bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective analysis of HER2-low in young breast cancer patients.
Authors: Omar Abeid Mohamed Athman , Darwish Azza Mohamad Amin 
Published: June 2021

e12515 Background: Traditionally, breast cancer (BC) is considered human epidermal growth factor receptor-2 (HER2) positive based on HER2 overexpression or amplification (HER2 3+ or ISH positive HER2 2+). However, an emerging subgroup of HER2 negative (HER2 1+ or 2+ and ISH negative) known as HER2-Low is associated with poor prognosis than HER2-normal (HER2 0). Currently, there is an increased interest in developing new drugs targeting HER2-Low BC to improve survival. The fact that BC in young constitutes a significant minority outside the western world but is underrepresented in clinical trials, it is worth conducting a dedicated study of HER2-low in this population to determine whether it affects their outcome. Methods: Confirmed HER2 negative BC patients aged ≤40 diagnosed in 2012-2017 were retrospectively reviewed in two centers in Alexandria, Egypt. Patients were classified as HER2-low (1+, 2+) and HER2-normal. The clinicopathological characteristics and survival outcome were determined and compared. Results: There were five hundred HER2 negative BC patients; 82% were hormone receptor-positive (HR+) vs.18% triple-negative (TNBC). Among the HER2 negative, only 31% were HER2-Low (n = 155), of which 20% was HER2-Low 1+ while 11% was HER2-Low 2+. In comparison, HER2-Low was significantly more HR+ than HER2-normal (89% vs. 79% respectively, p = 0.009). Other tumor characteristics (T-size, nodal status, Ki-67, lymphovascular invasion - LVI, extracapsular extension - ECE) were similar in HER2-Low and HER2-normal. So were the disease-free survival (DFS) and overall survival (OS). Nevertheless, sub-grouping HER2-Low into 1+ and 2+ showed significant differences in tumor characteristics between HER2-normal, HER2-Low 1+, and HER2-Low 2+, in nodal status, tumor stage, ECE, and HR status. Moreover, DFS was significantly lower in HER2-Low 2+ (63.5%) compared to HER2-normal (70%) and HER2-Low 1+ (75%); p = 0.039. Also, the OS was also significantly lower in HER2-Low 2+ compared to HER2-normal, 90% vs 96% respectively, p = 0.023. Conclusions: Our results suggest no significant difference in DFS and OS between HER2-Low and HER2-normal in young BC patients. However, subdividing HER-low into HER2-low 1+ and HER2-Low 2+ better discriminates this group; HER2-Low 2+ had significantly poor DFS and OS and this should be considered in the clinical trials.
Concordance between 21-gene score (Oncotype DX) and clinical-pathologic prognostic models in early-breast cancer in Medellín, Colombia.
Authors: Lujan Mauricio , Lema Mauricio , Moran Diego , Preciado Beatriz , Egurrola Jorge , Lema Camila 
Published: June 2021

e12521 Background: The genomic-based 21-gene recurrence-score assay (Oncotype DX, Genomic Health)(ODx) is used to decide on the use of adjuvant chemotherapy (ACT) in luminal-type Early-Breast Cancer (LT-EBC). Patients with low RS can safely avoid ACT. Other predictive models based on standard clinical and histopathological (C&H) variables also have been developed. These include, Magee equations (ME), Predict model (PM), and Tennessee nomogram score (TNS). This study aims to establish the concordance between ODx and ME, PM and TNS models in a set of patients with EBC in Medellín, Colombia. Methods: Patients with unifocal, stage I and IIA, LT-EBC (HR+/Her2-) with results for ODx were included. For inclusion, key standard C&H variables needed to be available as to allow accurate assessment of ME, PM and TNS predictive models. ODx was used as the reference test and the predictive models as index tests. Low-risk (LR) was defined < 18 in all three ME; < 3% in the PM; and a probability calculated for LR > 90% in the TNS. A second analysis was performed in the > 50 years-old cohort (+50C), using standard and a modified criteria. In the last one, intermediate-risk (IR) patients were either excluded or grouped with high-risk scores for analysis. Concordance between the models and the ODx was evaluated using Cohen's kappa index (K). The degree of concordance was classified according to the categories established by Landis and Koch. AUROC (area under receiver operating characteristics) was estimated. Statistical analyses were performed with Stata v16. Results: 122 patients were included. Median age: 58 (IQR 49-66). Main histology was ductal carcinoma (85.2%), and median size was 15 mm (IQR 10-20). LR was adjudicated in 80.3%, 57.4%, 89.3% and 69.7% with ODx, ME, PM and TNS, respectively. Concordance between the ODx and ME and PM in the all patient population was fair, with K of 0.35 (95% CI: 0.18-0.50; p < 0.001), and 0.24 (95% CI: 0, 04 - 0.45; p < 0.001), respectively. Concordance of ODx and TNS was inferior with a K of 0.16 (95% CI: 0.03-0.34, p = 0.04). AUC for ME, PM, and TNS was 0.61 (95% CI: 0.49-0.73), 0.61 (95% CI: 0.52-0.70) and 0.59 (95% CI: 0.48-0.70), respectively. 85 patients were included in the +50C (69.7%). For one analysis, 41 patients with IR with either ME or PM were excluded. Concordance between the ME and the ODx was fair. LR in both ME and ODx was found 41/43 patients (95.5%, 95% CI 87.9-100). As for PM and TNS, the degree of concordance with ODx were low, and non-significant, respectively. Concordance between ODx LR was found in 36/37 patients with LR in all three ME, PM and TNS (97.3%, 95% CI: 90.7-100). Discrimination capacity: 79%. Conclusions: The high cost of ODx can be safely avoided in stage I/IIA luminal-type EBC and > 50 year-old with low-risk scores in all three ME, PM, and TNS.
Predominance of the luminal B molecular subtype in a group of women with infiltrating breast ductal carcinoma in the Colombian coffee region: Analysis by immunohistochemistry.
Authors: Toro Paula , Pava-De Los Rios Juliana , Pava-Ripoll Alex Enrique , Chica Sebastian , Perez Edgar , Villegas Manuel , Preciado Juan Paulo , Celis Camilo , Mejía Andrés Felipe 
Published: June 2021

e12571 Background: Breast cancer is the most common cancer in women and constitutes a public health problem due to its high rates of morbidity and mortality. Diagnosis is made through routine histopathology studies that are complemented by phenotypic expression studies of hormone receptors (estrogen and progesterone receptors), human epidermal growth factor 2 (HER2) and cell proliferation index (Ki67) for their subtyping into molecular groups (luminal A, luminal B, Her2, and triple negative), which have different prognostic and therapeutic implications. Globally, a high prevalence of the Luminal A subtype has been reported, predominantly in North America, Europe, and some Latin American countries; however, the reports in the Colombian population are heterogeneous. The objective of this research is to establish an incidence profile of these molecular subtypes in a population of the coffee region in Colombia. Methods: Samples of 377 patients with a diagnosis of infiltrating breast cancer were collected retrospectively between 2015 and 2018. Inclusion criteria included: 1) Availability of personal data (year of diagnosis and age) 2) Infiltrating breast carcinoma. 3) Diagnosis between 2015 and 2018. 4) Study of complete immunohistochemistry and/or in situ hybridization (ISH) markers. Results: The histological subtypes included: NOS infiltrating ductal carcinomas (339 cases; 89.9 %), infiltrating lobular (23 cases; 6.1 %), infiltrating mucinous (6 cases; 1.5 %), infiltrating papillary (1 case; 0.2 %) and mixed patterns: ductal - lobular (3 cases; 0.7 %) and mucinous - ductal (5 cases; 1.3 %), of whom 56.2% (212 cases) correspond to luminal B, 22.2% (84 cases) to Luminal A, 14.8% (56 cases) to triple negative and 6.6% (25 cases) to HER2. Conclusions: These findings contrast with the prevalence reported worldwide. Therefore, in the population of the Colombian coffee region, this predominance of the molecular subtype luminal B should be considered when establishing prognosis and treatment plan by the medical staff.
MELK is a downstream target of Del-1 and promotes breast cancer progression.
Authors: Lee Soo Jung , Chae Yee Soo , Lee Jeeyeon , Kang Jieun , Kim Eun Ae , Jung Jin Hyang , Park Ho Yong , Lee In Hee 
Published: June 2021

e12578 Background: Del-1 is a promising prognostic marker for breast cancer in our previous study. However, the downstream targets and biological effectors of Del-1 remain unclear and still untargetable in breast cancer. We performed transcriptome analysis using RNA-seq and explored the mechanism of Del-1 in regulating the progression of breast cancer to find druggable target. Methods: Total RNA was isolated using RNAiso Plus (TaKaRa, Otsu, Shiga, Japan), Libraries were prepared from total RNA using the NEBNext Ultra II Directional RNA-Seq Kit. High-throughput sequencing was performed as paired-end 100 sequencing using NovaSeq 6000 (Illumina, Inc., USA). OTSSP167(OTS167) were treated for inhibition of MELK. The effects of MELK on cell proliferation, invasion were determined using MTT, Matrigel Transwell assays. The tumoral expression of Del-1 and MELK were determined based on tissue microarrays and immunohistochemistry results from 440 early breast cancer patients. Results: To investigate Del-1 downregulation effect on breast cancer, we performed RNA-seq of Del-1 knock downed MDA-MB-231 and MCF 7-Tamoxifen resistant (TamR) cell line. Compared with si-control, MELK gene were downregulated in both knock downed cell lines. While a high Del-1 and MELK mRNA expressions were found in all the breast cancer cell lines, both expressions were significantly higher in MDA MB-231. MELK inhibitor (OTS167) treatment to breast cancer cell line MDA-MB-231 and MCF 7-TamR showed similar results as Del-1 down regulation by si-RNA. Inhibition of MELK suppressed proliferation and invasion of breast cancer cell line. Tumoral MELK expression correlate with increased aggressiveness and poor clinical outcomes in 440 breast cancer patients. Conclusions: Our results indicate that Del-1 may regulate MELK expression which has a role in breast cancer progression. In conclusion, modulation of Del-1 status by targeting MELK may be a new therapeutic strategy for breast cancer patients.
Long-term outcomes and predictors of recurrence in patients with early-stage node negative breast cancer.
Authors: Dogan Izzet , Aydin Esra , Paksoy Nail , Ferhatoglu Ferhat , Ak Naziye , Ibis Kamuran , Onder Semen , Tukenmez Mustafa , Cabioglu Neslihan , Muslumanoglu Mahmut , Saip Pinar , Aydiner Adnan 
Published: June 2021

e12597 Background: In this study, we aimed to assess the outcomes, and predictors of recurrence in patients with early-stage node-negative breast cancer. Methods: We evaluated data of the patients who were treated between 1988 and 2018 years retrospectively. Demographical, clinical, pathological, and treatment features of the patients were recorded. SPSS 25 version was used for statistical analysis. We used Kaplan-Meier and Cox regression analysis to assess survival analysis. Also, we performed logistic regression and ROC analysis for recurrence predictors. Results: In total, 347 patients were included in the study.The median age was 50 (range, 18-81) at diagnosis. The percent of the patients who had stage 1 and 2 were 86.6% and 13.4%, respectively. The most common histopathological type was invasive ductal carcinoma (71.6%). Estrogen receptor and progesterone receptor positivity were 80.3% and 62.1%, respectively. Her2 receptor positivity was 15.9%. The number of patients who had undergone lumpectomy and mastectomy was 85.5% and 14.5%, respectively. Sentinel lymph node biopsy was performed on 78.7% of the patients, and axillary lymph node dissection 21.3%. Also, the patients received adjuvant radiotherapy (88.7%), adjuvant chemotherapy (48.5%), and adjuvant hormonotherapy (82.1%). Tumor recurrence was occurred in 31 (8.7%) patients (local recurrence-45.2% and metastasis-54.8%). Five-, ten- and twenty-years recurrence ratios were 4.3%, 8%, and 23%. Also, contralateral breast cancer has occurred in 19 (5.3%) patients. During the study period, 30 (8.4%) patients died. Ten-years and twenty-years survival ratios were 91.6% and 76.6%, respectively. In univariate analysis, aged over 65 years (p = 0.004), nuclear pleomorphism (p = 0.049), mitosis (p = 0.003), and necrosis (p = 0.002) were statistically significant for recurrence. In ROC analysis, the tumor's longest size was not statistically significant for recurrence (for over 1.45 cm, p = 0.07). Conclusions: In this study, we determined thirty-years outcomes in patients with early-stage node-negative breast cancer. In the follow-up, we detected the recurrences ratios, between ten and twenty years, were more common than the first ten-years. Despite a small number of patients who had a recurrence, we showed that being age over 65 years and pathological features (nuclear pleomorphism, mitosis, and necrosis) were statistically significant for disease recurrence in univariate analysis.
Chemotherapy-elicited exosomal miR-378a-3p and miR-378d to promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling.
Authors: Zhang Jin 
Published: June 2021

e12615 Background: Not all breast cancer (BC) patients who receive neoadjuvant chemotherapy achieve a pathologic complete response (pCR), but the reasons for this are unknown. Previous studies have shown that exosomes produced in the tumor microenvironment in response to chemotherapy promote a chemotherapy-resistant phenotype in tumors. However, the role of BC chemo-elicited exosomes in regulating chemoresistance is poorly understood. Methods: Using commercial kits, serum exosomes were extracted from patients before neoadjuvant chemotherapy, after one cycle of chemotherapy and after four cycles of chemotherapy consisting of doxorubicin (DOX) and paclitaxel (PTX). Their miRNAs were sequenced, and the correlation between the sequencing results and chemotherapy effects was further verified by RT-qPCR using patient serum exosomes. Cell Counting Kit-8 (CCK-8) was used to detect chemosensitivity. Stemness was assessed by CD44+/CD24- population analysis and mammosphere formation assays. Chromatin immunoprecipitation (ChIP) experiments were performed to verify the binding of signal transducer and activator of transcription 3 (STAT3) to the promoter of miRNAs. Results: Here, we provide clinical evidence that chemotherapy-elicited exosomal miR-378a-3p and miR-378d are closely related to the chemotherapy response and that exosomes produced by BC cells after stimulation with DOX or PTX deliver miR-378a-3p and miR-378d to neighboring cells to activate WNT and NOTCH stemness pathways and induce drug resistance by targeting Dickkopf 3 (DKK3) and NUMB. In addition, STAT3, which is enhanced by zeste homolog 2 (EZH2), bound to the promoter regions of miR-378a-3p and miR-378d, thereby increasing their expression in exosomes. More importantly, chemotherapeutic agents combined with the EZH2 inhibitor tazemetostat reversed chemotherapy-elicited exosome induced drug resistance in a nude mouse tumor xenograft model. Conclusions: This study revealed a novel mechanism of acquired chemoresistance whereby chemotherapy activates the EZH2/STAT3 axis in BC cells, which then secrete chemotherapy-elicited exosomes enriched in miR-378a-3p and miR-378d. These exosomes are absorbed by chemotherapy-surviving BC cells, leading to activation of WNT and NOTCH stem cell pathways via the targeting of DKK3 and NUMB and subsequently resulting in drug resistance. Therefore, blocking this adaptive mechanism during chemotherapy may reduce the development of chemotherapy resistance and maximize the therapeutic effect.
Impact of pre-treatment lymphocyte monocyte ratio and neutrophil lymphocyte ratio on pathologic response in breast cancer patients receiving neoadjuvant chemotherapy.
Authors: Mosalem Osama , Alsubait Saud , Kherallah Shouq , Gogineni Venumadhavi , Wang Ling , Rana Jatin , Isaac Daniel 
Published: June 2021

e12623 Background: Hematologic markers have been looked at as potential prognostic biomarkers in a variety of cancers. Ni and colleagues (2014) have shown that an elevated pre-treatment lymphocyte-to-monocyte ratio (LMR) was significantly associated with improved disease-free survival (DFS) in patients with locally advanced breast cancer receiving neoadjuvant chemotherapy (NACT). Given the prognostic implications of hematologic inflammatory parameters, we sought to understand if such biomarkers will predict response to neoadjuvant chemotherapy (NACT) in patients with breast cancer. Methods: We conducted a retrospective review of breast cancer patients treated with NACT at our institution (2008-2018). Data on patient characteristics, stage, pathologic characteristics, and blood counts were collected. Blood parameters prior to NACT were used to calculate LMR and neutrophil-to-lymphocyte ratio (NLR). To test the impact of LMR and NLR on pathologic response, a two sample mean test was used first as univariate analysis. Next, logistic regression was employed for multivariate analysis controlling for patient characteristics with interaction of LMR and NLR with ER, PR and HER2 status. Results: A total of 50 patients were included. 38% of patients achieved a pathologic complete response (pCR). The mean LMR was 3.69 (1.4-12.5), and the mean NLR was 2.55 (0.66 – 9.31). On univariate analysis, a high NLR was associated with a higher likelihood of achieving a pCR (OR = 1.64, 95% CI = 1.01-2.63). A high LMR was associated with a higher likelihood of pCR; however, this was not statistically significant (OR = 1.08, 95% CI = 0.78-1.47). On multivariate analysis, patients with HER-2 positive disease with a high LMR had a significantly higher chance of having a pCR (OR = 1.72, 95% CI = 1.06-2.78). Conclusions: Our study showed that NLR was a predictor of pCR in breast cancer patients receiving neoadjuvant chemotherapy. A high NLR was associated with achieving a pCR on univariate analysis. Multivariate analysis suggested that HER-2 positive disease with a high LMR had a significantly higher chance of achieving a pCR. The results of this cohort correlate with previous reports by others showing that pre-NACT LMR and NLR provide prognostic information in patients with breast cancer. Although limited by sample size, this adds to the growing body of literature supporting peripheral blood counts as a biomarker for outcomes in breast cancer.
Modeling shows the NK3R antagonist, ACER-801, reduces treatment-induced vasomotor symptoms.
Authors: Baillie Rebecca , Schelling Chris , Ridgewell Rick , Kudrycki Katherine , Chung Douglas , Friedrich Christina , Reed Mike 
Published: June 2021

e13013 Background: Hot flashes or vasomotor symptoms (VMS) are a common side effect of hormone deprivation (HD) therapy. Up to 80 % of cancer patients treated with tamoxifen (antiestrogen treatment) or leuprolide (androgen deprivation) have VMS. In some cases, patients discontinue HD therapy due to VMS severity and lower quality of life; therefore, reducing VMS is critical for patient compliance. NK3 receptor (NK3R) antagonists have previously been shown to reduce VMS in postmenopausal women. ACER-801 is a candidate NK3R antagonist drug intended to alleviate VMS severity when used with HD therapy. We used Quantitative Systems Pharmacology (QSP) modeling to predict the likely efficacy of ACER-801 in patients on HD therapy and evaluate the potential of hepatic drug-drug interactions between ACER-801 and tamoxifen or leuprolide. Methods: The model is composed of KNDy neurons in the arcuate nucleus with NKB, dynorphin, and estradiol effects on KNDy neurons, HPG axis, sex hormones, and neuroendocrine feedback. ACER-801, tamoxifen, and leuprolide PK, PD, and hepatic metabolism are included in the model. The model was developed, qualified, and tested using literature data. A tamoxifen-treated postmenopausal female virtual patient (VP) and leuprolide-treated male VP were created based on typical patients included in clinical trials. VMS severity and frequency were estimated based on the level of NKB binding to NK3R. Results: In the male VP, simulated leuprolide administration induced hypertrophy of KNDy neurons and VMS over six months. Coadministration of ACER-801 with leuprolide reduced VMS frequency and severity to near 0 in short-term (5-week) simulations. Simulations predict ACER-801 will not alter leuprolide metabolism nor increase plasma testosterone concentrations. Tamoxifen treatment increased VMS by 15% in simulations with the postmenopausal VP. Coadministration of ACER-801 with tamoxifen in this VP reduced VMS by 75% compared to tamoxifen monotherapy. ACER-801 had minimal effects on plasma estradiol concentrations in the postmenopausal VP. Drug-drug interactions between ACER-801 and tamoxifen were dependent on the simulated bioavailability of ACER-801. Using current estimates of ACER-801 bioavailability in the model, the hepatic concentration of ACER-801 had limited effects on tamoxifen metabolism, which are not expected to necessitate dose adjustments. Conclusions: Using a QSP neurobiology model as a research tool enabled us to evaluate the efficacy of the NK3R antagonist, ACER-801, to treat HD therapy-induced VMS. Simulations show ACER-801 may be highly efficacious for the treatment of induced-VMS. The research provided estimates of DDI with ACER-801 and tamoxifen and what clinical experiments would be needed to confirm those estimates.
Single center observational study of the efficacy of chemotherapy in breast cancer patients treated before and after the widespread use age of CD4/6 inhibitors: Is there evidence that chemotherapy response is impacted by prior use of CD4/6 inhibitors?
Authors: Hogg Martin S. , Mugisa Tweisge , Gaur Smriti 
Published: June 2021

e13019 Background: Recently CD4/6 inhibitors have radically changed treatment pathways, leading to a deferment of chemotherapy for advanced disease. Patients still relapse following this treatment; we wish to share our experience of chemotherapy both before and after this change and explore whether there is a change in efficacy. In England CD4/6 inhibitors are prescribed according to the guidelines set out by NHS England (NICE), and are generally utilised in the first line setting unless there is visceral crisis. Methods: This is a retrospective double cohort observational single centre study comparing the efficacy of a chemotherapy regimen (vinorelbine and capecitabine vin cap) before and after the incorporation of CD4/6 inhibitors into breast cancer treatment (Jan 2017- Nov 20). The doublet chemotherapy is widely used at our centre providing a well tolerated and effective alternative to intravenous treatments such as taxanes or single agent capecitabine. Data was collected contemporaneously using e prescribing software and audited retrospectively Results: In the audit period n=19 treated with cap, n= 97 with vin cap, n= 24 treated with CD4/6, (of whom 5 relapsed). 5 patients received abemaciclib first line, as initial therapy, all G3, stage 11A or above, median number of cycles 4.2, I received ribociclib, G2, stage 111A, 7 cycles and 17 received palbociclib, 10 first line, 4 following 1 course chemo, 2 after 2 courses and 1 and after 3 courses, 30% G3 and 70% G2, mean number of cycles 11.06. Patients who received first line cap progressed after a median of 3.5 cycles, with a range of 0-22 months (RR= 47%), for cape vin a median of 8.6, a range of 0-60 months (RR=77%), post CD4/6 mean of 8, median of 9, a range of 0-17 (RR=80%). Conclusions: Those post CD4/6 requiring chemo relapsed far short of the median TTP of around 26months and may have specific characteristics predicting poor response to CD4/6. Despite small numbers salvage chemotherapy remains effective with similar responses. First line vin cap is more efficacious and better tolerated than Cap.[Table: see text]