bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment for markers of poor prognosis in a real-world evidence study of treatment patterns in patients with HR+/HER2- locally advanced or metastatic breast cancer in Korea and Taiwan.
Authors: Novick Diego , Rajan Narayan , Cheng Rebecca Ming-Huei , Lee Sae Young , Koo Dong Hyun , Wei Alice , Szende Agota , Colman Sam 
Published: May 2020

e13083 Background: To assess how patient characteristics impact treatment patterns and real-world effectiveness among patients with hormone receptor (HR+)/human epidermal growth receptor 2-negative (HER2-) locally advanced and metastatic breast cancer (ABC) in Korea and Taiwan. Methods: We conducted a retrospective chart review comprising 227 female patients aged ≥ 18 years and diagnosed HR+/HER2- ABC in Korea and Taiwan between 2015-2017. Those having at least one of the following characteristics, shown previously to negatively impact prognosis, formed the poor prognostic cohort (PPC): ECOG PS > 0, not bone-only disease, liver metastases, or negative PgR status. Anonymized data on patient characteristics, treatment pathways, progression-free survival, and grade 3 or higher adverse events (AEs) of interest was abstracted. Descriptive statistics and Kaplan Meier methods were used to assess the outcomes. Results: The mean (range) age was 57.1 (29 - 83) years. A total of 193 (85.0%) patients were PPC. Endocrine regimens were the most frequent first-line therapies used by 50.3% and 67.6% of patients in the PPC and non-PPC cohorts, respectively. Chemotherapy regimens were used by 25.9% and 17.6% as initial systemic therapy and by 60.1% and 35.3% at any time following diagnosis of ABC, for PPC and non-PPC, respectively. The median progression-free survival time, based on first-line therapy, was 8.3 (95%CI: 6.9 – 10.4) months for PPC versus 11.5 (95%CI: 5.5 – 12.0) months in non-PPC. The proportion of patients with at least 1 grade 3 or higher AEs of interest during first-line therapy was higher in the PPC cohort compared to the non-PPC cohort, 54.4% vs. 44.1% respectively. The most common AEs reported were leukopenia, asthenia/fatigue and neutropenia occurring in 27.5%, 28.0% and 20.7% of the PPC cohort and 23.5%, 2.9%, and 14.7% of the non-PPC cohort, respectively. Conclusions: The existence of one or more poor prognostic factors is associated with a higher chemotherapy use any time following diagnosis of ABC, as well as lower median progression-free survival and a higher likelihood of having an adverse event during first line therapy, compared to non-PPC cohort. These results suggest that patient poor prognostic characteristics can be drivers for therapy selection.
BRCA1/2 and CHEK2 mutation prevalence in patients with breast and/or ovarian cancer in the South of Russia.
Authors: Petrusenko Natalia A. , Timoshkina Natalya N. , Vashchenko Larisa N. , Yakubova Darya , Verenikina Ekaterina V. , Menshenina Anna P. , Zhukova Galina V. , Kit Oleg I. 
Published: May 2020

e13088 Background: The development of breast cancer (BC) and ovarian cancer (OC), as well as their chemoresistance may be due to the presence of mutations in many genes, but most often in BRCA1/2 and CHEK2. Early diagnosis and subsequent preventive interventions improve the survival of patients with mutations in the BRCA1/2 genes. Genotyping of the gene inactivation events predicts a high sensitivity of BC and OC to platinum-containing cytostatics. Our purpose was to study the spectrum of germline mutations in the BRCA1/2 and CHEK2 genes in BC and/or OC patients in the South of Russia. Methods: The study included 622 patients of 10 nationalities with BC and/or OC from the South of Russia. Genomic DNA was isolated from peripheral blood leukocytes; mutations were detected by Real-Time PCR in the BRCA1 (185delAG, 300T > C, 2080delA, 4154delA, 5382insC, 3819delGTAAA, 3875delGTCT), BRCA2 (6174delT), CHEK2 (1100delC, IVS2+1G > A, 470T > C) genes. Results: Mutations in the BRCA1/2 gene were found in 13.5% of cases, in CHEK2 – 6.2%. In the BRCA1/2 gene, the frequency of 5382insC mutation was 76.2%; 4153 delA – 9.5%; 300T > G – 7.1%; 2080delA – 3.6%; 185delAG, 3875delGTCT, 6174delT - 1.2% each. In the CHEK2 gene: 470Т > C – 73.1%; IVS2+1G > A – 23.1%; 1100delC – 3.8%. Two patients showed a combination of 5382insC mutation in the BRCA1 gene and 470T > C mutation in the CHEK2 gene. The observed prevalence of mutations in BRCA1 was generally consistent with that for European countries (p = 0.062). Identification of 470T > C mutation in CHEK2 in two cases confirmed the final diagnosis of Li-Fraumeni syndrome (OMIM: 609265); however, we failed to establish a family history of cancer in one patient. A high-risk cancer group was formed for prophylactic purposes based on the data of genotyping for major mutations in the BRCA1/2 and CHEK2 genes in patients with BC/OC and their healthy relatives. Conclusions: The frequency of BRCA1/2 and CHEK2 mutations in the studied multinational population of Caucasian patients with BC and/or OC was 17.2%. The 5382insC BRCA1/2 (76.2%) and 470Т > C CHEK2 (73.1%) mutations were the most frequent which corresponded to the occurrence of these SNPs in populations of European countries.
Aspirin attenuates YAP and β-catenin expression by promoting β-TrCP to overcome docetaxel and vinorelbine resistance in triple-negative breast cancer.
Authors: Ma Ji , Xia Hongwei , Fan Zhenhai , Tang Qiulin , Zhang Tao , Bi Feng 
Published: May 2020

e13099 Background: YAP and β-catenin play critical roles in the carcinogenesis of several cancers, but their functions in chemoresistance remain unclear in triple-negative breast cancer (TNBC). Herein, we examined the expression and function of the two proteins in the chemoresistance of TNBC. Methods: We examined the expression levels of YAP and β-catenin in TNBC samples by immunohistochemistry (IHC) and their roles in prognosis. Dynamic changes in the two proteins in TNBC tissues were determined by RT-PCR. CCK-8 assays, colony formation assays, flow cytometry, migration assays and nude mouse models were used to investigate the functions of YAP and β-catenin in drug-resistant TNBC cells. The involved signalling pathways were detected by western blot assays. Results: TNBC patients with high YAP and/or β-catenin expression had a higher risk of relapse or mortality than patients with low YAP and/or β-catenin expression, and changes in the expression of the two proteins might be a promising predictive biomarker for neoadjuvant chemotherapy sensitivity. Inhibition of YAP or β-catenin enhanced the cytotoxicity of the anti-microtubule agents docetaxel and vinorelbine against TNBC cells in vitro and in vivo. Moreover, YAP and β-catenin were upregulated in docetaxel- or vinorelbine-resistant TNBC cells, while inhibition of YAP or β-catenin enhanced the sensitivity of drug-resistant cells. Interestingly, aspirin, a kind of acetylsalicylic acid, reversed the drug resistance of cells and in combination with aspirin and docetaxel or vinorelbine significantly inhibited the growth of drug-resistant TNBC cells. The involved mechanism is that aspirin impaired YAP or β-catenin expression by upregulating the E3 ubiquitin ligase β-TrCP. Conclusions: Both YAP and β-catenin act as key biomarkers of prognosis and anti-microtubule drug resistance in TNBC, and the combined use of aspirin and anti-microtubule drugs inhibits YAP and β-catenin, presenting several promising therapeutic approaches for TNBC treatment.
Role of E2F3 and shugoshin I in epithelial-to-mesenchymal transition and cell invasion in breast cancer.
Authors: Jusino Shirley , Chellappan Srikumar P. , Saavedra Harold I. 
Published: May 2020

e13100 Background: Triple-negative breast cancer (TNBC) is the most aggressive and poorly prognostic breast cancer subtype, yet there are currently no biological therapies against this subtype. Our laboratory is finding the sources of novel biological targets in TNBC by studying the E2F transcription factors, which are essential for cellular proliferation and maintenance of genomic stability. While the deregulated Rb/E2F pathway signals the epithelial-to-mesenchymal transition (EMT), the underlining mechanism of how E2Fs drive EMT in TNBC remains unknown. We recently published that the E2F transcriptional activators (E2Fs) are overexpressed in the vast majority of TNBC and that their overexpression upregulates mitotic kinases such as TTK, which we have shown to induce EMT and invasion in TNBC cells. We also demonstrated that the E2Fs maintain genomic integrity in part through Shugoshin I (SGO1), which normally controls chromosome cohesion; however, the role of SGO1 in EMT in breast cancer is unknown. Our hypothesis is that E2F3 and SGO1 are highly expressed in TNBC and that their overexpression modulates EMT genes, thus promoting cell invasion. Methods: To test our hypothesis, we conducted siRNA transfection to knockdown E2F3 and SGO1 in MDA-MB-231 and Hs578t, which are TNBC cells. After 48 hours, we evaluated mRNA levels of EMT-related genes after E2F3 or SGO1 depletion using RT-PCR analysis. We also evaluated the effects of SGO1 depletion in protein localization by immunofluorescence. Furthermore, we evaluated the invasive behavior of MDA-MB-231 and Hs578t cells after SGO1 depletion using a Boyden Chamber Assay. Results: Our results demonstrate that E2F3 and SGO1 depletion decrease MMP3 mRNA levels. Moreover, E2F3 and SGO1 depletion restore E-cadherin expression and localization. Furthermore, E2F3 and SGO1 depletion significantly reduce cell invasion in MDA-MB-231 and Hs578t cells. Conclusions: Our results suggest that SGO1 is a promising drug target for breast cancer metastasis since EMT and invasion are essential early steps in breast cancer metastasis and E2F3 is presently undruggable.
PD-L1 IHC 22C3 pharmdx demonstrates precision and reproducibility in detecting PD-L1 expression in triple negative breast cancer.
Authors: Kulangara Karina , Watts Brittany , Vilardo Monika , La Placa Christopher , Frederick Judith , Tabuena-Frolli Siena , Jansson Malinka , Kersch Kristopher 
Published: May 2020

e13104 Background: PD-L1 IHC 22C3 pharmDx is an FDA-approved, companion diagnostic assay intended for use in the detection of PD-L1 protein in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC), gastric or gastroesophageal junction (GEJ) adenocarcinoma, esophageal squamous cell carcinoma (ESCC), cervical cancer, urothelial carcinoma, and head and neck squamous cell carcinoma (HNSCC) tissues. Methods: Additionally, device precision (inter- and intra-observer, inter-instrument, inter-operator, inter-day, inter-lot, and intra-run) and robustness have been validated at Dako North America for triple negative breast cancer (TNBC) using the Combined Positive Score (CPS) ≥1 cutoff. Device precision (excluding inter- and intra-observer) has also been validated for TNBC using the CPS ≥10 cutoff. External validation studies for TNBC (inter- and intra-site, inter- and intra-observer) were conducted at three CAP-accredited and/or CLIA-licensed laboratories using the CPS ≥1 and CPS ≥10 cutoffs. Results: The precision, robustness, and external validation studies achieved point estimates greater than 85% for positive, negative, and overall percent agreement. Conclusions: Internal and external validation studies demonstrate that PD-L1 IHC 22C3 pharmDx is sensitive, specific, precise, robust, and reproducible in evaluating PD-L1 expression at CPS ≥1 and CPS ≥10 cutoffs using TNBC tissue.
A retrospective single-center study investigating the clinical significance of grade in triple-negative breast cancer.
Authors: Hamm Caroline M. 
Published: May 2020

e13108 Background: Triple negative breast cancer is defined as estrogen (ER), progesterone (PR), and human epidermal growth factor receptor (HER-2) proteins negative. The grade is the degree of similarity of tumor cells to normal cells under microscope and is an important biomarker of overall patient outcomes or prognosis with higher grades having a poor prognosis. As recent chemotherapy trials noted moderately undifferentiated grade 2 tumors showing higher rates of relapse, we hypothesize that grade can also be a predictive biomarker or determinant of response to specific treatment. Methods: We reviewed 305 patient charts of triple negative breast cancer patients from 2004-2017 at Windsor Regional Cancer Center analyzing the significance of grade with respect to oncological variables, survival-time, and time to relapse. Statistical analysis was performed using Fleming-Harrington, Pairwise Testing, and COX regression, where applicable. Results: Univariate analysis showed statistically significance difference in chemotherapy type (P = 0.008) and a marginal one in ER & hormone therapy status (P ~0.09) between the grades. The overall survival rates were 90.12%, 64.4%, and 77.2%, for grade 1, 2, 3 respectively. The overall difference in survival among the three groups was statistically significant, based on Fleming-Harrington test (P = 0.019). Comparing only between grade 2 and grade 3, we found that after five years, grade 2 patients had a 5.5-fold increased risk of death (HR = 5.5; 95% CI 1.2-25.6) and 2-folds higher risk of relapse (HR = 1.9; 95% CI 1.1-3.2). Grade 3 does significantly better than grade 2 in time to relapse with relapse rates of 70%, 55.6 %, and 75.6%, respectively for grades 1, 2, and 3 (P = 0.04). Conclusions: Tumor grade has a significant positive predictive value in determining relapse with grade 2 tumors demonstrating poorer disease-free survival as compared to grade 1 & 3, less time to relapse, and increased risk of death. This has implications in stratifying triple negative breast cancer patients by grade in future clinical trials while ongoing research yields new targets for chemotherapy.
Genomic origin and immune-related status of pulmonary sarcomatoid carcinoma.
Authors: Liu Xuewen , Wang Fang , Chen Xinru , Hou Xue , Chang Lianpeng , Xie Zhi , Liu Yongdong , Li Qian , Li Pansong , Guan Yan-Fang , Zhang Xuchao , Wang Sha , Xu Chunwei , Wang Hui , Yi Xin , Zhang Jianjun , Xia Xuefeng , Moran Cesar , Chen Likun 
Published: May 2020

e13500 Background: Pulmonary sarcomatoid carcinoma (PSC), composed of sarcomatous component (SaC) and carcinomatous component (CaC), is a rare and generally aggressive subtype of non-small-cell lung cancer (NSCLC). Little is known about the genetic origin, TMB, and PD-L1 status of PSC. Methods: 31 immunohistochemically (IHC) confirmed PSCs were enrolled and tumor samples were subjected to microdissection to obtain SaC and CaC. Different components were subjected to targeted sequencing with a 1021-gene-panel. Somatic mutations were used to assess TMB and construct phylogenetic tree. PD-L1 expression level was determined by IHC. Independent cohorts of 90 lung adenocarcinomas (LUAD) from the Geneplus database and 167 sarcomas from TCGA were used for genomic comparison. Results: 87% of patients (pts) were male, with a median age of 57.0 years. 52% were smokers. The most recurrently mutated genes were TP53 (80%), MET (24%), NF1 (21%), EGFR (21%), and KRAS (21%) in CaC, while TP53 (76%), MAP3K1 (21%), NF1 (21%), MET (21%), and KRAS (21%) in SaC. 55.4% of the variations (SNV, small indels, SV, and CNV) were shared within SaC and CaC. TP53, MET, NF1, and EGFR were mostly frequently found in shared mutations. Overwhelming majority of PSCs (29/30) had common mutations between SaC and CaC implying a monoclonal origin. EGFR were mutated significantly less in adenocarcinoma components (AdC) than LUAD (Fisher Exact test, 4/24 vs 52/90, p < 0.001). High-frequency mutated driver genes in SaC, MET, EGFR, NF1, and ALK, were rarely detected in leiomyosarcomas and uterine sarcomas. The median of TMB in SaC and CaC were both 12.9 mutations/Mb (range, SaC 2.88-33.1, CaC 2.88-47.5), with high correlation between the two components (p < 0.001). PD-L1 expression levels in the two components also had high correlation (p < 0.001). More pts showed high PD-L1 expression ( > = 50%) in SaC rather than CaC (8 versus 3). Conclusions: A majority of PSCs share a monoclonal origin. PSCs with AdC exhibited lower mutated frequency of EGFR than LUAD. SaC and CaC had similar higher TMB status than LUAD. SaC and CaC had similar level of PD-L1expression.
Genomic landscape and clinicopathological characteristics of lung cancer in young Chinese patients.
Authors: Zhang Jiexia , Tong Xiaoling , Bao Hua , Wu Xue , Wang Xiaonan , Shao Yang 
Published: May 2020

e13520 Background: Approximately 2-3% of lung cancer (LC) was found in very young patients (≤ 45 years old) and they were reported to have different clinical characteristics and genetic profiles when compared to older patients. However, it is still lack of large-scale genomic studies that could provide deep insights into the tumorigenesis, precision treatment and prognosis for this particular population. Methods: Clinically annotated data of targeted next generation sequencing (NGS) on 7858 tumor tissue specimens from LC patients were analyzed. For all specimens, a total of 422 or 425 cancer-related genes were interrogated with a mean coverage depth greater than 500x. Results: Of 7858 LC cases, 814 of them were younger than 45 (age at diagnosis), which were compared to 7044 old LC cases ( > 45 years old). Clinical information showed that young LC are more prevalent in female, to be more advanced disease and to have more adenocarcinoma in histology. Somatic genomic data analysis revealed that compared to old LC, young LC has significantly higher ALK/ROS1/RET fusions, ERBB2 mutations and 5q amplification(FDR < 0.1), but lower mutational frequencies in KRAS, CDKN2A, ERBB4, FAT1, NF1, lower copy number gain (CNG) of PIK3CA, MDM2, FGFR1, and less 5q deletion(FDR < 0.1). Interestingly, in young LC, genetic differences between female and male are not significant, with TP53 and EGFR being most frequently mutated in both sexes. Similarly, the differences between young and old female LC are also limit, with young female LC having more ALK fusions (13.43% vs. 5.1%, FDR < 0.01), less EGFR mutations and MDM2 CNG than old female. On the contrary, male patients demonstrated much wide disparity between young and old LC: young LC was enriched with ALK/ROS1/RET/ERBB2 fusions and mutations in EGFR, ERBB2 and SMAD2, while old LC have more mutations in KRAS, TP53, CDKN2A, and CNG of PIK3CA (all FDR < 0.1). We also found that EGFR exon19 deletion (19del) was significantly enriched in young LC, especially in male, while p.L858R showed preference in old LC. Conclusions: The data suggest that the prevalence of different genetic alterations is both age and sex related. The high level of ALK/ROS1/RET fusions and less CNV in young LC could potentially lead to more effective treatment and better prognosis. We also noted that genomic alterations in young LC were not significantly different across sexes, but the disparity by sex was enormously enlarged in old LC, which might be correlated to their life-long exposures, such as smoking, life styles and sex-affected factors.
Immunofocus-PD-L1 high throughput quantitative next generation sequencing assay.
Authors: Williams Gareth Haydn , Thatcher Robert Paul , Haddow Tiffany Eira , Hardisty Keeda-Marie , Loddo Marco 
Published: May 2020

e13521 Background: Immunohistochemical (IHC) assays are presently used as the gold standard predictive tests for immunotherapy but are compromised due to a number of potential variables. Comparative studies have demonstrated differing levels of PD-L1 staining between assays which appears independent of the antibody binding epitope. Secondly, inter-reader reliability even between expert pathologists is problematic particularly for assessment of PD-L1 positive immune cell populations. Methods: To improve predictive testing for anti PD-L1/PD1 immunotherapies we have developed and validated a Next Generation Sequencing Platform, Immunofocus, able to perform high-throughput quantitative PD-L1 gene expression levels in routine diagnostic PWET biopsies. We applied Immunofocus to a cohort of 130 NSCLCs and compared PD-L1 gene expression levels with PD-L1 IHC scores generated using the VENTANA PD-L1 (SP142) Assay. The PD-L1 IHC assessment was carried out double blinded by an independent laboratory. PD-L1 IHC scores were calculated using an algorithm combining tumour proportion score (TPS) with a PD-L1 positive immune cell (IC) score and immune cell area. Results: An exceptionally high degree of correlation was observed between the NGS PD-L1 levels with the combined PD-L1 IHC scores (P < 0.001). Therapeutic cut points for NGS PD-L1 levels were identified corresponding to PD-L1 IHC defined clinical cut points. Notably, ~20% of patients with negative PD-L1 IHC scores showed high NGS PD-L1 expression levels. We hypothesize that these cases represent false negatives and identify a cohort of patients who have shown significant response rates to anti-PD-L1/PD-directed immunotherapies. Conclusions: The Immunofocus NGS PD-L1 assay has potential to greatly improve patient selection for immunotherapy by removing the IHC assay variables and inter-reader variability which compromise current PD-L1 IHC tests while also providing standardized high throughput in the clinical setting. Immunofocus is able to integrate gene expression with somatic mutation analysis allowing capture of networks regulating the immune-checkpoint including for example adaptive and innate resistance pathways, JAK1/2 pathways, differential MHC expression, TEFF gene signature, neoantigen surrogates such as DDR defects and TMB. The integration of NGS PD-L1 expression with other putative biomarkers of response is presently ongoing to further improve prediction of response.