically significant; however, all other single comorbidities were not. Overall survival (OS) in patients with more than one comorbidity HR = 1.36 (1.08-1.69, p = 0.006), was statistically significant. Conclusions: Patients with only one comorbidity be it MI, CAD, HTN, HLD did not have statistically significant results in OS. However, breast cancer patients with pre-existing HF are at 6.35-fold higher risk of mortality than those without HF. Patients with more than one comorbidity listed above were at 1.36-fold higher risk of mortality. Our results indicate that risk factor reduction may help improve survival in patients with breast cancer. Prospective validation of these findings is warranted.
Tobacco still haunting Kentuckians: Adolescent and young adult (AYA) cancer trend from the Kentucky SEER database.
Authors: Jacob Aasems , Parasramka Saurabh , Hao Zhonglin , Durbin Eric B.
Published: May 2020

e13626

Background: Kentucky has the highest incidence and mortality for AYA cancers in the US. When the incidence of AYA cancers increased 4% between 2012-16 nationally, it was 12.3% in the state of Kentucky. Understanding the burden and factors associated with it may help develop effective risk reduction strategies. Methods: SEER database was used for analyzing population estimates (2012-2016) while records from the NCI-designated cancer center in the state was used to assess current trends and clinicopathologic features. Pearson test was used to estimate correlation and Kaplan-Meier and Cox regression models were used to compare survival outcomes. Results: A total of 5825 AYA patients were identified in the state’s SEER database between 2012-16. A majority (62.4%) were female, from non-Appalachian region (71%) and rural counties (64%). Thyroid, breast, melanoma, cervical and CNS malignancies were the most common. While sarcoma, leukemia and gastric cancer decreased in incidence, breast, melanoma, cervical and colorectal cancer have increased from 2012-2016, similar to a general trend nation-wide. County-wise estimation of cancer incidence showed a significant correlation with prevalence of smoking (Pearson r = 0.34, p < 0.001) independent of educational, employment or economic status. A total of 1129 AYA cancer patients treated between 2016-19 at the Markey Cancer Center were analyzed. Baseline characteristics were similar to statewide trend. About 10% of the cancers were metastatic at diagnosis and 14% died from the disease. Nearly half (44%) of the patients were smokers. Smoking was independently associated with higher risk of death (HR 0.46 95%CI 0.33, 0.64, p < 0.0001) and early cancer recurrence (HR 0.56, 95%CI 0.3, 0.9, p = 0.026). Metastatic disease at diagnosis was also more common among smokers compared to non-smokers. (58% vs 41%, p = 0.002). There was no significant difference in OS or risk of recurrence between rural/urban or Appalachian/Non-Appalachian counties. Conclusions: The high prevalence of smoking (24.3%), especially among youth (14.3%) could be the root of the higher incidence of AYA cancers in the state of KY although multiple socio-economic and geographic factors might be influencing. Second-hand smoke exposure at home is also the highest in the country at 32% with rates as high as 80% in some counties. Awareness about these disturbing statistics is required to set in motion more community and legislative interventions to reduce cancer incidence among the youth.
Hematological malignancies in the adolescent and young adult (AYA) population in Singapore.
Authors: Poon Eileen Yi Ling , Wong Evelyn , Goh Wei Lin , Hong Jiancheng , Wong Victoria , Quah Daniel , Tan Yee Pin , Tan Yung Ying , Chan Selene , Chan Jason Yongsheng , Somasundaram Nagavalli , Harunal Rashid Mohamad Farid Rin
Published: May 2020

e13630

Background: Hematological malignancies is thought to be one of the more common Adolescent and Young Adult (AYA) cancers and constitute leukemias and lymphomas. However, little is known about its incidence and prevalence in Asia. We also do not have any data on its behavior or its prognosticators. The outcomes of this group of patients is also unknown when compared to the pediatrics or geriatrics, but is expected to be not as ideal. There is no consensus on whether this group of patients should be treated as pediatrics or as the older adults. We have sought to evaluate the prevalence and trends in a single large-volume tertiary cancer centre in Asia. Methods: We extracted data on all patients with cancer between 16-39 years old who were seen at our centre (National Cancer Centre Singapore) during the period of 1st January 2015 and 31st December 2019. In total, we had 2583 patients. We then excluded all other cancer types except those with a hematological malignancy and 5 other patients due to incomplete data. Results: There were 319 patients with a hematological malignancy. 153 (48%) were female and 166 were male(52%). Most of the patients presented between 30-39 years old (171, 53.6%). There were 54 (2.1%) leukemias and 265 (83.1%) lymphomas. Of those with leukemias, 46 (85.2%) had acute leukemia and 9 (14.8%) had chronic leukemias. Among the lymphoma patients, there were 194 (73.2%) Non Hodgkin Lymphoma (NHL) patients and 69 (26.0%) Hodgkin Lymphoma (HL) patients. There were 149 (46.7%) B Cell lymphomas and 38 (11.9%) T Cell lymphoma patients. The most common B cell Lymphomas is Diffuse Large B Cell Lymphoma (128, 85.9%) and the most common T Cell Lymphomas is Peripheral T-cell Lymphoma (28, 73.7% patients). Conclusions: AYAs with a hematological malignancy form a significant portion of the cancers we see in this age group. Yet, little information is available with regards to their clinico-pathological characteristics, especially in Asia. Work is underway to further elucidate these differences so that we can better their outcomes.
Comparing breast cancer characteristics and outcomes between black U.S.-born patients and black immigrant patients from individual Caribbean islands.
Authors: Cerbon Danielle , Schlumbrecht Matthew , Ragin Camille , Barreto Coelho Priscila , Hurley Judith , George Sophia
Published: May 2020

e13633

Background: Caribbean-born black immigrants (CBI) represent 57% of all black immigrants in the US; they come mainly from Haiti, Jamaica, Dominican Republic (DR), and Cuba. Breast cancer (BC) is the leading cause of cancer deaths in women living in the Caribbean, however, our previous retrospective cohort of 1131 black women with BC shows that CBI have a better overall survival compared with US-born black (USB). The Caribbean has a majority of African ancestry; nonetheless, different ancestral populations differ in genetic composition, making the Caribbean a distinct population with several health disparities within it. Therefore, we stratified our study by each Caribbean country compared to USB patients with the objective of further studying the difference in BC outcomes between USB patients and CBI. Methods: We identified BC patients through a Safety Net and Private Hospital Tumor Registries. We selected the most populace sites: Haiti, Jamaica, Bahamas, Cuba and DR; and used data from 1,082 patients to estimate hazard rations (HRs) using Cox proportional hazards regression and Kaplan Meier analysis for overall survival; Chi Squared and independent sample t-test to verify associations in categorical variables. Results: The study has 250 Haitian, 89 Jamaican, 43 Bahamian, 38 Dominican, 38 Cuban and 624 USB women. Haitians underwent less surgery (HB 61.2% vs USB 72.9%; P = 0.001) and had less triple negative BC (18% vs USB 27.8%; P = 0.006). Bahamians were the youngest at diagnosis (50.5 years vs. USB 57.6 P < 0.001) and presented at more advanced stages (stage 3/4, 54.3% vs USB 35.3%; P = 0.02). Jamaicans and DR underwent more radiation therapy (43.8%, P = 0.002 and 44.7%, P = 0.028 vs. USB 28%). Jamaican women had a better overall survival compared to USB patients (median of 154.93 months, 95% CI: 114.1-195.5 vs 98.63 months, 95% CI: 76.4-120.8; Log-Rank Mantel Cox P = 0.034). Favorable factors for survival were: radiation therapy in Haitian and USB (aHR = 0.45, 95% 0.27-0.77; P = 0.004); and surgery in USB (aHR = 0.26 (0.19-0.36), p < 0.001), Bahamians (aHR = 0.05 (0.01-0.47), p = 0.008) and Jamaicans (aHR = 0.08 (0.03-0.24), p < 0.001). Conclusions: This study underlines the vast heterogeneity in the Caribbean population and demonstrates that Jamaican immigrants with BC have a higher overall survival compared to USB patients, proposing that genetic and other cancer related factors inherent to country of origin impact survival within Caribbean immigrants and highlighting the need for further studies in this immigrant sub-group.
Germline DNA repair gene mutations in Taiwan prostate cancer patients.
Authors: Huang Wilson , Yeh Shauh-Der
Published: May 2020

e13640

Background: Genetic testing for inherited mutations in DNA-repair genes such as BRCA1, BRCA2, ATM, PALP2, FANCA has been proposed for high-risk and metastatic prostate cancer patients for personalized therapy and management. Although the prevalence of germline DNA-repair gene mutations among Caucasian populations are known, the frequency of such mutations in Taiwan prostate cancer patients has not been established. In this study, we performed next-generation sequencing (NGS) analysis of BRCA1, BRCA2, ATM, PALP2, and FANCA in 49 prostate cancer patients stratified according to the NCCN risk criteria using blood sample collected from a single hospital center. Methods: 4ml whole blood samples are collected in EDTA tube from prostate cancer patients of low-intermediate, high to very high, regional, and metastatic risks. The samples are subjected to buffy coat fractionation, genomic DNA extraction, library preparation, full-exon NGS, and comparative analysis with all known germline variants. We identified and correlated the frequency of germline DNA-repair gene mutations with patient’s age at diagnosis, Gleason grades, initial PSA, family history of prostate cancer, and NCCN risk. Results: A total of 49 blood samples were tested and analyzed for BRCA1, BRCA2, ATM, PALP2, and FANCA mutations. Among all cases, 6.1% (3/49, 95% confidence interval [CI]: - 0.6%-12.8%) carried pathogenic mutations: 2.0% (1/49) in BRCA1, 2.0% (1/49) in BRCA2, and 2.0% (1/49) in ATM. They were compatible with previously reported mutations and no new germline variants were detected. These mutations were associated with initial PSA and NCCN risk; all identified mutations belonged to Gleason grade 5 and high to very high risk subgroups. No clinical association was observed with patient’s age of diagnosis and family history. Conclusions: In this single hospital center study, we observed a modest incidence of DNA-repair gene mutations in the Taiwan prostate cancer cohort. Germline DNA-repair gene mutations were observed in high risk prostate cancer patients with the highest Gleason grade. Frequencies of the mutations did not differ significantly according to age at diagnosis or family history of prostate cancer. These results were similar to the reported findings in the Caucasian populations. Our findings confirmed the necessity of genetic testing in Taiwan prostate cancer patients. [Table: see text]
Prevalence & pathogenic features of hereditary breast/ovarian cancer syndromes: Implementation of a genetic/familiar cancer risk assessment unit.
Authors: Ramón Jorge , Rodriguez Rey Laura , García Luis Eduardo , Sánchez Cabrero Darío , Higuera Oliver , Gallego Alejandro , Ruiz Gimenez Leticia , Rodriguez Salas Nuria
Published: May 2020

e13645

Background: Currently studies found more than 25 genes associated with inherited Breast/Ovarian cancer. This syndrome shows morphologic, immunophenotic and molecular differences in comparison with sporadic ones. For example, BRCA1/2 are commonly ductal invasive carcinomas, with high grade of differentiation and high mitotic index, showing expression of basal o myoepithelial markers and overexpression of cell cycle proteins. Our study describe the outcomes since the implementation of Genetic/Familiar cancer risk assessment a tertiary hospital. Methods: A retrospective chart review was performed among all patients evaluated in Genetic counseling clinic in our hospital, since September 2008 to March 2019. Patients who fulfill criteria for Breast/Ovarian Cancer syndromes were included. We were specially interested in those with pathogenic, likely pathogenic or uncertain significance variants. All variants were named according to the practice of the BIC database, and the GenBank entries. Description on clinical features of tumor and frequency of implicated genes are considered for statistical analysis. All data were calculated in Stata IC 15. Results: 320 patients were eligible, 62,2% (n = 199) had cancer diagnosis. The most frequent tumor diagnosis was breast, 68,8% (n = 137), featured by: ductal carcinoma (82,5%), high grade differentiation (55,2%), triple negative (22,6%), local/locally advanced stage (86,13%) and bilateral component (16,1%). 11,6% had Breast cancer and 3,4% Ovarian cancer as second malignancies, respectively. Variant alterations were found in 24 different genes. BRCA 2 had the highest frequency (40,9%; n = 139 variants detected), BRCA 1 (24,7%; n = 84), ATM(7,4%; n = 25), PALB2(5,3%;n = 18) and BRIP1(2,9%, n = 10). 230 variants (68,3%) were pathogenic or likely pathogenic variants. Pathogenic mutation variant distribution in BRCA2 were c.3264dupT (n = 12); c.6275_6276delTT (n = 8); c.9026_9030delATCAT (n = 8). The most frequent mutations in BRCA1 were: c.1674delA (n = 7); c.302-1G > A (n = 4); c.3331_3334delCAAG(n = 4). Among all patient with BRCA 1/2 mutations, 30,7% were undergone to prophylactic surgery, without statistical association with survival (p = 0,310). Conclusions: Our findings support literature about highly relation between BRCA1/2 and Breast/Ovarian Cancer. In our population, BRCA2 showed high frequency of pathogenic mutations. Patients with BRCA mutations and prophylactic mastectomy did not show statistical benefit in survival.
Cancer risks associated with the HOXB13 c.251G> A variant in men and women referred for hereditary cancer genetic testing.
Authors: Jones Melanie , Rosenthal Eric Thomas , Copeland Karen , Kidd John , Bernhisel Ryan , Comeaux Matthew , Rawson Randi , Mancini-Dinardo Debora
Published: May 2020

e13653

Background: The HOXB13 c.251G > A (p.G84E) variant is associated with increased prostate cancer risk, possibly at younger ages. Studies on this variant have focused primarily on men, although genetic testing for hereditary cancer risk is most often performed in women. There remains a need to assess whether male and female carriers of this variant have increased risk for other cancers. Methods: We identified male and female carriers of the HOXB13 c.251G > A (p.G84E) variant among individuals referred for hereditary cancer panel genetic testing from October 2018 – December 2019. Non-carriers had no pathogenic variants in any gene or variants of uncertain significance in HOXB13. Personal and family (1st- and 2nd-degree relative) cancer histories were obtained from provider-completed test request forms. Multivariable logistic regression (MLR) models were conducted separately for males and females to estimate cancer risks for the variant as odds ratios (ORs), and 95% Wald confidence intervals (CIs) adjusted for age, ancestry and personal/family cancer history. Results: The analysis included 197,978 patients: 4.5% (8,998/197,978) male and 95.5% (188,980/197,978) female. The HOXB13 variant was present in 0.44% (40/8,998) of tested males, 45% (18/40) of whom had a diagnosis of prostate cancer. The variant was present in 0.32% (621/188,980) of tested females. Male carriers with prostate cancer were diagnosed at younger ages (median, 56; Interquartile ratio [IQR], 52, 62) than non-carriers (median, 63; IQR, 57,70), but this difference was not statistically significant. The MLR model calculated a 3.30 OR for prostate cancer in male carriers of c.251C > A ( P = 0.01; 95% CI 1.30-8.39). In an analysis combining males and females, carriers were significantly more likely to report prostate cancer in a family member than non-carriers ( P = 3.5 x 10−7; OR 1.61, 95% CI 1.34-1.93). There was no apparent association with increased risk for other cancers among carriers versus non-carriers, or among relatives of carriers compared with relatives of non-carriers. Conclusions: The HOXB13 c.251G > A (p.G84E) variant was associated with significantly increased risk of prostate cancer, confirming previously published studies. We found no evidence of association with other cancers. For unaffected male carriers, who may frequently be identified through testing of a female relative, identification of this HOXB13 variant provides an opportunity for more precise prostate cancer risk stratification and screening.
Technical validation of a high-sensitivity target capture NGS assay using unique molecular identifier approach.
Authors: Mao Ruifang , Xiao Shanshan , Lin Rui , Wang Yuchen , Wang Tao
Published: May 2020

e13657

Background: Identification of a broad spectrum of somatic mutations is crucial to guide targeted therapy such as for non-small cell lung cancer (NSCLC) patients. In the clinical environment, it requires well validated NGS workflow both for the wet-lab and dry-lab procedures. Here we describe a high sensitivity target NGS assay to accurately capture single nucleotide variants (SNVs), short insertions and deletions (indels), copy number alterations and gene rearrangements for formalin-fixed paraffin-embedded (FFPE) NSCLC patient samples. Extensive analytical validation was performed following the checklists of College of American Pathologists. Methods: Next generation sequencing (NGS) libraries were prepared using extracted DNA from FFPE tissue NSCLC patient samples. The protocol for library generation was optimized in several steps and incorporated 10bp unique molecular identifiers (UMIs). The libraries were sequenced on Illumina HiSeq X-Ten platform. The sequence data was analyzed by an in-house bioinformatics pipeline to call somatic mutations at an average depth of 4000X. Results: We tested the accuracy of 68 clinical tumor samples that were also validated by conventional or alternative methods in the third party CAP accredited labs. We observed 100% sensitivity and 100% specificity compared with the other lab¡¯s validation results. To define the limit of detection (LOD) for different mutation types, clinical DNA samples containing different variants were diluted with normal DNA. The LODs for SNV (as in EGFR L858R) and indel (as in EGFR 19del) were 0.5% and 1%, respectively. Addressing the LOD of fusion and copy number alteration is usually challenging. Our NGS assay was able to achieve 2% LOD for gene rearrangement (fusion) and 3.5 copies for copy number amplification. The high reproducibility was also achieved by inter- and intra- replicate experiments. Our NGS assay showed better performance than other widely used commercial NGS assay panels. Conclusions: We have validated an NGS based approach with UMI technology that is able to achieve high accuracy and sensitivity as low as 0.5% for detection of somatic mutations, which will improve the clinical testing performance for NSCLC FFPE samples with low allele frequencies of driver mutations.