bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiology of adenoid cystic carcinoma in the United States.
Authors: Boyle Tirza Areli Calderón , St. Laurent Samantha , Semus Simon , Joseph Nedra
Published: May 2020

e13600

Background: Adenoid cystic carcinoma (ACC) is a rare malignancy of the secretory glands, accounting for approximately 1% of head and neck cancers and 10% of salivary gland neoplasms. ACC primarily occurs in the major and minor salivary glands; however, it is found in other sites of the head and neck, breast, female genital tract, prostate and skin. There is limited scientific literature on the epidemiology of ACC and no published incidence or prevalence estimates across all anatomic sites. Methods: Using data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries, ACC cases were identified by International Classification of Diseases for Oncology 3rd Edition histology codes. Data from 2012-2016 were used to estimate age-adjusted incidence rates (IR) and 5-year limited duration prevalence (LDP). Data from 2000-2016 were used to approximate 16-year LDP. IR and LDP were estimated overall and by age, sex and race. IR was calculated for each anatomic site. Total incident and prevalent cases were projected using the 2020 US Census population. Analyses were conducted in SEER*Stat (v8.3.6) and SAS 9.4. Results: In the US, ACC age-adjusted IR was 0.35 per 100,000 and 5- and 16-year LDP were 1.48 and 3.24 per 100,000, respectively (Table). ACC IR and LDP (per 100,000) were highest in those aged 75-79 years (IR 1.45; 5-year LDP 5.82; 16-year LDP 14.25) and in females, and lowest among Native Americans/Alaska Natives. ACC IR (per 100,000) were highest in the oral cavity and pharynx (IR 0.19), salivary glands (IR 0.12), respiratory system (IR 0.07) and breast (IR 0.05). As of January 1, 2020, 10,777 patients were living with ACC in the US who had been diagnosed 2000-2016. Conclusions: This study describes the US epidemiology of ACC across all anatomic sites and provides incidence and prevalence estimates not currently published in the literature. Improving understanding of the epidemiology of this rare cancer has important implications for the development of effective clinical and public health interventions. [Table: see text]
CA 15-3 elevation in U.S. women without breast cancer.
Authors: Hu Xiao , Cao Yu
Published: May 2020

e13609

Background: Cancer antigen 15-3 (CA 15-3) is an epitope of Mucin 1 transmembrane glycoprotein, used to monitor response to therapy in metastatic breast cancer. Elevated CA 15-3 levels have been noted in other malignant and non-malignant conditions. This is the first population-based study examining CA 15-3 elevation in US women without breast cancer. Methods: Women without breast cancer were identified from the National Health and Nutrition Examination Survey 2001-2002 with CA 15-3 measurements via Meso Scale Discovery immunoassay. CA 15-3 levels were dichotomized per previously reported cutoffs of 20, 25, 30, and 40 U/ml, and also logarithmically transformed. Logistic and linear regression models were used to examine associations between CA 15-3 and demographic characteristics, gynecologic/reproductive history, inflammatory markers, non-malignant chronic conditions and non-breast malignancies. Results: Of 2432 women ages 20-85 (mean 48) years old, eighty (3.3%) had CA 15-3 ≥30 U/ml. Based on cutoff ≥30 U/ml, univariate logistic regression showed ages 40-59, uterine fibroids history, and salpingectomy history were associated with normal CA 15-3; Mexican American ethnicity and increasing C-reactive protein were associated with elevated CA 15-3. Multivariate logistic regression confirmed that only ages 40-49 (OR = 0.162, p = 0.0013) and uterine fibroids history (OR = 0.216, p = 0.0373) remained significantly associated. Similar results were found using other cutoffs. Univariate linear regression showed ages 40-59, salpingectomy history, and longer oral contraceptive pill (OCP) use correlated with lower CA 15-3; Black ethnicity, increasing ferritin, endometriosis history, and lung cancer history correlated with higher CA 15-3. Multivariate linear regression revealed significant associations: ages 50-59 (17.1% lower CA 15-3 vs ages < 40, p = 0.028); race other than White, Black, Hispanic, Mexican (32.0% lower CA 15-3 vs White, p = 0.039); longer OCP use (14.0% lower CA 15-3 for 2-5 yrs’ OCP use, p = 0.023; 21.0% lower for > 10 yrs’ OCP use, p = 0.006; vs OCP use < 2 yrs); endometriosis history (22.9% higher CA 15-3 vs no history, p = 0.051). CA 15-3 levels were not significantly associated with chronic liver conditions, coronary artery disease, or metabolic conditions (elevated BMI, diabetes, hyperlipidemia). Conclusions: Perimenopausal women, uterine fibroids history, and longer OCP use were associated with lower CA 15-3 levels, while non-White ethnicity and history of endometriosis were associated with higher CA 15-3. These findings help to elucidate interpretation of CA 15-3 in clinical practice.
Disparities in cancer premature mortality in Brazil: Predictions up to 2030 and sustainable development goals.
Authors: De Camargo Cancela Marianna , Borges Lopes de Souza Leonardo , Leite Martins Luis Felipe , Correa Schilithz Arthur , Souza Dyego , Hanly Paul , Barchuk Anton , Soerjomataram Isabelle , Sharp Linda , Pearce Alison
Published: May 2020

e13614

Background: Premature mortality affects the economy directly due to the loss of productivity of individuals who decease, thus ceasing to contribute economically to the country. The 1/3 reduction in premature mortality (30-69 years) from chronic noncommunicable diseases is goal 3.4 of the UN Sustainable Development Goals (SDG). Although cancer is a chronic disease, it comprises more than 100 different conditions, with different risk factors and prognosis. This study aimed to calculate current and predicted premature mortality by 2030 for Brazil and regions, compare with SDG 3.4 target and identify regional progress and future needs. Methods: Mortality data were extracted from the National Mortality Information System of Brazil (SIM) and subsequently corrected for ill-defined causes. Crude and age-standardized mortality rates per 100,000 inhabitants were calculated. NordPred package by software R was used to calculate predictions up to 2030 and compared with the goal of 1/3 reduction of premature deaths. Results: Comparison of observed (2011-2015) and predicted (2016-2030) mortality rates show a 12.0% reduction in the likelihood of death among men and 4.6% among women nationally. Although predicted rates for 2026-2030 are lower than those observed in 2011-2015 predicted number of deaths increases by 75,341 for men and 90,513 for women. Lung cancer mortality rates are predicted to decrease more among men than women, while colorectal cancer mortality will increase for both sexes. Conclusions: The profile of cancer premature mortality is diverse in Brazil. Nationally, only male lung cancer will be close to reaching SDG 3.4 target, endorsing government’s long term efforts to reduce tobacco consumption. Colorectal cancer mortality increases in most regions, reflecting the epidemiological transition. Despite progress in cervical cancer control, it will continue to be a major challenge, especially in the North and Northeast. Our results provide a baseline for public policies for both prevention and access to treatment to reduce premature mortality in Brazil. Differences in cancer patterns show the need to plan and to adapt regionally for each reality.
Mortgage discrimination and breast cancer survival among older women in the United States.
Authors: Beyer Kirsten M. M. , Zhou Yuhong M. , Laud Purushottam W. , McGinley Emily , Yen Tina W.F. , Nattinger Ann B
Published: May 2020

e13615

Background: Although racism and racial residential segregation are widely considered to contribute to health disparities, including in breast cancer, studies examining the impact of mortgage discrimination, a factor contributing to residential racial segregation, and breast cancer survival are limited. The objective of this study is to examine the relationship between redlining (mortgage discrimination based on property location) and survival among older women with breast cancer. Methods: Using the Home Mortgage Disclosure Act (HMDA) database, we estimated redlining for all census tracts in the Metropolitan Statistical Areas (MSAs) within 15 Surveillance Epidemiology and End Results (SEER) areas. This measure was linked by tract with a SEER-Medicare cohort of 27,516 women aged 66-90 years with an incident stage I-IV breast cancer in 2007-2009 and claims information through 2014. We used cox proportional hazards regression models with survival time as the outcome variable and a 4-level categorical logged redlining variable as the key predictor. We also modeled the hazard ratio using redlining as a continuous variable. Models were stratified by stage, ER/PR status, and age group and adjusted for comorbidity and MSA-level standard error. Results: At a median follow-up of 72 months, one-third of the cohort was deceased. The majority of the cohort had no comorbidities and had hormone receptor-positive, early stage (I/II) cancers. Redlining was associated with poorer survival. When redlining is discretized into four groups with approximate equal-sized intervals, the first and second highest redlining groups are significantly associated with all-cause mortality (HR = 1.226 [1.108, 1.355] for the highest group; HR = 1.159 [1.095, 1.228] for the second highest group). When redlining and its quadratic terms are included in the model, the original and square terms are significantly associated with all-cause mortality (HR = 1.177 [1.111, 1.248] for redlining; HR = 0.982 [0.973, 0.991] for squared redlining). Conclusions: The study suggests that redlining could negatively contribute to breast cancer survival. Persistent place-based mortgage discrimination, as a manifestation of institutional racism, could have long-term effects on people’s health, possibly by impacting health care access or exposing residents to harmful neighborhood conditions. Housing policies that seek to reduce or eliminate place-based mortgage discrimination could contribute to reducing breast cancer survival disparities.
Cardiac events and breast cancer survival analysis in caucasians and minorities: A retrospective study in central Illinois.
Authors: Cheema Asad , Maini Ruby , Koester Cameron , Tandan Nitin , Lara Garcia Odalys Estefania , Regmi Manjari Rani , Parajuli Priyanka , Niaz Zurain , Abedrabo Sabree , Sahib Hamsa , Mirihagalle Noupama , Johnson Alexander , Ibrahim Abdisamad M. , Bhandari Bishal , Delfino Kristin , Robinson Kathy , Desai Meghna R. , Kulkarni Abhishek
Published: May 2020

e13622

Background: Breast cancer is the most prevalent malignancy affecting the female population in the United States and poses a significant mortality risk. In central Illinois, our objective was to analyze cardiac events (described as a new diagnosis of heart failure, heart failure hospitalizations, and acute coronary syndrome) in patients diagnosed with breast cancer and overall survival. Methods: A retrospective analysis completed in February 2020 identified patients (n = 1618) based on ICD diagnosis codes with a primary diagnosis of breast cancer. The inclusion criteria comprised of confirmed pathology report with diagnosis of breast cancer between January 2014 and December 2017. A cohort of 478 patients was identified as having met the inclusion criteria. Baseline characteristics and qualitative information were obtained from retrospective chart review. Continuous variables were described with measures of central tendency (mean, median) and dispersion (range, standard deviation). Categorical variables were summarized as frequencies and percentages. Furthermore, comparison between categorical variables were analyzed using Chi-Square test. Survival curves were estimated using kaplan-meier methodology and analyzed with a log rank test. Qualitative variables were analyzed using chi-square test and reported as hazard ratio using SAS software. All significance was assumed at the p < 0.05 level. Results: Of the 478 patients that were included as part of the analysis, 425 (89.6%) were of caucasian background and 49 (10.34%) were minorities (Asian, African American, and Hispanic). In regards to heart failure, our data demonstrated increased heart failure hospitalizations in minorities (7.89%) compared to caucasians (1.22%) which was a significant association (p = 0.026). In the overall survival among caucasian and minority groups there was no statistically significant difference (hazard ratio 0.939 with a 95% CI between 0.218-4.048), however it showed slight trend suggesting improved survival in the caucasian population. Conclusions: Our data illustrates that minorities with breast cancer experienced a higher incidence of heart failure when compared to the caucasian population. This supports closer observation at cardiac risk factors of such patients and medical optimization in an effort to prevent cardiac complications. While we did not see a significant difference in overall survival, further studies may be warranted in such population.
Healthcare disparities and the demand for expanding hereditary breast cancer screening guidelines in African Americans.
Authors: Ciuro Jordan Alana , Ahsan Samira , Beyer Alisha , Jackson Nancy
Published: May 2020

e13636

Background: The role of predictive genetic testing on cancer care continues to rise in the healthcare community due to increased development, high demand and utilization of multi-panel testing and genome sequencing. BRCA1 and BRCA2 (BRCA1/2) mutations constitute some of the most common, targetable and clinically important markers in breast cancer. Individuals who harbor BRCA1/2 mutation have a substantially increased risk of developing a multitude of cancers, including breast and ovarian cancer. Early detection of these mutations leads to genetic and prevention counselling. The National Comprehensive Cancer Network (NCCN) guidelines recommend BRCA1/2 screening in high risk individuals however has not incorporated differences within ethnic cohorts. Methods: This study reviewed data collected from a genetics clinic in a tertiary community hospital from 2008 to 2018 to analyze the prevalence of BRCA1/2 mutations in various ethnicities as well as identify high risk personal characteristics and family history. A retrospective chart analysis was conducted on 1090 high risk patients seen for genetic counselling for hereditary breast and ovarian cancer syndrome. Results: Among cases, BRCA1/2 mutations were significantly more common in African American when compared to non-Ashkenazi Jewish Caucasians (8.1% vs 3.6%, p = 0.020). African Americans were more likely to have a personal history of any cancer compared to non-Ashkenazi Jewish Caucasians (90.4% vs 84.5 %, p = 0.048). African Americans were also more likely to have personal history of breast cancer compared to non-Ashkenazi Jewish Caucasians (86.4% vs 79.6%, p = 0.048). Regarding family history, there was no significant difference in the prevalence of cancer. Conclusions: In conclusion, we observed a significantly higher rate of BRCA1/2 in the African American population when compared to non-Ashkenazi Jewish Caucasians. Given the documented social barriers such as insurance and lack of knowledge of family history, the prevalence of BRCA1/2 might be underrepresented in literature. It is critical for healthcare providers to assess probability of BRCA1/2 mutations in the African American population and consequently order genetic testing when appropriate. Future studies are needed in this ethnic cohort to establish if a more tailored approach would help identify higher risk individuals.
The actionable genomic mutational landscape in solid tumours.
Authors: Loddo Marco , Hardisty Keeda-Marie , Thatcher Robert Paul , Haddow Tiffany Eira , Williams Gareth Haydn
Published: May 2020

e13642

Background: The recent exponential increase in targeted agents and immunotherapies provide new therapeutic opportunities for patients with advanced cancers who have failed first line therapy. However, lack of comprehensive precision oncology testing as part of routine pathology assessment means potential therapeutic opportunities are difficult to identify or remain undiscovered for many patients. Methods: To address this unmet clinical need we established Oncofocus, a clinically validated, ISO15189/2012 and CLIA accredited, precision oncology test optimized for analysis of small diagnostic PWET clinical biopsy samples (sample acceptance 94%). Oncofocus detects actionable genetic variants in 505 genes linked to 764 anti-cancer targeted therapy protocols, either on-market FDA and EMA approved, carrying ESMO and NCCN guideline references or currently in clinical trials. Oncofocus trending data was analyzed for a real-life cohort of 1111 patients with the aim of determining the frequency of actionable mutations in this population. This cohort represent patients with advanced stage disease who underwent Oncofocus testing having failed first line treatment protocols. Results: Analysis of trending data revealed a complex mutational landscape in which 90% of solid tumors harbored actionable mutations. The majority of patients harbored one or more actionable mutations (median 2, range 0-13) affecting key cancer related regulatory networks including the PI3K/AKT/MTOR and RAS/RAF/MEK/MAPK signaling pathways, DNA-damage repair pathways and cell cycle checkpoints. Actionable genetic variants across 33 DNA Damage and Repair (DDR) genes were identified in 30% of tumors. Using a defined predictive cut point of > 10% for tumor proportion score, PD-L1 expression levels were significantly raised in 19% of cases. Abrogation of DDR function and elevated PD-L1 levels were identified in 5% of patients, a subpopulation potentially more responsive to immunotherapy. Notably, many of the actionable mutations identified did not show linkage with histological type or site of origin. Conclusions: Our data indicates that comprehensive precision oncology testing should be strongly considered as part of the diagnostic work up for all patients with advanced cancers, independent of tumor type, thereby ensuring capture of all targeted therapy opportunities and accelerating “site agnostic” molecular basket clinical trials. Comprehensive precision oncology testing was performed successfully on routine biopsy samples circumventing the requirement for fresh tissue or large sample specimens.
Validation of the fully automated idylla system for microsatellite instability detection in Chinese colorectal cancer patients.
Authors: Wang Qian , Zhang Jing , Yu Chengli , Bao Longlong , Cai Xu , Jiang Wenhua , Huang Dan , Zhu Xiaoli , Bai Qianming , Zhou Xiaoyan
Published: May 2020

e13644

Background: Mismatch repair (MMR)/microsatellite instability (MSI) testing is recommended by NCCN Guidelines to screen for Lynch Syndrome as well as to predict response to immune checkpoint inhibitors in solid tumors. Conventional methods for MSI detection, immunohistochemistry (IHC) and polymerase chain reaction (PCR), often require non-tumor controls as well as a long turnaround time. The Idylla system, in contrast, is a fully automated quantitative PCR unit with a turnaround time of 2.5 hours. Neither does it require normal tissue or special training to operate. The Idylla MSI Test has been CE-marked for its reliability among Caucasian colorectal cancer (CRC) patients, but has never been validated in Chinese CRC population. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were collected from 87 CRC patients and were subjected to MMR/MSI detection using IHC, PCR and the Idylla test separately. The Idylla MSI Test incorporates 7 novel MSI loci, ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, and SULF2. The sensitivity and specificity of the Idylla system were evaluated in comparison with PCR and IHC. Results: Of the 87 patients enrolled, both IHC and PCR identified 55 to be MMR-deficient (dMMR)/MSI-high (MSI-H), of which 4 were MSS using Idylla, and 32 to be MMR-proficient (pMMR)/microsatellite stable (MSS) where Idylla classified one as MSI-H, yielding a sensitivity of 92.7%, a specificity of 96.9% and an overall concordance of 94.3%. Re-examination of the 5 discordant cases (4 false negatives and 1 false positive) using DNA extractions instead of tissue slices on the Idylla platform displayed 100% consistency with IHC/PCR. Confirmation on the Idylla system using recut sections corrected 3 false negatives and 1 false positive, with all tumor contents of ≥20%, 1 Idylla-defined MSS sample with 5% tumor content remained discordant even after sample enrichment. Conclusions: The Idylla system provides a fast, reliable, and user-friendly solution to MSI detection in Chinese CRC patients with high sensitivity and specificity. Upfront assessment of tissue sample quality ( i.e. tumor area and tumor cell fraction) is critical for the accuracy of this test. The reproducibility of the assay warrants further investigation.
Determine the impact of hybrid capture-based comprehensive genomic profiling (CGP) on the treatment strategies in patients with solid tumors: A national, multicenter, retrospective study.
Authors: Disel Umut , Kose Fatih , Bilici Ahmet , Özgüroğlu Mustafa , Saglam Sezer , Seker Mesut , Aksoy Sercan , Tek Ibrahim , Eralp Yesim , Mandel Nil Molinas , Demir Gokhan , Arslan Cagatay , Demiray Mutlu , Salepci Taflan , Ozturk Mehmet Akif , Selcukbiricik Fatih , Temizas Gokce , Fidan Ebru Gul
Published: May 2020

e13646

Background: Most of the frequent cancers present a large number of very rare targetable genomic alterations. Moreover, some oncogenic drivers are shared across several diseases, and their targeting could improve outcome. We think that testing a large number of genes across all tumor types could improve outcomes in patients with “hard-to-treat” advanced cancers. The most important factor for the cancer patient to benefit from precision medicine therapy is the detection of the targeted driver mutations. The objective of this study is to determine clinical advantages of hybrid capture based comprehensive genomic profiling over classical diagnostic methods in the treatment strategies of patients with advanced stage diverse solid tumors in Turkey. Methods: This study was designed as a national, multicenter, descriptive, non-drug, retrospective cohort study. Study data were collected from medical files of patients. Besides, a survey was conducted to investigate the impact of CGP results on the treatment decisions of the clinicians. Results: The study included the data of 118 patients (55; %46.6 female, 63; %53.4 male). The mean period between the diagnosis and CGP analysis was 748 days. For either due to progression (97; 75.2%) or intolerance to therapy (12; 9.3%), the treatment of some cases was discontinued after CGP analysis. The results of the electronic survey for the clinicians indicated that the 57;48.3% of the clinicians change their treatment approach based on the results of the CGP analysis, of these 24; 42.1% preferred on-label treatments,3; 5.3% clinical trials and the 30; 52.6% preferred off-label treatments. 59;69.8% of the clinicians declared that their patients can reach to the revised treatment. 48;42.1% of the clinicians expressed that CGP support was very important in the last treatment decision. This is the interim descriptive statistics of the study. Conclusions: This is the preliminary results of the study. Conclusions will be done after the final analysis of the study
Economic burden of not testing for FLT3 to treat acute myeloid leukemia.
Authors: Henderson Raymond , Smart Dave , French Declan , Clark Jordan , Bloom Kenneth Joel , Hosty Derek , Lawler Mark
Published: May 2020

e13652

Background: Acute myeloid leukemia (AML) is a hematologic neoplasm with poor 5-year survival (33%; US 2016), a median survival of only 4 months for relapsed/refractory cases, and in 2016, a US incidence of 19,950 cases and 10,340 deaths. With the largest patient cohort over 65, AML treatment costs in the first year are > $25,000 per patient per month (PPPM); the initial month’s cost is $82,328. Mutations in the FMS-like tyrosine kinase 3 ( FLT3+) pathway confer resistance to standard chemotherapy and reduce the likelihood of survival after relapse. In 2017 and 2018, the FDA approved midostaurin and gilteritinib, two current FLT3+ precision medicines for AML. Here, we determine the economic burden of not testing for FLT3+. Methods: AML healthcare costs were assessed and modelled for the following settings: hospital, outpatient, emergency, and primary care. Pharmaceutical activity and cost data were extracted from the Centers for Medicare and Medicaid Services (CMS) database, employing Diaceutics’ proprietary Global Diagnostic Index. Our model forecasts the economic impact of precision testing to guide FLT3+ precision medicines in 2017 through 2019. Our algorithm calculates the number of AML patients with FLT3+ based on AML Medicare patients in the Healthcare Cost and Utilization Project database and FLT3+ prevalence and switching data. Results: Total US 2016 AML costs were $1.574 billion (bn), consisting of (i) hospital care $1 bn (including $229 million (mn) for bone marrow transplantation and $20.5 mn for pharmaceuticals); (ii) outpatient care $9.8 mn; (iii) emergency care $553.9 mn; (iv) primary care $6.6 mn. Analysis of CMS data revealed a paucity of FLT3+ testing to guide therapy. We estimate that after testing, 2,164 FLT3+ Medicare patients could benefit from precision medicine interventions, generating 2,965 quality-adjusted life years (QALYs) or 2,783 QALYs when administering midostaurin or gilteritinib respectively. Conclusions: This study is the most detailed analysis of the economic burden of AML among US Medicare patients to date and is the only AML cost-of-illness study to incorporate data concerning patients’ QALYs lost by failure to employ precision medicine. This study not only illustrates the minimal FLT3 testing conducted, but also the lack of precision medicines administered.
Genomic characterizations of KIT and PDGFRA in Chinese pan-cancer patients.
Authors: Xiong Xianze , Zhou Feng , Luo Ming , Li Jingdong , Zheng Haiping , Liu Changjun , Chen Xiong , Wang Wenjing , Wang Weifeng , Wang Kai
Published: May 2020

e13654

Background: KIT and PDGFRA gene mutations have been identified as biomarkers for targeted therapy in gastrointestinal stromal tumor. Mutations and amplification of KIT and PDGFRA are also considered as potential targets in solid tumors in clinical trials. We assessed the characteristics of KIT and PDGFRA alterations in a variety of cancers and tried to provide genomic landscape of these genes. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumors and their matched blood samples were collected from 10,010 patients for 450 cancer genes targeted next-generation sequencing (NGS) panel.The testing was carried out in a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Genomic alterations including single nucleotide variations, short and long insertions/deletions, copy number variations, and gene rearrangements were assessed. Results: Alterations of KIT and PDGFRA were detected 2.1% and 1.6% respectively in Chinese pan-cancer patients. KIT alterations was detected most frequently in gastrointestinal stromal tumor (68.8%), soft tissue sarcoma (10.8%), melanoma (10.3 %), thymic tumors (7.7%) and small cell lung cancer (5.1%), and PDGFRA alterations was detected in gastrointestinal stromal tumor (18.7%), melanoma (5.2 %), primary hepatic carcinoma (4.3%), bone sarcoma (4.2%) and soft tissue sarcoma (3.4%). Particularly, KIT and PDGFRA amplifications accounted for 0.68% and 0.58% respectively in pan-cancer patients and were highly co-existed. Conversely, KIT and PDGFRA mutations were mutually exclusive which indicated an independent role of driver genes. Furthermore, tumor with microsatellite instability high (MSI-H) status had a significantly higher rate of KIT or PDGFRA mutations compared to microsatellite stable (MSS) tumors (p < 0.001). Conclusions: KIT and PDGFRA alterations occurred in 2.1% and 1.6% respectively in Chinese pan-cancer patients and mutually exclusive with known driver genes. KIT and PDGFRA alterations may act as driving oncogenic factors across cancers and warrant drug development strategy.
The prevalence of CDK12 alterations in Chinese cancer patients and the association with tumor mutation burden(TMB) and survival.
Authors: Li Ke , Guo Xi , Mao Yunhua , Yang Mengmei , Huang Mengli , Xie Wenzhuan , Liu Xinyi , Wang Dejuan , Qiu Jianguang , Zu Xiongbing
Published: May 2020

e13663

Background: Cyclin-dependent kinase 12 (CDK12) is a cyclin-dependent kinase that regulates transcription and RNA splicing, thereby modulating multiple cellular processes. It has been suggested that CDK12 loss-of-function mutations lead to a higher neoantigen burden and favorable responses to PD-1 inhibitors in advanced prostate cancer. Given this potentially actionable molecular subtype, we sought to determine the prevalence of CDK12 alterations in Chinese cancer patients and the association with TMB and overall survival(OS). Methods: The prevalence of CDK12 alterations were queried in 3D Medicines database with 15,745 Chinese cancer patients involved. Whole-exome sequencing data of 464 patients with prostate adenocarcinoma(PRAD) from the Cancer Genome Altas (TCGA) were downloaded to explore the association between CDK12 gene alteration and OS. And the association with TMB were analyzed in a cohort of 731 patients with various cancer types published by Memorial Sloan Kettering (MSKCC) (Samstein et al., Nature Genetics, 2019). Results: Any CDK12 and known or likely deleterious CDK12 mutations were identified in 598(3.8%) and 98(0.62%) patients, respectively. Across all cancer types, prostate adenocarcinoma(PRAD) was found to have the highest frequency of deleterious mutations(8.75%, 23/263), followed by breast cancer (4.97%, 25/503). Mutations were also detected in multiple cancer types including bladder cancer, ovarian cancer, lung cancer, colorectal cancer and so on with a frequency of less than 1%. CDK12 mutations were associated with shorter OS (HR = 15.25; 95% CI, 2.88-80.73; p < 0.001) in TCGA PRAD and cholangiocarcinoma datasets, which was not seen in other cancer types. Patients harboring CDK12 mutation had a significant higher TMB(p < 0.001) in the pan-cancer study of publicly-available cohort from MSKCC. Conclusions: CDK12 alterations existed across tumor types in Chinese patients with relatively high frequencies detected in PRAD and breast cancer and represent extremely rare events in multiple cancers. CDK12 mutation was a poor prognostic factor in PRAD and cholangiocarcinoma. In a pan cancer analysis patients with CDK12 mutation tended to have a significant higher TMB and may benefit from PD-1/L1 blockade immunotherapy.
Clinical significance of serial tumor next generation sequencing (NGS) in 155 pediatric cancer patients.
Authors: Zhao Xiaonan , Li Marilyn M. , Schubert Jeff , Wu Jinhua , Lin Fumin , Wertheim Gerald B , Surrey Lea , Luo Minjie , Zhong Yiming , Wu Chao , Cao Kajia , Aplenc Richard , Bagatell Rochelle , Mosse Yael P. , Olson Timothy S. , Santi Mariarita , Tasian Sarah K. , Storm Phillip , Maris John M. , Hunger Stephen
Published: May 2020

e13666

Background: Molecular profiling using NGS technology is critical for tumor diagnosis, risk stratification, and treatment selection. There are limited data in childhood cancers regarding evolution of genomic changes under the selective pressure of chemoradiotherapy. Here we report on serial testing of hematologic and solid pediatric tumor specimens across the spectrum of diagnosis, during treatment and disease relapse. Methods: Since 2016, 2,144 somatic NGS assays from 1,727 unique cancer patients were performed using the Comprehensive Hematological Malignancy Panel (CHMP) or the Comprehensive Solid Tumor Panel (CSTP). Serial tumor analysis was performed on 155 patients. All tumors were profiled for SNVs/indels, copy number alterations (CNAs), and fusions. The clinical impact on diagnosis, prognosis, and therapy was assessed. Results: 85 and 70 patients were tested with CHMP and CSTP, respectively. 86.5% (134/155) of patients underwent 1 subsequent genetic testing, while 13.5% (21/155) were serially tested for 3 - 6 times. Relapsed or therapy-refractory tumor was the most common indication for repeat CHMP and CSTP analysis of tumor genomics (64.5%, 100/155), primarily to survey for new targetable cancer driver mutations. The second most common reason for serial testing with CHMP was to monitor clonal evolution for patients with bone marrow failure syndromes and/or myelodysplastic syndromes, which resulted in a new cancer diagnosis in 14.6% (6/41) patients. For CSTP, the second most common reason for serial testing was to test a different part of the same tumor for tumors with histologic and/or radiographic heterogeneity (27.1%, 19/70). Of all patients with serial testing, 70 had at least one clinically significant new SNV/indel, 44 had distinct CNAs, and 4 had new clinically actionable fusions. Overall, clinically significant new results were detected in 81 (52.3%) patients, including 53 patients with new clonal changes indicating disease evolution, 31 of diagnostic significance, 9 of prognostic significance, and 8 suggesting new treatment options. Conclusions: Taken together, these data highlight the clinical importance of serial testing of pediatric tumors for potential biomarkers that may impact patients’ care at various time points across the spectrum of their diseases.
Biomarker testing patterns and trends among patients with metastatic lung cancer.
Authors: Wang Suwei , Huang Hu , Arriaga Yull Edwin , Tkacz Joseph , Preininger Anita M , Solomon Metasebya , Jackson Gretchen Purcell , Dankwa-Mullan Irene
Published: May 2020

e13667

Background: Guidelines for biomarker testing of metastatic lung cancer patients aid oncologists in making targeted treatment decisions. Despite evidence demonstrating the benefits of genomic and immune biomarker identification in these patients, variations in testing exist. This population-based, retrospective, observational study examined trends in testing rates and timing, assessing associations between testing and patient characteristics, sociodemographic factors, and regional patterns using insurance claims data. Methods: We evaluated patterns of biomarker testing in the IBM MarketScan database between 1/1/2013-12/31/2018. Inclusion criteria consisted of lung cancer patients with an initial diagnosis of metastasis within the study period, continuous insurance coverage from 12 months before to 4 months post-diagnosis, and biomarker testing (EGFR, ALK, ROS1, BRAF V600E, NTRK, PD-L1) within 4 months of diagnosis. Temporal trends were evaluated by the Cochran-Armitage method. Multivariate logistic regression evaluated associations between testing rates and patient-specific factors (i.e., age, gender, comorbid conditions), insurance type, and region (i.e., Northeastern, North central, Southern, and Western) in the United States (US). Results: Of the 8977 patients with metastatic lung cancer, 1040 (12%) had claims for biomarker testing. During the study period, testing rates increased significantly, from 8.4% in 2013 to 20.6% in 2018 (P <.0001); the likelihood of testing increased by year (2014, OR 1.20, 95% CI 0.97 - 1.48 vs. 2018, OR 2.83, 95% CI 2.26 - 3.54). Of patients tested, 25.8% (N = 268) were tested on the day of diagnosis, 70.7 % (N = 735) within 30 days, and 85.6% (N = 890) within 60 days. A lower likelihood of testing was associated with increasing age (OR = 0.97, 95% CI 0.96 - 0.98), enrollment in preferred provider health plans (OR 0.69, 95% CI 0.53 – 0.93), or pre-existing comorbidities of congestive heart failure (OR 0.76, 95% CI 0.59 – 0.98) or diabetes (OR 0.82, 95% CI 0.68 – 0.99). Testing was more likely to occur in females (OR 1.24, 95% CI 1.09 – 1.42), age < 55 years (OR 1.67, 95% CI 1.32 – 2.12) or residence in Northeastern US (OR 1.26, 95% CI 1.05 -1.51). Conclusions: Biomarker testing rates for an insured cohort of metastatic lung cancer patients increased significantly over time, but the likelihood of testing varied based on age, sex, insurance type, comorbidities, and region. Results of this study may inform policy or outreach strategies by highlighting population-based factors influencing biomarker testing rates.
Application of next generation sequencing (NGS) in gastrointestinal stromal tumor (GIST).
Authors: Li Bin , Bai Jun , Zhu Lingjun , Zhang Sen , Wang Guihua , Dai Pingping , Huan Jiaojiao , Gao Wei , Xia Xuefeng , Guan Yan-Fang , Yi Xin , Yang Ling
Published: May 2020

e13675

Background: The majority of GISTs harbor activating mutations in KIT or PDGFRA. However, the clinical relevance of other genomic alterations, tumor mutation burden(TMB), microsatellite instability(MSI) as well as ctDNA-based clinical utility were poorly examined. Methods: A total of 106 samples obtained from 92 patients (Table) were sequenced by NGS with 1021 cancer-associated gene panel. Results: In 62 treatment naïve patients, the most common primary localization was stomach (29), followed by small intestine (22). KIT mutations were found in 52 (89.0%) cases. The most frequent alterations occurred in exon 11(48/55), followed by exon 9(6/55) and then exon 17(1/55). The primary foci of GIST patients harboring KIT exon 9 mutations was small intestine mainly. There was one patient presented with PDGFRA mutation in exon 18 (1.9%,1/62). All these cases were absent of BRAF, RAS, PIK3CA mutations, while actionable mutations detected from other genes, including CDKN2A(6/62), NF1(4/62) TSC1(2/62), PTEN(2/62) and BRCA2(2/62). Six (6/62, 10.0%) patients were KIT/ PDGFRA wild type and two of them (33.3%) detected pathogenic mutation in NF1 gene, with diagnosed age at 36 and 38 years old respectively. TMB and MSI status were analysed in 30 GIST using NGS method and no TMB-H or MSI-H sample found. Thirty-six patients who resistance to imatinib or sunitinib were screened. Nine (47.4%) and four patients (16.0%) harbored resistant mutations in KIT gene detected from tumor and blood sample cohort, concurrent sensitive and resistance mutations remain the major subtype (Table). The low percent of ctDNA detection were consistent with previous studies that clinical characteristics (tumor size, Ki67, etc.) could influence the results. Conclusions: Panel-based NGS could comprehensively elucidated the landscape of GIST and identified more tumor-specific genetic alterations which can be managed by targeted therapy. But immunotherapy and liquid biopsies remains challenging and needs further investigation from our results. [Table: see text]
Prevalence of BRCA1/2 pathogenic variants in triple negative breast cancer patients stratified according to age at diagnosis.
Authors: Blatnik Ana , Banjac Marta , Strojnik Ksenija , Hotujec Simona , Stegel Vida , Škerl Petra , Šetrajčič Dragoš Vita , Klančar Gašper , Novakovic Srdjan , Borstnar Simona , Besic Nikola , Žgajnar Janez , Perhavec Andraž , Krajc Mateja
Published: May 2020

e13677

Background: Triple negative breast cancer (TNBC) is strongly associated with germline BRCA1 pathogenic/likely pathogenic variants (PV/LPVs), with up to 28% TNBC patients being BRCA1 PV/LPV carriers. More recently, PALB2 variants have also been shown to be associated with TNBC. Genetic testing in Slovenian hereditary breast and ovarian cancer (HBOC) patients yields consistently high BRCA1/2 detection rates. Four BRCA1 PVs are particularly common, suggesting possible founder effects. Our aim was to analyze the results of panel based genetic testing in Slovenian TNBC patients, with an emphasis on BRCA1/BRCA2 mutational spectrum and detection rates depending on age at diagnosis. Methods: We evaluated the results of genetic testing, performed using a multi-gene panel in 1000 consecutive breast cancer cases. Only 210 patients with TNBC were included in further analysis. We analyzed the mutational spectrum and BRCA1/2 detection rates in TNBC patients stratified according to age at diagnosis. Results: In 80/210 (38.1%) TNBC patients PV/LPVs in BRCA1/2 were identified. Of these, the majority (74/80) were BRCA1-positive. The following variants: c.181T > G, c.5266dupC, c.1687C > T, and c.844_850dupTCATTAC were identified in 64.4% of BRCA1 carriers. BRCA1/2 detection rate decreased with age at diagnosis but was still 18.2% after age 60 (for BRCA1/2 detection rates stratified according to age at diagnosis see table). In 12/210 (5.7%) TNBC patients PV/LPVs in three other genes were identified (3.3% PALB2, 1.4% CHEK2, and 1% ATM). Conclusions: Prevalence of PVs in BRCA1 appears very high in Slovenian TNBC patients and warrants further population-based allele frequency studies with implications for future population screening. High rates of BRCA1/BRCA2 PVs in patients older than 60 years at diagnosis justify testing all TNBC patients, especially in view of treatment options which now include PARP inhibitors. PALB2 was the second most commonly mutated gene in our patients. [Table: see text]
Tumor sequencing aids to identify individuals with hereditary cancer.
Authors: Imizcoz-Fabra Teresa , Cañada-Higueras Eva , García de Vicuña-Bilbao Nerea , Ramírez-Horcada Beatriz , Bielsa-Colás Arancha , Mora Maria Isabel , Ursúa-Noain Javier , Prat-Barásoain Olga , Abengozar Marta , Alkorta-Aranburu Gorka , Herraiz Maite
Published: May 2020

e13678

Background: Early identification of individuals with hereditary cancer significantly improves survival in patients and relatives. New genomic tools can identify germline pathogenic variants via tumor-only genomic sequencing in addition to treatment guiding biomarkers. Methods: Our tumor sequencing protocol in medical practice since 2018 via Oncomine Comprehensive Assay (OCA) interrogates several hereditary cancer associated genes; therefore, we aimed to evaluate OCA’s capacity to point out individuals’ with hereditary cancer. But first, OCA’s technical validity was evaluated by testing up to 20 year old FFPE block isolated tumor genomes of individuals known to carry 19 pathogenic variants. Results: All variants were present in the OCA raw dataset but 26% were not called by the commercial software due to specificity of the variant calling algorithm and bias caused by amplicon-based enrichment and limited coverage. Even with this limitation, OCA’s clinical utility was evaluated next. A pathogenic variant candidate to be germline was identified in 5% (26/510) of tumor genomes routinely tested looking for treatment guiding biomarkers, but up to 8% (26/317) when excluding lung cancer patients. Importantly, 73% (14/19) of the ones that were followed-up by peripheral blood testing were confirmed to be germline, so inherited nature of the cancer was confirmed in 9% of ovarian, 8% of endometrium, 5% of biliary tract, 4% of breast, 1% of colorectal and 1% of lung cancer patients whose tumor genome was tested for routine treatment guiding biomarker identification. Conclusions: OCA is a useful genomic tool for identifying individuals with hereditary cancer that opens a new era in clinical practice in oncology. An increased awareness among physicians about this new genomic tool includes understanding the importance of peripheral blood confirmation to define the germline nature of the OCA-identified candidate variant; and proper genetic counseling and germline testing when OCA does not find a candidate variant in a patient with strong family history due to the lack of comprehensive identification of every type of pathogenic variants in all known genes associated with inherited cancer via tumor sequencing tools like OCA.
A DNA-mutational panel for liquid biopsy-based pan-cancer early detection.
Authors: Yi Zhao , Chen Weizhi , He Ji
Published: May 2020

e13687

Background: Early detection through liquid biopsy can significantly increase the successful chances of treatment. The sensitivity and specificity of early detection are limited by lower signal-to-noise ratio. Thus, well design of liquid biopsy panel is important. Methods: We adopted comprehensive data sources for designing the liquid biopsy panel, including databases of TCGA, ICGC, COSMIC, MSK Cancer Hotspots, while the panel of HCCscreen and CancerSeek. We also considered the database of somatic mutations in Chinese cancer patients generated by us (Genecast (Beijing) Biotechnology Co., Ltd.). We first calculated pan-cancer carrier ratio of somatic mutations in each database and constructed the distribution of mutation counts on step-wise increased carrier ratio. Then, we selected the set of somatic mutations with “elbow point” carrier ratio from each database as part of the panel. Finally, we integrated collected hotspots with the panel of HCCscreen and CancerSeek. Results: We selected 408, 521, 214, 146 and 330 hotspots from databases of TCGA, ICGC, COSMIC, MSK Cancer Hotspots and somatic mutations in Chinese cancer patients, respectively. After integration with the panel of HCCscreen and CancerSeek, this designed panel contains 3,334 bases distributed on 23 chromosomes and 915 gene models. Comparison of hotspots collected from different databases showed that few of them shared the same genomic location except for ones from the database of MSK Cancer Hotspots, indicating the well complementarity between them. Especially, there are 186 unique hotspots collected from the database of somatic mutations in Chinese cancer patients, which can improve the sensitivity of early detection for Chinese and Asian population. Next, we evaluated detected sensitivity of the designed panel based on sequencing data of plasma samples from more than 12,000 Chinese cancer patients collected in Genecast. The result showed that the maximum sensitivity is 66.67% for small cell lung cancer and the overall sensitivity is 45.71% for 26 cancer types, in which hotspots uniquely collected from the database of somatic mutations in Chinese cancer patients accounted for 5.11%. Conclusions: We designed a liquid biopsy panel for pan-cancer early detection and evaluated its sensitivity based on sequencing data of plasma samples from more than 12,000 Chinese cancer patients. Satisfactory performance of our designed panel shows its potential application in cancer screening for healthy and highly risky individuals.