bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive genomic profiling of Taiwanese patients with breast cancer using a novel targeted panel: Preliminary analyses from a prospective triple-negative cohort.
Authors: Huang Chi-Cheng , Yeh Yi-chen , Ho Hsiang-Ling , Liu Chun-Yu , Tsai Yi-Fang , Tseng Ling-Ming 
Published: June 2023

e12553 Background: Breast cancer is one of the leading causes of cancer-related deaths in women, and there is a demand in developing an Asian-based genetic profiling database to improve treatment outcomes. This study aims to determine the molecular alterations and identify potential therapeutic targets from a cohort of Taiwanese triple negative breast cancers using a novel next-generation sequencing (NGS) targeted panel. Methods: The VGH-TAYLOR study was designed to understand the genetic profiling of different subtypes of breast cancer in Taiwan. The study population comprised both early- (first-line surgery or neoadjuvant therapy) and late-stage (early/late relapse or de novo stage IV disease) of breast cancers, and we conducted molecular profiling with the illumina TruSight Oncology 500 assay using both DNA and RNA extracted from FFPE tissues from a subset of 101 prospectively enrolled breast cancers, which were previously assayed with a commercialized panel of 161 genes. Results: A total of 100 breast cancers from VGH-TAYLOR study were successfully assayed, with the majority (n = 97) being triple-negative, two HER2 over-expressed and the remaining one being HER2-low phenotypically. The most prevalent actionable alterations (more than 5% of study cohort) came from BRCA2 (24%), BRCA1 (12%), PALB2 (5%), PIK3CA (38%, both mutations and amplifications), ERBB2 (14%, both mutations and amplifications), ERBB3 (10%) and PTEN (12%). One-quarter of assayed samples were categorized into tumor mutation burden (TMB)-high cancers ( > 10 mutations per million bases), which came from 15 out of 74 (20%) early-stage and 10 out of 26 (38%) late-stage patients (chi-square test p-value: 0.06). In general, the novel panel with 500 targeted genes reported more actionable alterations than the former one with limited interrogated genes ( BRCA2: 7%, BRCA1: 12%, PALB2: 7%, PIK3CA: 45%). Conclusions: Our study ascertained the clinical applicability and feasibility of comprehensive genomic profiling from a cohort of Taiwanese breast cancers. Overall, the successful rate for NGS with QC metrics are around 90%. The novelty benefits from more investigated genes as well as multi-gene biomarkers such as TMB and microsatellite instability (MSI) status. Patients with a positive finding from the genomic assay may benefit from an immune checkpoint inhibitor (TMB-high and MSI), poly ADP- ribose polymerase (PARP) inhibitor (homologous recombination deficiency genes: BRCA1/2 and PALB2), selective estrogen receptor degrader ( ESR1), tyrosine kinase inhibitor ( ERBB2/3), phosphoinositide 3-kinase inhibitor ( PIK3CA) and so on. Further studies with more samples enrolled and longer follow up are warranted to elucidate the true value of comprehensive genomic profiling for breast cancer.
Correlation of neutrophil-to-lymphocyte ratio and stromal tumor infiltrating lymphocytes across early breast cancer subtypes.
Authors: García-Torralba Esmeralda , Ivars-Rubio Alejandra , Perez-Ramos Miguel , Navarro Manzano Esther , Blaya-Boluda Noel , de la Morena Barrio Pilar , Garcia-Garre Elisa , Marin Zafra Gema , Moya Hernandez Miguel Angel , Guirao Garcia Maria Esperanza , Chaves Benito Asuncion , Garcia Martinez Elena , Ayala Francisco 
Published: June 2023

e12558 Background: The tumor microenvironment plays a key role in the treatment response and prognosis of breast cancer (BC) patients, but the integrity of the peripheral immune system is also relevant. Understanding the biological correlation of immune-related prognostic factors, such as neutrophil-to-lymphocyte ratio (NLR) and stromal tumor infiltrating lymphocytes (sTIL), is necessary to improve its clinical applicability and the possible generation of more complex biomarkers that can direct treatment. Methods: Observational and single-center cohort of 1006 early BC patients (2009-2020). Pre-treatment NLR in peripheral blood and sTIL at diagnostic biopsy were determined. The correlation between NLR and sTIL (Spearman's Rho) overall and by subtypes, as well as its prognostic value for overall (OS) or disease-free survival (DFS) by Cox regression were evaluated. Results: NLR could be determined in 965 (96%) patients; in536 (53%) patients both NLR and sTIL were available. No statistical differences in baseline characteristics between both cohorts were found. Median age: 50 (range: 24-89); 93% infiltrating ductal carcinoma; 39.4% grade 3; 42.2% stage III; subtypes: hormone receptor (HR)+/HER2- (78.2%), HER2+/HR(+/-)(9.9%), triple negative breast cancer (TNBC) (11.9%); 70.5% treated with neoadjuvant chemotherapy. Median sTIL was 5% (SD: 16.2) with higher values in grade 3 (p < 0.001), HR- (p < 0.001) and HER2+ (p = 0.001). The median NLR was 1.95 (SD: 1.20), with no differences by subtype. There was no overall relationship between NLR and sTIL (ρ:0.32, p = 0.456). Correlation was also ruled out for each molecular subtype: HR+/HER2- (ρ:0.05, p = 0.301), HER2+/HR(+/-) (ρ:0.16, p = 0.251) and TNBC (ρ:0.21, p = 0.104). In a univariate predictive model for survival (N = 965), NLR showed prognostic value for DFS (HR 0.96, 95%CI: 0.80-1.17, p = 0.711) or OS (HR 1.02, 95%CI: 0.85-1.23, p = 0.798), neither in the whole group nor in the analysis by immunochemical subtypes. Conclusions: No correlation was observed between two of the most relevant biomarkers of immune activation in the tumor (sTIL) and peripheral (NLR) compartment in a series of early BC patients. NLR was not predictor of survival in our cohort. The absence of relationship between sTIL and NLR could suggest differences in the immune response in both compartments or else the need to find more accurate peripheral immune activation markers.
Demographic characteristics of encapsulated papillary carcinoma.
Authors: Luker Andrew , Wu Xinxin , Keirns Darby , Malan Augustus , Silberstein Peter T. , Hsia Beau 
Published: June 2023

e12562 Background: Encapsulated papillary carcinoma (EPC) is a very rare form of breast cancer characterized by fibrous encapsulation and expansile growth, causing 1-2% of all cases. A summary of 25 case reports found that although two-thirds of cases had invasive growth, EPC responded well to local therapy and is considered a favorable diagnosis as a result. Because classification and diagnostic criteria for EPC continues to be debated, examination of the demographics could prove useful in determining trends. Methods: A retrospective cohort study done using data from the National Cancer Database (NCDB) from 2004–2020 found 314 patients with an EPC diagnosis through histology. The following demographics were considered: age, sex, race, Hispanic identity, distance from residence to treatment facility, insurance coverage, type of facility, and Charleson-Deyo score. These variables were then analyzed through descriptive statistics. Results: 314 patients were identified with a steadily increasing number of cases diagnosed per year until 2018, when cases per year dropped from 46 to 6 or below for the remaining 3 years (2018, 2019, 2020). Of these 314 patients, 16 were male and 298 were female. (5.1% and 94.9%, respectively). The average age of diagnosis was 69.6 years with a standard deviation of 11.8 and a range of 30 to > 90 years. The majority (99.7%) were found in the breast, with the remaining found in the endometrium. The majority of individuals (82.2%) had Charlson-Deyo comorbidity scores of 0. The majority of patients were non-Hispanic White, accounting for 88.9% of the total. A higher number of patients belonged to the highest income bracket, with 35.0% in the top quartile compared to those in other quartiles. The majority of patients had Medicare insurance, making up 63.1% of the total. More patients resided in counties with over 1 million people (56.7%) compared to those living in counties with a population below 1 million (43.3%). Most patients were treated at non-academic cancer centers (65.6%). On average, patients lived 19.8 miles (SD = 74.7, range = 1.8 – 370) from the treatment facility. Conclusions: Based on our literature review, this is the first NCDB analysis on EPC and thus addresses a significant knowledge gap on the topic. With an average age of diagnosis at 69.6 years, it is not surprising that the majority of patients were insured through Medicare. Male cases, while rare, support previous literature. Most commonly, EPC patients were most diagnosed in metropolitan areas. The majority of cases were diagnosed in the breast and most patients were treated at non-academic medical centers. While the vast majority of cases occurred in non-Hispanic white patients, it is unclear how much is due to race and how much is related to disparities in healthcare access and underdiagnosis in non-white races. Thus, further research is needed to understand which demographic factors prove to be the strongest predictors of EPC.
Clustering whole-exome sequences of breast cancer and associations with staging and molecular subtype.
Authors: Man Kingson , Lim Alice , Eftekhari Zahra , Wong Chi Wah 
Published: June 2023

e12563 Background: Large-scale genetic sequencing of breast cancer has enabled modern approaches to precision medicine, with the discovery of a handful of variants now known to be associated with breast cancer. However, it is critical to identify additional gene variants in breast cancer that are associated with clinically relevant features of cancers, such as staging and molecular subtype. Methods: We took an unsupervised machine learning approach that clustered the somatic whole exome sequences (WES) of 1533 breast cancers. We performed k-modes clustering on the binarized mutational state of the top 250 most frequently mutated genes. Following two rounds of clustering, 11 distinct “barcodes” for each genetic cluster’s mutation profile became apparent. We systematically tested each genetically defined cluster for associations with molecular subtypes of breast cancer. We performed non-parametric significance testing by randomly permuting cluster assignments to generate an empirical null distribution of the effect of clustering on proportions of the clinical factor of interest. Results: As an example of our set of results, two clusters showed roughly three-fold enrichment of triple-negative breast cancer (TNBC) patients, compared to the whole-group proportion. We calculated SHAP values to provide model explainability and identify the genes that placed a cancer into a particular cluster; TP53 and TTN were the strongest drivers in relation to TNBC. Genetic clusters were also found to associate with T-, N-, and M-stages. Conclusions: Our approach, which uses unsupervised machine learning on WES to create genetic groups of cancers, considers the joint mutational state – present or absent – of multiple genes for their clinical relevance. This reveals many additional variants that may have been previously overlooked or of uncertain significance.
Multicenter study to evaluate the efficacy and standardize radiofrequency ablation therapy for early breast cancer.
Authors: Kinoshita Takayuki , Takayama Shin , Takahashi Masato , Fujisawa Tomomi , Futamura Manabu , Yamamoto Naohito , Shien Tadahiko , Aogi Kenjiro , Ohnishi Tatsuya 
Published: June 2023

e12570 Background: Early-stage breast cancer is increasingly detected by screening mammography, and we aim to establish radiofrequency ablation therapy (RFA) as a minimally invasive, cost-efficient, and cosmetically acceptable local treatment. In our Phase I study, localized tumors with a maximum diameter of 2 cm, preoperatively diagnosed by imaging and histopathology, were treated with RFA. A 90% complete ablation rate was confirmed histopathologically. Our phase II multicenter study of RFA without resection for early breast cancer will evaluate the long-term safety and efficacy of RFA as well as its cosmetic results, which are a perceived advantage of this technique. Methods: From Nov. 2009 to Nov. 2012, 58 patients with early-stage breast cancer received non-surgical RFA therapy. Patients had localized solitary N0 tumors with a maximum diameter of 1 cm. In our experimental therapy, a radiofrequency electrode needle is inserted through the skin into the breast lesion under imaging guidance, followed by thermal ablation with radiofrequency waves. RFA will be conducted under general anesthesia. The Cool-tip™ RF Ablation Single Electrode Kit (Medtronic, CO, USA) will be used to standardize the evaluation of the ablation effect. They underwent RFA and SNB under general anesthesia and adjuvant therapy and breast radiation. Follow-up evaluation for residual tumor at 3, 6, and 12 months after RFA included clinical examination, diagnostic imagings and vacuum-assisted biopsy. Surgical resection was recommended for patients with suspected residual disease or incomplete ablation. The primary endpoint was the frequency of adverse events. Secondary endpoints included the complete ablation rate and ipsilateral breast relapse-free rate. Results: The follow-up period ranged from 15 to 109 months (median, 85 months). The 57 patients completed the non-surgical RFA procedure and underwent diagnostic imaging and needle biopsy after 3 months. Seven patients with suspected incomplete ablation underwent surgical resection; incomplete ablation was confirmed in 5 (8.6%, 2 with invasive and 3 with non-invasive ductal carcinoma). During subsequent follow-up, 1 patient each was diagnosed with contralateral breast cancer and ipsilateral breast tumor relapse. No distant recurrence was documented. Cosmetic results were excellent in 94% of patients. Conclusions: Our phase II multicenter study of RFA without resection for early breast cancer will evaluate the long-term safety and efficacy of RFA as well as its cosmetic results, which are a perceived advantage of this technique. Clinical trial information: UMIN000008675 .
Long term survival in patients with bony oligometastatic breast cancer treated with curative intent: An institutional case series.
Authors: Iancu Alexandra , Vinayak Shaveta , Gwin William R , Linden Hannah M. , Specht Jennifer M. , Symonds Lynn Katherine , Davidson Nancy E. , Hunter Natasha 
Published: June 2023

e12574 Background: Despite recent advances in treatment, metastatic breast cancer is widely recognized as a generally incurable condition. However, oligometastatic disease remains a poorly characterized condition with few clinical trials exploring treatments and outcomes. The term itself lacks a formal definition but is often used to refer to breast cancer displaying ≤5 metastatic sites, not necessarily in the same organ. Surgical management of discrete metastases has failed to demonstrate long-term benefit, while radiotherapy for isolated bone metastases has shown promise in some retrospective studies resulting in prolonged disease-free interval. Metastatic breast tumors overexpressing HER2 represent a category where systemic therapy may offer some prolonged remission or even cure. Methods: We are conducting a retrospective review of breast cancer patients with oligometastatic disease, as defined by ≤5 sites of disease, treated at Fred Hutch Comprehensive Cancer Center (FHCC) from 2000 to 2022; we will characterize FHCC provider practices, therapies delivered, goals of treatment, and long-term outcomes. This larger ongoing effort will be reported in a separate publication. Among a cohort of patients initially identified and undergoing record review, we reviewed all patients with bone-only disease and report their outcomes here. Results: We initially identified 17 cases of oligometastatic breast cancer currently undergoing treatment at FHCC. Of these, we noted that five patients had bone-only metastases and displayed marked similarities in treatment and outcome. All presented with de novo metastatic disease, and all five had ≤2 sites of metastasis, all in the axial skeleton. Four had HER2+ tumors; of these, three were also hormone-receptor positive. The remaining patient had triple-negative disease. All were treated with curative intent, with radiation to isolated bone metastases delivered concurrently with adjuvant radiation to breast/axilla. All are living today, with a median 56 months of follow up. One remains on a systemic metastatic regimen with a CDK4/6 inhibitor, while the rest are off therapy or are completing a standard adjuvant regimen. Conclusions: Oligometastatic breast cancer represents a heterogeneous entity that may in some instances be curable, but we lack sufficient data to identify which patients may benefit from therapy with curative intent. Standard curative treatment combined with radiotherapy to isolated bone metastases produced long-term survival in five current FHCC patients, which is consistent with other reports on patients with a low burden of bone-dominant metastatic disease. Further research is needed to validate curative approaches to therapy for this understudied population.
Ozone-loaded Pt(IV) prodrug self-assembled micelles with high bioavailability, low toxicity as a novel irradiation-controlled release treatment and the immune microenvironment editor for triple-negative breast cancer.
Authors: Zheng Dan , Luo Ting , Shi Hubing , Xu Tianyue 
Published: June 2023

e12575 Background: A considerable part of TNBC shows poor response to the immune checkpoint blockades (ICBs) due to the immunosuppressive microenvironment. Chemotherapy performs well in synergizing with ICBs by improving tumor immunogenicity or eliminating the immunosuppressive tumor microenvironment. However, limited bioavailability, significant systematic toxicity and immunosuppressive metastatic niche induced by chemotherapy restrict its systematic application. Methods: We constructed the Pt(IV)-prodrug self-assembled micelles of O3_PFD@PtF with an ozone-loaded perfluorodecalin as the core (O3_PFD), and Pt(IV)-fluorocarbon chains assembled micelle as the shell (PtF). Results: The particle sizes of the prodrug were about 130.5 nm of PFD@PtF and 174.7 nm of O3_PFD@PtF, and both of the two showed good stability in the environment of different pH value and temperature. The Pt(IV) in the prodrug can be reduced and released in the sodium citrate solution. In addition, ozone was well stabilized by the PFD@PtF as the ROS donor and decomposed rapidly upon the irradiation excitation. O3_PFD@PtF boosted the level of GSH by promoting the intracellular redox balance with ROS and then the Pt(IV) was reduced to Pt(II) to release only within tumor. The prodrug was efficiently endocytosed into TNBC cells. Compared to cisplatin, a higher amount of Pt(II) was detected inserted into DNA in the O3_PFD@PtF combining irradiation treating group, which was released through depleting GSH donated by ROS. Accordingly, a remarkable reduction in IC50 was recorded in TNBC cells when O3_PFD@PtF was applied synergizing with irradiation. Furthermore, a relatively low IC50 was detected in non-ozone loaded prodrug-treated TNBC cells, which was attributed to the high concentration of background GSH, whereas the IC50 of PtF in Hacat was significantly higher than in other treating groups due to the low concentration of background GSH. Excellent inhibiting rates of the TNBC cells proliferation were observed in O3_PFD@PtF plus irradiation group 96 hours after treating, outperforming the conventional cisplatin plus irradiation group. We also observed a medium proliferation rate of TNBC cells in O3_PFD@PtF treating group in the absence of irradiation, which may be attributed to the Pt(II) released by the automatic decomposition of ozone. More importantly, cisplatin was reported to induced immunogenic cell death when synergizing with irradiation, but not alone. The dual potential to enhance TNBC proliferation inhibition and edit its immune microenvironment are now continuously detected. Conclusions: As a novel nano-prodrug with high efficiency and safty, O3_PFD@PtF plus irradiation is expected to improve the response of TNBC to ICBs by editing the tumor immune microenvironment.
Defendor special: Interim analysis of TCHP with primary empegfilgrastim prophylaxis (long-acting G-CSF) for treatment outcomes in early HER2+ breast cancer.
Authors: Zhukova Lyudmila , Ibragimova Tansylu , Ganshina Inna , Filonenko Daria , Sorokina Irina 
Published: June 2023

e12586 Background: TCHP is the standard regimen for neoadjuvant therapy (NAT) of HER2-positive early breast cancer (HER2+ eBC) and requires primary G-CSF prophylaxis (PP). Pathological complete response (pCR) after NAT reflects better pts outcomes. Long-acting G-CSF presents more balanced neutrophils (NEU) count vs short G-CSF. Preclinical data show tumor-associated neutrophils (TANs) as anti-tumor effector cells in eBC. There are limited data on the clinical benefit of TCHP in the subset of patients with HER2 amplification by ISH in the low-moderate of HER2 protein expression. This sub-group analysis of multicenter prospective study was designed to evaluate the pCR after TCHP with PP by empegfilgrastim (E) or filgrastim (F) in pts with HER2+ eBC. Methods: HER2+ eBC pts (n=199) with II-III stages are getting NAТ: 6 docetaxel/ carboplatin/ trastuzumab + pertuzumab + empegfilrastim/ filgrastim (TCHP+E/F). Short G-CSF (F) uses according to routine clinical practice, long-acting G-CSF (E) - 24h after each NAT cycle. This descriptive analyse were performed for pts who completed the whole NAT regimen. The study endpoints: pCR (ypT0/is, ypN0) in intention-to-treat (ITT) population and according to HER2 status: 3+ vs 2+ ISH positive (+). ClinicalTrials.gov No NCT04905329. Results: At the data cut-off (01’2023) 199 pts with HER2+ BC completed planned NAT and surgery (71 pts – TCHP+E; 128 pts – TCHP+F). pCR rate according to HER2 status and in ITT population in 2 G-CSF groups is presented. In TCHP+E group pCR rate exceeds KRISTINE trial data despite a more enriched pts’ population with poor prognosis (34% pts with IIIB - IIIC vs 17% pts in KRISTINE trial) while TCHP+F showed comparable results with historical control. The superior pCR rate under PP with E was also observed in HER2 (3+) pts sub-group vs PP with F. However, in HER2 (2+ ISH+) the results are similar in 2 G-CSF groups. The mature data are awaited. Conclusions: TCHP+E shows superior pCR rate vs TCHP+F in the ITT and HER2 (3+) population. The obtained results affirm data of preclinical research on the ability of G-CSF to switch tumor immunity from “cold” to “hot” in the eBC. We assumed that balanced NEU count under long-acting G-CSF stimulation enhances TANs infiltration is increasing therapy efficiency. In HER2 (2+ ISH+) population pCR results were comparable in 2 G-CSF groups. Discrepancies between gene amplification and protein overexpression resulted in declined amount of HER2-inhibitors-HER2 receptor active complexes. It can be TANs failure to kill anti-HER2-antibody-opsonized cancer cells by a trogoptosis. Our hypothesis requires further confirmation with translational research. Clinical trial information: NCT04905329 . [Table: see text]