bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ki-67 and Cyclin D1 in subtypes of triple-negative breast cancer with different androgen profiles.
Authors: Vashchenko Larisa N. , Karnaukhov Nikolay S. , Gudtskova Tatiana N. , Kvarchiya Mramza V. , Karnaukhova Elena A. , Luganskaya Roza G. , Bakulina Svetlana M. 
Published: May 2019

e12552 Background: The purpose of the study was to analyze Ki-67 and Cyclin D1 expression in subtypes of triple negative breast cancer (TNBC) with different androgen profiles. Methods: Tissues of 60 patients with verified TNBC (T1N1M0/T2N0M0, ER-/PR-/Her2-) were studied. Immunohistochemical staining was performed with antibodies to androgen receptors (AR), CK5/6, Ki-67, Cyclin D1, and EGFR. Basal-like (BL) subtype was identified when > 25% cells were CK5/6+ and/or EGFR+ (any staining). Tumors with ≥10% positively stained cells were considered AR+. Parametric statistical methods were used. Significance of the difference between the two means was assessed by the Student's t-test. Results: BL TNBC showed significantly higher Ki-67 expression (81.9±3.1%), compared to other subtypes (70.8±3.1%), p < 0.05. A number of TNBC samples demonstrated Cyclin D1 overexpression ( > 30% stained cells) with no correlation with Ki-67 expression (r = 0.12). High Cyclin D1 levels were less common in BL TNBC (32.4% tumors), compared to other subtypes (43.5% tumors), but its average values were significantly higher (89.9±4.7% vs. 66.5±6.6%, p < 0.05). AR+ tumors were observed in 11 cases (18.3%). Levels of Ki-67 were similar in TNBC with different AR profiles. The percentage of BL tumors was similar in AR+ and AR- cancers (63.6% and 61.3%, respectively). Expression of Cyclin D1 was more frequent in AR+ TNBC (45.5%), vs. 34.7% in АR-. Average levels of Cyclin D1 were significantly higher in AR+ tumors (51.8±13.7%), vs. AR- (31.6±5.1%). Conclusions: TNBC differs in the Cyclin D1 leves; some tumors show its overexpression. Inhibition of cyclin-dependent kinases blocks the cell cycle, which may be useful in the TNBC treatment, which currently has no targets for therapy.
Targeting serum response factor as a novel therapeutic approach for triple-negative breast cancer.
Authors: Prencipe Maria , Gonzalez Claudia Aura , Russell Niamh , Gallagher William M. , Crown John 
Published: May 2019

e12560 Background: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer (BC) which lacks estrogen receptor, progesterone receptor and HER2 amplification. Due to the fact that up to 50% of TNBC express AR and that AR expression has been associated with poor prognosis, targeting AR in TNBC is attracting increasing interest. However, although targeting AR in prostate cancer results in initial response, resistance eventually develops, resulting in treatment failure. We previously identified Serum Response Factor (SRF) as an important transcription factor in a cellular model of castrate-resistant prostate cancer. We showed a relationship between SRF and AR which potentially plays a role in the resistance to AR-targeted therapy. Therefore, we hypothesise that AR resistance mechanisms could be bypassed by targeting SRF, singly or in combination with AR-inhibitors. Methods: In this study three TNBC cell lines with different SRF/ AR levels were selected to investigate the effect of SRF inhibition on cell viability, cell migration and cell invasion. Immunohistochemistry was used to assess SRF expression in 3 BC TMAs: TMA1 (n = 144) and TMA2 (n = 512) with different subtypes of BC and TMA3 with 138 TNBC patients. Results: MTT assays showed response to CCG1423 in the two cell lines positive for SRF (MDA-MB-231 and HS578t) with IC50 values of 20 uM, while MDA-MB-453 (SRF negative) did not respond (IC50 > 80uM). In addition, a synergistic effect on cell viability was demonstrated when CCG1423 was used in combination with MDV3100. Scratch assays to assess cell migration showed a slower gap-closure post- CCG1423 treatment compared to controls. In addition, CCG1423 treatment significantly reduced both cell lines’ ability to invade by approximately 50% at 48 hours post-treatment (p < 0.05). Analysis of SRF expression in clinical samples showed higher SRF protein expression in TNBC vs. non-TNBC patients. In addition, one TMA (n = 144) showed that higher SRF expression was associated with shorter overall survival (HR 1.99 [CI (1.02, 3.87)], P value 0.039) and shorter disease specific survival (HR 2.93 [CI (1.19, 7.21)], P value 0.014). Conclusions: Our data support the rationale for using SRF as an alternative target to AR, alone or in combination with AR-antagonists.
Associations with response to poly (ADP-ribose) polymerase (PARP) inhibitors in metastatic breast cancer: Results of a meta-regression analysis.
Authors: Desnoyers Alexandra , Saleh Ramy , Nadler Michelle , Amir Eitan 
Published: May 2019

e12567 Background: PARP inhibitors (PARPi), when given as single agents, have modest antitumor activity in patients with advanced breast cancer and germline mutation in BRCA1 or BRCA2. It is unclear whether some subgroups derive greater benefit from treatment. Methods: Two electronic databases (MEDLINE, CENTRAL) and one registry (Clinicaltrials.gov) were searched from inception to November 2018 to identify trials of PARPi in patients with metastatic breast cancer. The response rates to PARPi were extracted and pooled. Analyses were performed for patients with a germline BRCA mutation. Meta-regression explored the influence of patient and tumor characteristics and previous chemotherapy on the objective response rate (ORR) as reported in individual studies. Analysis comprised of a linear regression weighted by individual study sample size using the weighted least squares (mixed effect) method. Quantitative significance was defined using methods described by Burnand et al. Results: Of 1855 citations, 11 studies comprising 813 patients were included in the analysis. 765 (94%) patients had a germline BRCA mutations; 48% of breast cancers were triple-negative. 76% of patients had received at least 1 previous line of chemotherapy in the metastatic setting and 30% were exposed to platinum-based chemotherapy. Pooled ORR was 47% in patients with a germline BRCA mutation. Meta-regression showed that previous chemotherapy in the metastatic setting ( = -0.94, p = 0.006), especially platinum-based chemotherapy ( = -0.89, p = 0.02) were associated with highly significant negative association with ORR. A highly quantitatively significant negative association was observed for age ( = -0.80, p = 0.10), but this did not meet statistical significance. Performance status ( = 0.44, p = 0.38) and hormone receptor status (hormone receptors positive: = 0.46, p = 0.30) were not associated with response. Conclusions: PARPi therapy is associated with lesser response in patient with prior chemotherapy exposure, especially platinum-based treatment. Younger patients may benefit more from PARPi. There was no association between ORR and hormone receptor status.
Indirect treatment comparison of the efficacy and safety of olaparib 300 mg tablets BID and talazoparib 1 mg once daily in the treatment of patients with germline BRCA-mutated (gBRCA) HER2-negative metastatic breast cancer.
Authors: McCrea Charles , Hettle Robert 
Published: May 2019

e12570 Background: PARP inhibitor treatment with olaparib or talazoparib has been shown to improve progression-free survival (PFS) versus chemotherapy treatment of physician’s choice in patients with germline BRCA-mutated (gBRCA) HER2-negative metastatic breast cancer. In the absence of head-to-head evidence, an indirect treatment comparison (ITC) analysis was performed to simulate the comparative efficacy and safety of alternative PARP treatment in this setting. Methods: Bayesian fixed effects ITCs of data published for OlympiAD (NCT02000622) and EMBRACA (NCT01945775) was conducted using the gemtc package in R. Efficacy analyses were performed on the primary endpoint of PFS by blinded independent central review. Safety analyses included the odds ratio (OR) of adverse event (AE)-related discontinuations, and common AEs of any grade reported in each study. All analyses compared olaparib with talazoparib. Results: Efficacy analyses show no significant difference in PFS across treatments (PFS hazard ratio of 1.09, 95% credible interval [0.72; 1.65]). Safety analyses predict differences in AEs across PARP treatment, including hematological events, alopecia, nausea and vomiting (Table). No difference in AE-related discontinuations was observed (0.93 [0.25–3.42]). Conclusions: Results of the ITC suggest that olaparib and talazoparib are equally efficacious on PFS, and differ in AE risk profile, with olaparib predicted to have fewer common hematological and alopecia events, but an increased risk of nausea and vomiting versus talazoparib. Observed differences require confirmation in comparative studies. Limitations of the analysis include heterogeneity in study design, reporting of AEs, and mix of chemotherapies used in the control arm of the studies. [Table: see text]
Satellite alpha transcript levels to predict risk of bilateral breast cancer and multiple primary cancer in patients with breast cancer who lack BRCA-related clinical features.
Authors: Kakizawa Nao , Suzuki Koichi , Tamaki Sawako , Ishikawa Hideki , Ichida Kosuke , Futsuhara Kazushige , Rikiyama Toshiki , Watanabe Fumiaki 
Published: May 2019

e12575 Background: Patients with breast cancer who undergo surgery have a risk of developing multiple cancers in the contralateral breast and other organs. We have reported that the overexpression of satellite alpha transcripts (SAT) facilitates chromosomal instability, which is involved in the development of multiple tumors in patients with colorectal and gastric cancer. Methods: In this study, we elucidated the significance of SAT in the development of multiple tumors in patients with breast cancer. Relative expression SAT (rSAT) level was calculated in normal and tumor tissues from 167 patients. Twenty-seven patients developed bilateral breast cancer (BBC) and 27 patients showed multiple primary cancer (MPC). We detected that 71 patients had factors associated with inherited breast cancer; age under 50yo, harboring family history of breast cancer, pathological diagnosis of TNBC, and history of ovarian cancer and we determined these factors as BRCA-related clinical factors. Results: We excluded 71 patients with BRCA-related clinical features, rSAT levels were higher in patients with BBC and MPC than in patients with SBC in tumor tissues ( P = 0.0121) and normal tissues ( P = 0.00586). A univariate analysis indicated significant predictors including rSAT > 1.5 in tumor tissues, rSAT > 2.4 in normal tissues. In a multivariate analysis, rSAT > 2.4 in normal tissues was a significant predictor of BBC (HR, 22.7; P = 0.00120) and MPC (HR, 11.1; P = 0.00885). Conclusions: Our data indicated that patients with breast cancer with high rSAT levels in their breast tissues have a 10- to 20-fold increased risk for the development of multiple cancers when they harbored no BRCA-related clinical features. These patients had been excluded from the high-risk group for BBC, however, our results shed light on these patients and we detected another risk factor which could predict multiple cancers.
Sarcoidosis as a paraneoplastic syndrome for breast cancer.
Authors: Barletta Pamela , Murthi Mukunthan , Salguero Douglas , Mirsaeidi Mehdi 
Published: May 2019

e12587 Background: Sarcoidosis is a multisystem granulomatous disease of unknown etiology. The pathogenesis of sarcoidosis is believed to be a result from a cellular immune reaction from exposure to occupational, environmental, or infectious elements that lead to the formation of noncaseating granulomas. Non-caseating granulomas are also present in cancer , and it is well known that the cancer cells carry neo-antigens, leading to a possible association between cancer and sarcoidosis. Several studies have shown an increased risk of breast cancer , in particular, in patients with sarcoidosis, but only a few studies have analyzed the incidence of sarcoidosis following breast cancer diagnosis. The present study aimed to identify patients with sarcoidosis following a diagnosis of breast cancer in our cohort of sarcoidosis. Methods: This is a retrospective case-series study between 2008-2018 of patients with sarcoidosis in the University of Miami Sarcoidosis Program. Sarcoidosis was defined per the World Association for Sarcoidosis and other Granulomatous Disorders guidelines. Breast cancer diagnosis was confirmed through pathology. We collected demographic data of age, gender, ethnicity and the time between diagnosis of breast cancer and sarcoidosis by chart review. Clincial data including clinical manifestations, laboratories, staging, and treatment were also collected. Results: Among 125 patients in our registry, 26 patients had a diagnosis of both cancer and sarcoidosis. In this, 12 (46%) developed sarcoidosis after the diagnosis of breast cancer and are the study population. Among them, 12(100%) were female. The most common ethnic group in the study population was European American with 8(67%) followed by African Americans 2(16.7%) and Hispanic 2(16.7%). Eight (67%) patients were treated with chemotherapy, 7(58%) with radiotherapy, of this, 6 (50%) received both. Mean (SD) age of onset of sarcoidosis was 61.9 ( 10.8) years . The mean time interval between breast cancer diagnosis and the onset of sarcoidosis was 5.58 ( 5.24) years ( (see Figure 1). Nine (75%) had pulmonary sarcoidosis and 3(25%) cardiac sarcoidosis. Among the subjects with pulmonary sarcoidosis 1(11.1%) had Stage 4, 4(44.4%) had Stage 2 and 4(44.4%) had stage 1. Conclusions: Our findings suggest sarcoidosis may be a paraneoplastic characteristic of breast cancer. The mechanism of granuloma development remains unclear. Cancer mediated immune dysregulation could be a potential contributing factor. Further studies are warranted to establish a definitive association.
Incidence of FGFR-TACC gene fusions in Chinese non-small cell lung cancer (NSCLC): A multicenter study.
Authors: Cai Xiuyu , Xu Chunwei , Wang Wen xian , Zhang Quxia , Chen Yu , Fang Yong , Wang Hong , Zhu You-cai , Zhuang Wu , Huang Yun-jian , Zhang Yinbin , Wang Liping , Wang Yafei , Chen Meifang , Yang Dongyong , Cai Shangli , Fang Meiyu , Chen Gang , Lv Tangfeng , Song Yong 
Published: May 2019

e13001 Background: Fibroblast growth factor receptors (FGFR) are transmembrane kinase proteins with growing importance in non-small cell lung cancer (NSCLC) biology given the frequency of molecular alterations and vast interface with multiple other signaling pathways. Furthermore, numerous FGFR inhibitors in clinical development demonstrate the expanding therapeutic relevance of this pathway. The aim of this study was to evaluate the prevalence of FGFR-TACC fusions in Chinese NSCLC populations, which had not been reported earlier, and to describe targeting potential in Chinese NSCLC populations. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2018. Capture-based comprehensive genomic profiling was performed on 2743 NSCLC FFPE samples sequenced to a mean coverage depth of > 650X for up to 381 cancer-related genes. Genomic alterations (GA) included short variant (SV) base subs and insertions/deletions, copy number alterations, and rearrangements/fusions. Tumor mutational burden (TMB; mut/Mb) was calculated on up to 1.2 Mb of sequenced DNA. Results: Of this entire cohort, just 16 (0.58%) patients were identified with FGFR-TACC fusions, including FGFR1-TACC 1 fusion (1), FGFR2-TACC2 fusion (3) and FGFR3-TACC3 fusion (12). Median patient age was 57 (range 36-84 years). Of the FGFR-TACC fusion NSCLC patients, 56.25% were detected in female patients. Biopsies were obtained from primary lung tumor (31.25%) and metastatic sites (68.75%). Overall TMB in the FGFR-TACC fusion was low (median 3.6 mut/Mb), although two cases (12.50%) had > 20 mut/Mb. Of the FGFR-TACC fusion NSCLC patients, two cases (12.50%) featured EGFR SV alterations. Conclusions: FGFR-TACC fusions occur in a subset of patients with NSCLC. Such patients should be considered for clinical trials featuring FGFR inhibitors (AZD4547). Moreover, NGS can provide information for targeted therapy. For NSCLC patients to benefit from more personalized cancer treatment, clinical therapy should improve with clinical diagnostics through multi-gene assays to determine the actual clinical benefits.
Pathogenic germline mutation profile in Chinese lung cancers and related-driver mutation pattern.
Authors: Peng Wenying , Wu Lin , Chang Lianpeng , Li Jin , Bai Jing , Zhang Yanyan , Guan Yanfang , Jiang Meilin , Pu Xingxiang , Xu Li , Wang Qianzhi , Xu Fang , Chen Bolin , Cao Jun , Yi Xin , Yang Ling , Xia Xuefeng , Zhang Jianjun 
Published: May 2019

e13003 Background: Many cancers could be driven by germline mutation exampled as BRCA1/2 in breast or ovarian cancer. However, the candidate predisposition variants for Chinese lung cancer are largely unknown. Methods: We reviewed 1797 Chinese lung cancer patients with paired tumor-normal samples sequenced by a 1021 gene panel. The annotation of germline variants within 95 selected susceptible genes was based on ACMG 2015 version guideline. Results: The frequency of patients identified with pathogenic or likely pathogenic (P/LP) germline variants were 5.95% (107 in 1797), which elevated to 10.1% (9 in 89) in patients younger than 40. Totally, 112 mutations from 35 genes were screened out. Recurrent pathogenic germline genes were BRCA2 (n = 14), FANCA (n = 9), RAD51D (n = 7), MUTYH (n = 7), ATM (n = 7) and TP53 (n = 5). The average age at diagnosis was numerically 2 years earlier in patients with P/LP (mean, 58.2 vs. 60.0, p = 0.22) than other patients without significance, but different genes contribute to discordant effects. Significantly early onset age was found in germline BRCA1/ 2 mutation (median, 52.5 versus 60.0 yrs in patients without P/LP, p = 0.0080) while later onset age was associated with germline PMS2 mutation (median, 74 versus 60.0 yrs, p = 0.0214 ). In terms of clinical actionable somatic mutation, the frequency of KRAS (15/89, 16.85% versus 121/1429, 8.47%, p = 0.012) and c-MET (6/89, 6.74% versus 31/1429, 2.17%, p = 0.018) in germline mutant patients were significantly higher, while TP53 (41/89, 46.07% versus 847/1429, 59.27%, p = 0.019) was apparently less mutated in P/LP lung cancer. As for frequency of EGFR, ALK, ROS-1, RET and BRAF, mutation frequency were not significantly different in lung cancer with germline mutation. Conclusions: Our study delineated the pathogenic germline mutation landscape in Chinese lung cancers for the first time. Predisposition genes demonstrated clinical actionable roles in onset age and therapeutic interventions. Further follow up may clarify the contribution of germline mutation to somatic mutation driven targeted therapy response and prognosis.
Evaluation of next generation sequencing for detecting HER2 copy number in breast and gastric cancers.
Authors: Lin Dongmei , Ji Jiafu , Niu Dongfeng , Li Lei , Yu Yang , Gao Yun , Zhang Wanchun , Li Zhongwu , Rao Guanhua , Gao Lianju , Cheng Gang 
Published: May 2019

e13004 Background: Amplicon-based next generation sequencing (NGS) approaches have been preferentially adopted by the clinical laboratories on the basis of a short turnaround time (TAT) and small DNA input needs. However, little work has been done to assess the amplicon-based NGS methods for copy number variation (CNV) detection in comparison with current standard methods like immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The correlation between NGS based CNV detection and the later standard methods has remained unexplored. Methods: We developed an amplicon-based panel to detect human epidermal receptor growth factor (HER2) amplification in formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 280 breast cancer and 50 gastric cancer patients. Assessment by IHC and FISH was conducted in parallel, and descriptive statistics were used to assess the concordance. Results: The copy number detected by NGS was correlated with either the average HER2 copy number (signals/cell) (r = 0.844; p < 0.001) or the HER2/CEP17 ratio (r = 0.815; p < 0.001). We determined a cut-off value for NGS to categorize HER2 amplification status by using 131 HER2 non-amplified FFPE samples. In breast cancer patients, the cut-off value was 2.910, with 95.28%, 99.23% and 97.29% sensitivity, specificity and concordance, respectively. However, this cut-off value displayed low sensitivity in gastric cancer patients (64.71%), and the following macro-dissection procedure was not effective for increasing sensitivity (57.14%). Thus indicated that HER2 copy number correlation between NGS and FISH in gastric cancer was different from breast cancer. Conclusions: Evaluation of HER2 copy number with NGS in our study was comparable with IHC and FISH in breast cancer patients, but concordance in gastric cancer was only moderate. NGS-based HER2 assessment may decrease the equivocal HER2 determinations in breast cancer patients assessed by FISH/IHC. The greater discordance in gastric cancer may reflect the underlying biological mechanisms, and further study is warranted.
Screening of differentially expressed genes of esophageal squamous cell carcinoma with cDNA microarray.
Authors: Fuchun Si , Jingyu Yue , Gao Si 
Published: May 2019

e13005 Background: Esophageal Carcinoma (EC) is one of the most common malignant tumors in digestive system and is the sixth leading cause of cancer-related mortality worldwide. To find out the genes related with the occurrence and development of EC can help to elucidate the pathogenesis and molecular mechanism of it. The aim of the present study was to find out differentially expressed genes of EC in different stages(cancerous tissue, paraneoplastic tissue, normal mucosa tissue) by cDNA microarray technique, so that to provide new molecular biomarker and approach for the treatment and diagnosis of EC, and contribute to comprehensively knowing the mechanism of EC occurrence and development. Methods: The whole RNA of 21 cases of EC cancerous tissue, paraneoplastic tissue and normal mucosa tissue were extracted, then using agarose gel electrophoresis to make quality control, Agilent human genome 4*44K gene chip was applied to screen differentially expressed genes. Results: 2659 differential expression genes between cancerous tissue and normal mucosa tissue were screened, included 1328 up-regulated genes and 1331 down-regulated genes; 2505 differential expression genes between cancerous tissue and paraneoplastic tissue were screened, included 1286 up-regulated genes and 1218 down-regulated genes. 48 significant up-regulation genes and 11 significant down-regulation genes were reported in association with EC for the first time. Through GO classification, screened differentially expressed genes mainly were involved in the following function and process: catalytic activity, signal transduction, molecular transport and combination, enzymatic activity regulation, transcription activity regulation, protein transportation function, cell growth and apoptosis, and so on. Conclusions: The screened differential expression genes of EC in different stages may provide experimental basis for further illuminating the occurrence mechanism of esophageal squamous carcinoma.