bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abrrant expression of a subset of epithelial–mesenchymal transition genes in triple-negative breast cancer before and after EC-T neoadjuvant chemotherapy.
Authors: Wei Liyuan , Wang Li , Zhang Xiaojun , Zhang Xu Dong , Gao Jinnan 
Published: May 2020

e12617 Background: Pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) is associated with favorable outcomes of patients with triple-negative breast cancer (TNBC). However, the heterogeneous nature of the disease often results in diverse responses to the same NACT protocol. In particular, a proportion of patients with residual disease (RD) develop metastasis at early stages after treatment. Further stratification of TNBC patients without pCR to NACT is needed for the development of novel strategies in the management of these patients. Methods: A retrospective series of ten TNBC patients with locally residual disease after NACT with the EC-T regimen at Shanxi Bethune Hospital between 2014 and 2018 were included. Total RNA from FFPE pre-NACT core biopsies and paired surgical specimens was subjected to the Affymetrix Human Transcriptome Array. Gene Set Enrichment Analysis (GSEA) was used to identify signal pathways and gene signatures associated with early metastasis after NACT followed by surgery. The Cox proportional hazard model and Kaplan-Meier survival curves on DMFS (distant metastasis-free survival) were employed to assess the prognostic value of the identified signature in TNBC patients from GEO datasets. Results: The epithelial-mesenchymal transition (EMT) pathway was markedly more enriched in pre- (NES = 1.92; p.adjust = 0.019) and post-NACT samples (NES = 2.02; p.adjust = 0.010) from patients who developed metastasis at relatively early stages ( < 18 months) after surgery compared with those who had been disease-free. Noticeably, the EC-T NACT differentially affected the expression of EMT genes resulting in global promotion or inhibition of the pathway in a case-dependent manner. Nevertheless, a subset of 6 EMT genes including LUM, SFRP4, DCN, MMP2, CXCL12, and HTRA1 was expressed constantly at higher levels in samples from patients who progressed to metastasis. The potential of this 6-EMT gene signature to predict TNBC metastasis was validated in the MDACC neoadjuvant series (GSE25066) that contained 113 TNBC patients with RD (55 with metastasis; p = 0.0008; HR = 0.36; 95% CI: 0.200-0.685) and the ICO–UMGC dataset (GSE103091) including 107 TNBC patients (31 with metastasis; p = 0.032, HR = 0.46, 95% CI:0.225-0.937). Conclusions: The expression of the 6-EMT gene signature at diagnosis may be a predictive value of metastasis of TNBC. Moreover, the persistently high expression of the signature may signal early metastasis in TNBC patients with residual disease after EC-T NACT.
Impact of antibiotics on residual cancer burden and pathologic response rates during neoadjuvant pembrolizumab in breast cancer (BC).
Authors: Kulkarni Amit , Jewett Patricia , Blaes Anne Hudson , Yee Douglas 
Published: May 2020

e12622 Background: Antibiotic exposure during immunotherapy has been shown to negatively affect clinical outcomes in metastatic melanoma and non-small cell lung cancer. We tested whether antibiotics exposure during neoadjuvant pembrolizumab (NA-P) affects residual cancer burden (RCB) and pathologic complete response rate (pCR) in the pembrolizumab-4 arm of the ISPY-2 trial. Methods: I-SPY2 is an adaptively-randomized, ph-II trial in patients with high-risk, stage II/III breast cancer (BC). In pembrolizumab-4 arm patients with HER2-negative BC received NA-P 200mg every 3 weeks for four cycles concurrently with 80mg/m2 paclitaxel weekly for 12 weeks, followed by four cycles of 60mg/m2 doxorubicin plus 600mg/m2 cyclophosphamide every 2 weeks. Data on antibiotic use during NA-P was reviewed. Patients who received at least one dose of systemic antibiotics were included in the antibiotic exposure group (ATB+). All other patients were included in the no exposure group (ATB-). RCB index was used to evaluate RCB as a continuous variable. A higher RCB index indicated higher RCB. RCB index and pCR rates were compared between ATB+ and ATB- groups. Association of antibiotic use with RCB and pCR rates was evaluated using linear regression and logistic regression respectively. Clinical variables for adjustment were age, stage and hormone receptor (HR) status. Results: 69 patients received NA-P with chemotherapy. All patients had HER2-negative BC. One patient was excluded due to missing data on antibiotics. 68 patients were included in the final analysis. 19/68 (28%) patients were in the ATB+ group. Antibiotic use in HR+ and HR- patients were 9/19 (47%) and 31/49 (63%) respectively ( P=0.23). Compared to ATB- group, patients in the ATB+ group had higher mean RCB index (1.05 vs 1.80, P=0.04) and lower pCR rate (53.1% vs 26.3%, P=0.05). Antibiotic use was associated with higher probability of RCB in univariate analysis (Coefficient estimate CE: 0.75, 95% CI 0.01-1.48, P=0.04) and multivariable analysis (CE: 0.89, 95% CI 0.11-1.65, P=0.02). HR positivity was independently associated with higher probability of RCB (CE: 1.07, 95% CI 0.38-1.77 P=0.002). Antibiotic use was associated with higher probability of not having pCR (Odds ratio 3.17, 95% CI 0.99-10.15, P=0.05). Conclusions: Patients with antibiotic exposure during NA-P in HER2-negative early stage BC were associated with higher RCB and lower pCR rates. Further validation in a larger independent cohort is needed to confirm these findings.
Economic evaluation of neoadjuvant chemotherapy for operable breast cancer.
Authors: Zdenkowski Nicholas , D'Silva Shefi Mary , Lawson Kenny , Reeves Penny , Boyle Frances M. 
Published: May 2020

e12637 Background: Neoadjuvant chemotherapy is widely and increasingly used for patients with operable breast cancer that is large or highly proliferative. Advantages include downstaging of the breast and. axilla, post-neoadjuvant salvage treatments for poor responders, surgical and reconstruction planning, prognostication and to give time for genetic testing. After neoadjuvant therapy, treatment options may change. We aimed to determine the financial impact to the health system, of neoadjuvant chemotherapy compared with surgery first. Methods: A literature search identified data on the probability of receiving certain investigations and treatments, and associated outcome probabilities for neoadjuvant and surgery-first patients. Published health utility results were used. These data were incorporated into a decision analytic economic model. A cost-utility analysis was undertaken, with sensitivity analyses to evaluate the impact of uncertainties in the data. Pricing was based on publicly available costings of investigations and treatment in Australian Dollars (AUD). A value of information analysis was undertaken to determine the value of further research to reduce uncertainty in results. Results: Expected costs for neoadjuvant vs surgery first differed by $77. Neoadjuvant therapy showed higher effectiveness that surgery first (QALY 0.708 vs 0.698 respectively. The average cost per QALY of neoadjuvant therapy was $7,232 AUD (ca. $4825 USD), below the threshold of $50,000 per QALY. In a sensitivity analysis, neoadjuvant therapy dominated when axillary dissection rate was lower than 60% and postmastectomy reconstruction rate was more than 27%. These factors had the greatest impact on results, which were otherwise robust. Probabilistic sensitivity analysis found that neoadjuvant therapy was cost-effective 71% of the time at a willingness-to-pay threshold of $50,000 per QALY. Value of information analysis found that primary research into treatment probabilities and outcome utilities is needed to validate these results. Conclusions: Neoadjuvant systemic therapy is a potentially cost-effective treatment. However, primary contemporary data in directly comparable patient populations is needed, including the impact of post-neoadjuvant systemic therapy.
Prognostic biomarker candidates of neoadjuvant chemotherapy for luminal B-positive locally advanced breast cancer.
Authors: Liu Zhaoyun , Wang Jinjin , Yuan Chenxi , Yu Zhiyong , Wu Wendy , Wu Lin , Yu Jinming 
Published: May 2020

e12638 Background: In the last decade, the treatment approach for locally advanced breast cancer (BC) patients has partly shifted from adjuvant treatment to neoadjuvant treatment. Systemic neoadjuvant treatment can downstage the tumor for less extensive surgery and improve cosmetic outcomes. Differential subtypes of BC responded unevenly to neoadjuvant chemotherapy. Luminal B type with the relatively higher prevalence (40% in all 4 subtypes) had better therapeutic effect to neoadjuvant treatment than luminal A type, but worse than HER2-positive patients. Methods: We enrolled 87 BC patients for genotyping with multiple cancer-related genes. Among them, 17 patients were luminal A, 21 were HER2-negative luminal B, 23 were HER2-positive luminal B, 17 were HER2-positive and 9 were triple-negative. According to the RECIST, the patients were divided into 1-4 and 5 grades. Fisher test was used to analyze the difference of SNV and CNV between the two primary tumors, as well as TMB difference between post-neoadjuvant chemotherapy and past-neoadjuvant chemotherapy. Results: Base mutations in all patients showed discrepant preference between 1-4 grades and 5 grade groups, G-to-A in 1-4 grades, while A-to-G, A-to-T and G-to-T in 5 grade. In luminal B group (combine liminal B-negative and luminal B-positive groups), FLT4 gene mutation occurred more frequent in 5 grade than 1-4 grades (4/16 vs 0/28, P = 0.01). CNV analysis in NFKBIA and ZNF217 distinguished the two therapeutic efficiency groups in luminal B-positive group. The amplification of NFKBIA and ZNF217 was higher in 1-4 grades than 5 grade (8/14 vs 1/9, P = 0.036; 9/14 vs 1/9, P = 0.017). TMB difference between post and past neoadjuvant chemotherapy in luminal B-positive group was also significant in 5 grade (4.36 vs 1.99, P = 0.002). Conclusions: NFKBIA and ZNF217 amplification notably differentiated the 1-4 grades and 5 grade groups in luminal B-positive patients, suggesting the potential prognostic biomarkers of neoadjuvant chemotherapy in this locally advanced breast cancer subtype, which would be improved by further large-scale cohort study. The differences of TMB and FLT4 gene mutation were also found between the two therapeutic efficiency groups.
Anti-PD-1 responsive circulating immune cells as biomarkers of response to neoadjuvant chemotherapy in HER2+ breast cancer (BC).
Authors: Gaynor Nicola , O'Donovan Norma , Crown John , Collins Denis 
Published: May 2020

e12646 Background: HER2+ BC patients (pts) achieving a pathological complete response (pCR) to neo-adjuvant therapy have better long-term survival outcomes. Alternative treatment strategies may be more beneficial for pts that will not achieve a pCR but there are no predictive biomarkers for stratification of pts to appropriate clinical studies. Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by immune cells like NK cells can be elicited by therapeutic antibody therapies including the HER2-targeting trastuzumab (T). We hypothesised that the presence of immune checkpoint-inhibited ADCC-mediating immune cells in the blood may identify pts with an immune-suppressed tumour microenvironment who will not achieve a pCR. We used an in vitro functional assay to assess the PD-1-inhibited ADCC response of pre-treatment peripheral blood mononuclear cells (PBMCs) from HER2+ BC pts as a potential biomarker of pCR. Methods: Pre-treatment PBMC samples (n = 21) were obtained from HER2+ BC pts who received neo-adjuvant chemotherapy (docetaxel, carboplatin) with a HER2-targeted therapy (T n = 5, T and lapatinib (L) n = 13, or L alone n = 3), ICORG 10-05 (NCT01485926). Pt response was determined as pCR (n = 7), partial response (PR, n = 10) or non-response (NR, n = 4). The immune function assay used a flow cytometry-based method to determine the T (10µg/µl)-mediated ADCC (T-ADCC) capacity of the PBMCs +/- the anti-PD-1 therapy pembrolizumab (P) (10µg/µl). The HER2+ BC cell line SKBR3 was used as the target cell line. Direct PBMC-mediated cytotoxicity against the non-MHC Class I-restricted leukemic K562 cell line was also determined. Statistical analysis was carried out using the MedCalc program. Results: There was no significant difference in direct cytotoxicity against K562 (pCR vs NR p = 0.13, pCR vs PR p = 0.52, PR vs NR p = 0.40), or in T-ADCC against SKBR3 (pCR vs NR p = 0.71, pCR vs PR p = 0.52, PR vs NR p = 0.32), between response cohorts in the absence of P. When T-ADCC was examined in individual pt samples, the addition of P resulted in significant increases in T-ADCC vs T-ADCC in the absence of P in 3/4 NR (p = 0.03, p = 0.01, p = 0.002) and 4/10 PR (p = 0.003, p = 0.007, p = 0.009, p = 0.01). No significant increase in T-ADCC was observed in the pCR cohort (0/7) as a result of the addition of P. Using pre-treatment PBMCs, the assay detected 7/14 (50%) of HER2+ BC pts who did not achieve a pCR. Conclusions: PD-1-inhibited ADCC-capable immune cells may identify a subset of HER2+ BC pts who will not achieve a pCR. Further investigation is warranted using a larger patient cohort.
A phase II single-arm, multicenter, open-label neoadjuvant study of pembrolizumab in combination with nab-paclitaxel followed by pembrolizumab in combination with epirubicin and cyclophosphamide in patients with triple-negative breast cancer: Neoimmunoboost.
Authors: Fasching Peter A. , Hartkopf Andreas , Kolberg Hans-Christian , Haeberle Lothar , Wetzig Sarah , Mau Christine , Engler Tobias , Rübner Matthias , Hübner Hanna , Theuser Anna-Katharin , Hummel Nadine , Uhrig Sabrina , Beckmann Matthias W. , Hein Alexander , Untch Michael 
Published: May 2020

e12647 Background: The NeoImmunoboost study (NCT03289819) was designed to evaluate the pathological complete response (pCR) rate and safety of a neoadjuvant combination of the PD-1 antibody pembrolizumab and nab-paclitaxel followed by pembrolizumab with epirubicin and cyclophosphamide in patients with early triple negative breast cancer (TNBC). Methods: This is a prospective, single-arm, multi-center, open-label phase II clinical trial. Female patients with early TNBC were eligible for trial participation. Patients received 12 cycles of weekly nab-paclitaxel intravenous (i.v.) 125 mg/m² body surface area (BSA) in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w; followed by 4 cycles of epirubicin i.v. 90 mg/m² BSA and cyclophosphamide i.v. 600 mg/m² BSA q3w in combination with 4 cycles of pembrolizumab i.v. 200 mg q3w. After 25 patients the protocol was amended, with an initiation boost of 1 cycle of pembrolizumab i.v. 200 mg q3w monotherapy prior to the chemotherapy. Primary trial endpoint was pCR. Secondary endpoints included safety and clinical response rate. Results: Between March 2018 and October 2019, 53 patients were included into the trial. Until now, 47 patients have completed trial treatment and 6 patients are still receiving therapy. 28 patients have received the initiation boost with pembrolizumab, 25 patients did not receive the initiation boost. Up to now, 4 patients terminated the therapy prematurely. Conclusions: pCR data of all patients will be available at the meeting and results of the pCR rates and selected secondary endpoints will be presented at the meeting. Clinical trial information: NCT03289819.
Test measuring signaling activity in live patient tumor cells to identify PI3KCA WT patients who may benefit from PI3K inhibitors.
Authors: Laing Lance G. , Khan Salmaan , MacNeil Ian A. , Kuzmicki Catherine , Rich Benjamin E. , Shukla Abhay , Brass Kelly , Sullivan Brian 
Published: May 2020

e13000 Background: Biological factors other than PIK3CA status, such as aberrant GPCR-linked signaling, may be important to measure when identifying patients eligible for PI3K inhibitors. A new assay, the CELx PI3K test, using an impedance biosensor was developed to measure ex vivo live tumor cell response to specific S1P agonists and PI3K antagonists to diagnose breast tumors with PI3K-involved hyperactive signaling. This study set out to: 1) compare CELx PI3K test results and xenograft results using cell lines with PIK3CA mutations; and 2) assess whether PI3K-involved hyperactive S1P signaling is found in PIK3CA WT breast cancer patient tumors. Methods: A panel of 17 fresh HER2-/PIK3CA WT tumor cells from breast cancer patients and three PIK3CA mutated breast tumor cell lines were obtained. Live cell response to an S1P agonist, PI3K-α antagonist (alpelisib), PI3K-γ antagonist (IPI-549), and a pan-PI3K inhibitor (taselisib) were measured using an xCELLigence RTCA impedance biosensor. From these responses, PI3K-involved signaling was quantified and characterized as normal or abnormal using a previously determined cutpoint. For the xenograft study, 16 NSG mice were injected with HCC1954 PIK3CA mutated breast cancer cells and randomly assigned to either the control or taselisib group (10 mg/kg). Results: Four of the 17 PIK3CA WT tumor cells had abnormal levels of combined PI3K-α and PI3K-γ signaling. Only one of the three PIK3CA mutated breast tumor cell lines (BT20) had abnormal levels of PI3K-α and pan-PI3K involved signaling. The HCC1954 cell line had normal PI3K-α and abnormal pan-PI3K signaling. CAL-51 reported normal PI3K-α and pan-PI3K signaling. The normal levels of PI3K-α signaling found in the HCC1954 and CAL-51 cell lines correlated with previously reported xenograft studies that found alpelisib had no anti-tumor effect. The xenograft study reported here using HCC1954 cells found taselisib induces a significant anti-tumor effect (T/C ratio = 0.21; p = 0.009; t-test). Conclusions: A sub-set of PIK3CA WT patient breast cancer tumors had abnormal PI3K-involved signaling comparable to levels found in PI3KCA mutated cell lines. Abnormal pan-PI3K signaling and normal PI3K-α signaling in the HCC1954 cell line correlated with xenograft results. This study thus suggests that measurement of PI3K-involvement in hyperactive S1P signaling in live patient breast cancer cells may provide a means to identify breast cancer patients who may or may not benefit from treatment with PI3K inhibitors.
Comparisons of survival time in BRCA-positive patients with metastatic breast cancer using electronic health records (EHRs).
Authors: Choi Yookyung Christy , Tyczynski Jerzy Edward , Zhang Dongmu 
Published: May 2020

e13004 Background: BRCA is a hereditary genetic mutation associated with a higher risk of breast cancer at younger age. Generally, BRCA gene testing is done in perceived high-risk individuals, and different management approaches might be considered given the high risk of breast cancer. This study examines treatment outcomes among BRCA-positive, metastatic breast cancer patients with consideration of prophylactic management by using US nationwide EHR data. Methods: This was a retrospective cohort study using Optum EHRs. The study cohort includes female adults who underwent their first systemic chemotherapy for metastatic breast cancer between 2013-2018 with a BRCA positive test result prior to the systemic chemotherapy, with ≥ 6 months baseline period from the chemotherapy. Physicians’ notes captured in Natural Language Processing (NLP) were further used to construct the cohort. Patients were followed from the earliest breast cancer diagnosis date until a censoring event (death or end of observation period). Death information was provided with national death certificate data. Descriptive statistics were used for patient characteristics and a stepwise Cox Proportional Hazard (CPH) regression model was fit to compare survival time. Results: Of 3624 patients included in the cohort, median age at the earliest breast cancer diagnosis is 50 years old (IQR 43-59), and a total of 540 (14.9%) deaths was observed. Prior to systemic chemotherapy, 1430 (39.5%) received mastectomy/lumpsectomy. 571 (15.8%) received hormone therapy prior to systemic chemotherapy. 646 (17.8%) had a clinical record indicating a triple negative breast cancer (TNBC). 2196 (60.6%) received more than 1 line of chemotherapy. Overall median survival days in the study cohort was 3778 days from the earliest breast cancer diagnosis. Median survival days in those with ER/PR positive and with TNBC status were 4150 days and 3124 days, respectively. From the CPH model, age, tumor mutation status, and prior mastectomy/lumpectomy were identified as significant factors; Hazard Ratio (HR) with each 1 year older in age at diagnosis was 1.02 (95% CL 1.01-1.03), that of TNBC vs ER/PR positive status was 2.27 (95% CL 1.87-2.77) and that of those with prior surgery vs without was 0.567 (95% CL 0.457-0.703). Conclusions: This study demonstrated the utility of EHR database for survival analysis. In metastatic breast cancer patients with a known BRCA-positive status, age at the initial diagnosis, tumor mutation status, and prior mastectomy/lumpectomy were significant factors in survival time.
STAT6 expression and trastuzumab resistance in HER2+ breast cancer.
Authors: Cobleigh Melody A. , DiScala Molly , Najor Matthew S. , Yung Timothy , Abukhdeir Abde M. 
Published: May 2020

e13006 Background: Approximately 20% of breast cancers are HER2-positive. Trastuzumab has improved patient outcomes significantly for these cancers. However, acquired resistance occurs in almost all patients with metastatic breast cancer. Therefore, identifying molecular changes that are associated with trastuzumab resistance is worthwhile. STAT6 is a transcription factor that regulates a variety of genes involved in cell cycle regulation, growth inhibition, and apoptosis. STAT6 expression is lost in approximately 3% of breast cancers, but little work has been done in the context of trastuzumab resistance in breast cancer. Methods: In isogenic cell line pairs, we observed that trastuzumab-resistant cells expressed significantly lower levels of STAT6 compared to trastuzumab-sensitive cells. Therefore, in order to study the consequences of STAT6 loss in HER2+ breast cancer, we knocked out both alleles of the STAT6 gene using somatic cell gene targeting. Results: We observed that loss of STAT6 resulted in resistance to trastuzumab treatment in HER2-over-expressing cells. Additionally, loss of STAT6 resulted in anchorage-independent growth and changed expression of several genes involved in epithelial to mesenchymal transition. Functional studies revealed that STAT6 loss caused a non-tumorigenic human breast cell line to form tumors in mice. Conclusions: Loss of STAT6 in breast cells results in enhanced growth properties and resistance to trastuzumab. This study suggests that STAT6 may play a role in the pathophysiology of HER2+ human breast cancer. Disclaimer: The work herein was completed while AMA was a faculty member at Rush University. AMA is currently an employee with the U.S. Food and Drug Administration. The views and data in this publication do not reflect the opinions of the U.S. Government or The U.S. Food and Drug Administration.