bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted genotyping for recurring variants in cancer susceptibility genes in non-Ashkenazi Jewish patients with breast cancer diagnosed ≥ 50 years.
Authors: Bernstein-Molho Rinat , Abu Shhada Narmeen , Laitman Yael , Netzer Iris , Shoval Shelly , Friedman Eitan 
Published: June 2024

e12547 Background: Several recurring pathogenic variants (PVs) in BRCA1/BRCA2 and additional cancer susceptibility genes are described in ethnically diverse Israeli population. Since 2019 testing for these recurring PVs is reimbursed unselectively for all breast cancer (BC) patients in Israel, while extended multi-gene panel testing is reimbursed based on specific clinical criteria. We aimed to evaluate the yield of genotyping for these recurring PVs in non-Ashkenazi Jewish BC patients diagnosed ≥ 50 years. Methods: Clinical and genotyping data of all BC patients undergoing oncogenetic counseling at the Oncology institute at Sheba medical center from June 2017 to December 2023 were reviewed. Results: Of 2706 BC patients (mean age at diagnosis 54 years; range, 20-92 years) counseled, 515 patients of non-Ashkenazi Jewish (all 4 grandparents) descent, diagnosed ≥ 50 years of age were genotyped, 55 with triple-negative BC (TNBC) and 460 with non-TNBC. One of the recurring PVs in BRCA1/BRCA2 were detected in 12.7% (7/55) of TNBC patients and 0.65% (3/460) in non-TNBC. One patient with non-TNBC had PMS2 PV. Low-penetrance variants (not all in BC related genes) were found in 2.5% of genotyped TNBC and in 3.7% of non-TNBC patients, including CHEK2 c.499G>A (n=3), APC c.3920T>A (n=4), and heterozygous MUTYH c.1187G>A (n=5). Following first-pass genotyping, 146 patients performed multigene panel testing, none carried a BRCA1/BRCA2 PV, and only 5/127 non-TNBC (3.9%) harbored PVs in CHEK2 (n=2), ATM c.103C>T (n=2) and NBN (n=1). Conclusions: The observed low rates of PV detection in non-Ashkenazi Jewish non-TNBC cases older than 50 years at diagnosis, mostly for clinically insignificant variants, questions the justification of unselected genotyping in this subset of patients.
FKBP10-inhibited β-catenin ubiquitination in the malignant transformation of breast epithelial cells.
Authors: Chen Wei-xian , Zhu Bei , Shao Quan-feng , Zheng Lin 
Published: June 2024

e12580 Background: Current model of breast cancer (BCa) progression suggests a linear and three-stage process from normal epithelial tissue to ductal carcinoma in situ (DCIS), and then invasive ductal carcinoma (IDC). Since the detailed mechanisms for BCa oncogenesis remain largely unclear and there is still a lack of root-cause level interventions, exploring the underlying molecular alterations during three-stage process of BCa carcinogenesis is urgently needed. Methods: Three-stage specimens from the very same patients were collected. High-throughput sequencing was applied to obtain the differentially expressed genes among normal, DCIS, and IDC samples. Expression level and prognostic value of the selected gene were evaluated by PCR, western blot, tissue chip, and bioinformatics analysis. MCF10DCIS and MCF10Ca cell lines were respectively used to establish DCIS and IDC tumor models in breast epithelial cell-specific gene knockout mice. Patient-matched DCIS and IDC organoids were also constructed. Signaling pathways associated with malignant transformation of breast epithelial cells were detected by using high-throughput sequencing in mouse models and organoids. Protein binding was evaluated by protein mass spectrometry and co-immunoprecipitation. Results: By using high-throughput sequencing, we found that FKBP10 levels were gradually increased in three-stage specimens from the very same patients and were associated with poor prognosis. By establishing DCIS and IDC models in FKBP10flox/floxCre+/- and FKBP10flox/floxCre-/- control mice, we confirmed that FKBP10 deficiency could suppress BCa formation. Besides, FKBP10 knockdown could reduce oncogenic potentials in patient-matched DCIS and IDC organoids. Wnt/β-catenin signaling pathway was related to malignant transformation of breast epithelial cells, when MCF10DCIS+FKBP10flox/floxCre+/- model, MCF10Ca+FKBP10flox/floxCre+/- model, FKBP10-knockdown DCIS and IDC organoids, and their corresponding controls were comprehensively compared. Moreover, FKBP10 was found to inhibit β-catenin ubiquitination with the help of deubiquitinase Trim13, thus activating Wnt/β-catenin signaling pathway and accelerating malignant transformation of breast epithelial cells. Increased level of β-catenin was able to promote FKBP10 expression in a feedback loop. We also confirmed that exosome-loaded FKBP10-targeting peptide could suppress tumor growth both in vitro and in vivo. Conclusions: FKBP10-inhibited β-catenin ubiquitination was responsible in the malignant transformation from normal tissue to DCIS, and then IDC. Our study would uncover novel regulatory mechanisms of FKBP10 in three-stage process of BCa carcinogenesis and provide a new therapeutic approach for clinical treatment.
Pathological complete response rate to anthracycline versus non−anthracycline based chemotherapy regimens in localized and regional HER2 neu positive breast cancer.
Authors: Halaweh Osama M. , AlAbbad Maram , Alshehri Abdulrahman , Alsubait Saud , AlDaabil Riyadh , Abushullaih Samer 
Published: June 2024

e12632 Background: Debate over the need of anthracycline as part of neoadjuvant chemotherapy in HER2-neu early breast cancer was addressed in many trials with results favoring similar outcomes with or without anthracycline. This was not adopted fully in Saudi Arabia because of concern regarding ethnic differences in response to treatment. We conducted this retrospective analysis to evaluate if there is any difference in pathological complete response rate (PCR) in patients with early HER2-neu positive breast cancer depending on neoadjuvant chemotherapy regimen. Methods: Patients with HER2-neu positive early breast cancer who were treated with neoadjuvant chemotherapy at Johns Hopkins Aramco Healthcare (JHAH) facility between the year 2018 and 2022 were all evaluated for pathological subtype, HER2-neu status and type of neoadjuvant chemotherapy administered. Pathological response status was evaluated in all patients and PCR was measured to see if there was any difference depending on the use of anthracycline (AC) or non-anthracycline (non-AC) based chemotherapy regimen. Patient demographics, tumor characteristics, clinical stage, treatments and outcomes were collected via JHAH’s oncology registry. Categorical variables are reported as frequencies and percentages. The association between chemotherapy regimen AC vs non-AC based and PCR was analyzed using Fisher Exact Test. p-value <0.05 was considered statistically significant. Analyses were conducted using JMP version 15. Results: In this study 59 HER2-neu positive early breast cancer patients were identified. We examined their clinical characteristics and treatment outcomes. Median age was 57. The most prevalent histology was invasive carcinoma of no special type (79.66%), Estrogen receptor positivity was observed in 72.88% of patients, while progesterone receptor positivity was seen in 62.71% of cases. Majority of patients were alive (96.61%) at the time of data collection. There was no significant difference in clinical stage in both groups. The association between chemotherapy type and pathological response was assessed. Among patients receiving AC chemotherapy (n=29), 55.17% achieved PCR, while for patients receiving Non-AC chemotherapy (n=30), the PCR rate was 50%. However, this difference was not statistically significant (p-value = 0.8). Conclusions: In our cohort of HER-neu positive early breast cancer patients who received neoadjuvant therapy there seems to be no significant difference in PCR with AC or Non-AC based chemotherapy regimens. This is concordant with the international trends.
Trastuzumab-induced cardiotoxicity in patients with metastatic HER2-positive breast cancer treated at a reference hospital in Mexico.
Authors: Leocachin-Parra Daniela Leticia , Bocardo-Galvan Jessica Berenice , Grajales Rocio , Carrillo-Estrada Montserrat 
Published: June 2024

e13032 Background: In Mexico, breast cancer represents the leading cause of cancer-related death in women, and up to 52% is diagnosed at a metastatic stage. Up to 20-25% of women with breast cancer have overexpression of the human epidermal growth factor receptor 2 (HER2) which is associated with an aggressive behavior. The most relevant adverse effect associated with therapy targeting this receptor is an increase of up to 4 times in the rate of myocardial dysfunction. There is limited research in the Mexican population, especially in the metastatic context. This review is intended to be conducted in the national population, including patients with HER2-positive metastatic breast cancer who have received trastuzumab treatment, to determine the main characteristics of such myocardial dysfunction using the definition of cardiac dysfunction proposed by the International Cardio-Oncology Society (ICOS) in 2021, as well as its current prevalence. Methods: Observational, descriptive, cross-sectional, retrospective study. Medical records of patients diagnosed with metastatic HER2-positive breast cancer between January 2017 and December 2022, who received trastuzumab and had a determination of left ventricular ejection fraction (LVEF) before treatment and at least two LVEF determinations during treatment to determine the presence or absence of cardiotoxicity. LVEF could have been determined by MUGA (Multigated Acquisition Scan) or by echocardiogram. Results: A total of 103 patients were included, with a mean age of 55 years. The found prevalence of cardiotoxicity was 30.09%. Among the most frequent clinical characteristics of these patients were obesity in 32.2% [n= 10], smoking habit in 12.9% [n= 4], and type 2 diabetes in 9.7% [n= 3]. The diagnosis of de novo metastatic disease was 48.4% [n= 15]. A history of ischemic heart disease was present in 3.2% [n= 1], and a frequency of 12.9% [n= 4] of patients with borderline LVEF (50-54%) was reported at baseline, with only 3.2% [n= 1] documented with a baseline LVEF < 50%. The median number of trastuzumab cycles administered during follow-up was 14 cycles, anthracycline therapy was documented in most patients, and previous exposure to thoracic and/or mediastinal radiotherapy with a dose exceeding 30 Gy was found in 35.5% [n= 11]. Referral to cardiology and/or cardio-oncology service was 51.6% [n= 16]. Discontinuation of anti-HER2 treatment was carried out in 3 patients (2.9%). Conclusions: We demonstrated a prevalence of cardiotoxicity from anti-HER2 agents in our population similar to that reported in the international literature. Multicenter studies are necessary to define the prevalence more accurately in the Mexican population, as well as prospective studies to demonstrate the association between cardiovascular risk factors and clinical characteristics with the development of cancer therapy-related cardiac dysfunction.
Expanding multiple features of extracranial metastasis to predict survival for patients with breast cancer brain metastasis: A population-based retrospective analysis.
Authors: Xu Hangcheng , Wang Yan , Sa Qiang , Wu Yun , Zhou Yiran , Wang Jiayu , Xu Binghe 
Published: June 2024

e13038 Background: Breast cancer brain metastasis (BCBM) is associated with poor survival outcomes and reduced quality of life. The Graded Prognostic Assessment (GPA) score model serves as a well-established tool for predicting the prognosis of BCBM. Notably, the presence of extracranial metastasis (ECM) is considered as a significant prognostic factor in the breast GPA. This study aims to further refine this factor to enhance the prognostic prediction for BCBM. Methods: This study included all inpatients diagnosed with BCBM at the Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS), from January 2010 to July 2021. The subsets were categorized by the presence, number, location, and control status of ECM. Baseline clinicopathological characteristics were documented and compared among subgroups. The primary endpoint was overall survival (OS) after the diagnosis of BCBM. We used the Kaplan–Meier method with log-rank test to compare the survival outcomes. Cox regression analyses were conducted to identify significant prognostic factors, which were then incorporated into a new Breast-GPA model. Results: A total of 286 patients with BCBM were included in the study. Kaplan–Meier survival curves suggested that patients without ECM when diagnosed with BCBM showed better survival (p=0.0068). In the subgroups with ECM, more than 3 organs involved, both bone and visceral metastasis and progressive ECM portended dismal OS (p=0.0032, 0.0014 and 0.00054). Multivariate analysis (MVA) demonstrated that the presence, number, and control status of ECM significantly influenced OS after BCBM (p=0.01, 0.03, and 0.048, respectively). The specific location of ECM also had a significant impact on the long-term survival (p=0.0014). By modifying the current GPA model to include categories for '3 or fewer controlled ECM', the predictive accuracy of the newly established GPA model was further enhanced. Conclusions: More extracranial sites, both bone and visceral invasion and uncontrolled ECM were independent prognostic factors for dismal survival outcomes of BCBM patients.
Mutational landscape of HER-2 low breast cancer.
Authors: Vosoughi Elham , Nafissi Nellie , Mahadevan Aditya , Lee Seungshin , Mehta Rita S. , Parajuli Ritesh 
Published: June 2024

e13040 Background: HER2-low breast cancer is defined as HER2 IHC score of 1+ or 2+/ISH- tumors. Anti-Her-2 therapies such as trastuzumab deruxtecan improve progression-free survival (PFS) and overall survival (OS) in patients with HER-2 low metastatic breast cancer. However, the mutational landscape of HER2-low BC is still not well defined. The aim of this study is to characterize the biological and clinicopathological landscape of HER2-low BC by next generation sequencing. Methods: We conducted a single institution, retrospective chart review of patients with metastatic breast cancer (MBC) from 1/2020 to 4/2023. We obtained Next generation sequencing data and correlated it with clinical outcomes. Patients with HER2 IHC score of 1+ or 2+/ISH- tumors referred as HER2-low, while with no HER2 IHC staining at all were referred as HER2-zero, and pts with HER2 IHC 3+ or HER2 IHC 2+/ISH+ referred as HER2+. Results: A total of 98 pts were enrolled:45 pts with HER2-low tumors, 29 pts with HER2+ and 24 pts with HER2-zero tumors. In the HER2-low cohort, 58% (26 pts) were initially diagnosed with loco regional disease while 42% presented with stage IV at diagnosis. On average patients were on 3 lines of therapy for metastatic disease (ranging between 1 to 12). Of those 35% received T-DXd. High Ki-67 proliferation (≥20), reported in 58% (26 pts). OS was 54.4 months, 95% CI [ 42.5,100.2]. In the HER2+ cohort, 31% of pts presented with stage IV at diagnosis. On average pts received 3 lines of therapy (ranging from 1 to 14). 69% of pts received T-DXd. High Ki-67 reported in 48% of pts. OS was 59.2 months, 95% CI [39.2,96,1]. In the HER2-zero, 62.5% of pts presented with stage IV. On average pts received 1 line of therapy (ranging between 1 to 5), 62% of pts had high Ki-67. OS of 41.6 months 95% CI [18.4, 77.9]. Conclusions: Although limited by the sample size, our data suggests that HER-2 low breast cancer tends to be more locally advanced or metastatic at the time of presentation. HER-2 low BC is associated with a higher Ki-67 index and tends to harbor more mutations. HER-2 low may not just be a target, but a unique biological entity and can be distinguished from HER2-Zero BC with higher prevalence of HR+ and other biomarkers and better OS. NGS data from a larger data set is required to better characterize HER-2 low breast cancer. We suggest that clinicians obtain NGS panel in all patients with HER-2 low MBC. [Table: see text]
Transcriptomic analysis of the tumor immune microenvironment (TIME) in patients with breast cancer with liver metastasis (BCLM).
Authors: Guo Weihua , Tan Jiayi , Chan Bryan , Mark Cynthia , Bitar Jin Sun , Bose Shikha , Pujara Vivek , Campbell Moray , Shiao Stephen Lawrence , Yuan Yuan 
Published: June 2024

e13045 Background: Breast cancer with liver metastasis (BCLM) is a significant predictor of worse prognosis and poor overall survival. Liver specific homing of breast cancer is not well understood, and the tumor immune microenvironment (TIME) likely plays a critical role in the process of forming BCLM. This retrospective study was conducted to determine the clinical risk factors and transcriptomic biomarkers associated with BCLM. Methods: A retrospective single institute chart review was conducted. Patient, disease characteristics and treatment variables were reviewed. Liver metastasis specific survival (defined by overall survival time from the diagnosis of liver metastasis) were compared across three breast subtypes (i.e., ER+/HER2-, HER2+, and triple-negative (TN) breast cancer) using Kaplan-Meier curves. Next generation sequencing (NGS) via commercial platforms were then used to obtain transcriptomic data. Transcriptomic analysis including differential gene expression analysis, gene set enrichment analysis (GSEA), as well as gene deconvolution analysis with TIMER2.0 were conducted for comparison of transcriptomic profiles and immune compositions across the three breast cancer subtypes. Results: 176 patients with BCLM and available liver metastasis biopsy were identified through retrospective chart review. Liver metastasis specific survival was compared, HER2+ BCLM patients (n = 17) had the best outcome and TN BCLM patients (n = 46) had the worst outcome with ER+ BCLM patients (n = 112) in the middle (p < 0.0001, ER+ vs TNBC p < 0.0001, ER+ vs HER2+ p = 0.038, HER2+ vs TNBC p = 0.00011). Principle component analysis on the transcriptomic data of 30 liver metastatic samples revealed different expression profiles between ER+ (n = 20) and TN (n = 7) BCLM, while HER2+ (n = 3) BCLM did not shown statistical differences with either group. B cell mediated immunity was upregulated in TN BCLM compared to ER+HER2- BCLM by GSEA (normalized enrichment score = 2.35, adjusted P-value = 0.19). Consistently, plasma cells were relatively enriched in TN BCLM compared to ER+ and HER2+ BCLM (p = 0.037) based on CIBERSORT estimation. In contrast, monocytes and neutrophils were enriched in ER+ BCLM (p = 0.0093 & 0.018) based on TIMER2.0 estimation. Additional NGS analysis is currently underway for increased sample size. Conclusions: BCLM in TNBC was associated with significantly worse overall survival. TIME in TN BCLM enriched for genes associated with B cell mediated immunity while ER+ BCLM had more monocyte/neutrophil mediated immunity.
The association between age, toxicity and outcomes of abemaciclib treatment in HR+/HER2- metastatic breast cancer.
Authors: Ovcaricek Tanja , Matos Erika , Borstnar Simona , Ribnikar Domen , Grasic Kuhar Cvetka , Cankar Kaja 
Published: June 2024

e13062 Background: The efficacy and safety of abemaciclib in patients (pts) with HR+/HER2− metastatic breast cancer (MBC) was demonstrated in the MONARCH clinical trials; however, real-world evidence is lacking, particularly in elderly pts. The dose reduction strategy used in the MONARCH trials has been shown to be an effective way of managing toxicity without compromising survival. Here, we provide real-world data on the efficacy and safety of abemaciclib treatment, focusing also on elderly pts with HR+/HER2− MBC and the association between abemaciclib dose reduction and survival. Methods: The efficacy and safety of abemaciclib in patients (pts) with HR+/HER2− metastatic breast cancer (MBC) was demonstrated in the MONARCH clinical trials; however, real-world evidence is lacking, particularly in elderly pts. The dose reduction strategy used in the MONARCH trials has been shown to be an effective way of managing toxicity without compromising survival. Here, we provide real-world data on the efficacy and safety of abemaciclib treatment, focusing also on elderly pts with HR+/HER2− MBC and the association between abemaciclib dose reduction and survival. Results: The median age of 134 pts was 62 yrs (IQR, 54-71), with 40 pts (29.9%) older than 70 yrs. Median rwPFS (mrwPFS) with abemaciclib + endocrine therapy in the ≥70 vs <70 age group was 15 vs 17 months (HR:1.1, 95% CI 0.70-1.76; p=0.65) and median OS (mOS) was 25 vs 34 months (HR:1.4, 95% CI 0.82-2.39, p=0.21). The most common rwAEs are shown (Table). Abemaciclib dose reductions occurred in 40% of pts ≥70 yrs of age compared to 28% of younger pts (χ2 (1)=1.98; p=0.22). There was no difference in mrwPFS between pts who had a dose reduction and those who did not (mrwPFS 15 vs 17 months (HR: 1.03, 95% CI 0.65-1.63, p=0.91) and mOS 28 vs 30 months (HR: 1.16, 95% CI 0.68-1.99; p=0.58)). Conclusions: The results of our study support the efficacy and safety of abemaciclib treatment in pts with HR+/HER2- MBC in real-world clinical practice. Age did not appear to be an important factor associated with higher rates of toxicity and similar efficacy of abemaciclib was demonstrated in the elderly pts population compared to younger pts. Importantly, abemaciclib dose reductions did not compromise survival. Clinical trial information: ERIDNPVO-0060/2022. [Table: see text]
Metastatic breast cancer in elderly women: A retrospective cohort study in Morocco.
Authors: Maadin Kaoutar , Mellas Nawfel , Benbrahim Zineb , Oualla Karima , Amaadour Lamiae , Arifi Samia 
Published: June 2024

e13073 Background: Breast cancer (BC) stands as the predominant malignancy among women worldwide, presenting a significant global public health problem. In Morocco, it is the leading cause of cancer-related mortality in females. However, there exists a limited understanding of outcomes and treatment patterns for elderly patients with metastatic breast cancer (MBC) in our context. Methods: We conducted a retrospective cohort study at the Department of Medical Oncology, Hassan II University Hospital of Fez, focusing on 92 female patients aged 65 years or older diagnosed with MBC, between January 2012 and December 2016. The primary objectives were to estimate overall survival (OS) and progression-free survival (PFS), describe treatment patterns, and characterize the clinicopathological, and prognostic aspects of MBC in elderly women in Morocco. Results: The cohort’s median age was 70.88 (range, 65-88years) with 45.6% of patients aged of 65 to 69 years, 34.8% between 70 to 74 years old, and 19.6% over 75. Most patients (77.2%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 to 1, and only 33.7% had comorbidities. De novo stage IV constituted 59.8% of all cases. Metastatic recurrences represent 40.2% with 16.2% having recurrence within 12 months, and 83.8% having a recurrence interval exceeding 12 months. The median time to recurrence was 45.5 months. Invasive ductal carcinoma (IDC) was the predominant histological type (81.1%), with SBR grade II (51%) and grade III (21.7%). Metastases were observed in pleuropulmonary (78.3%), bone (56.5%), lymph nodes (33.7%) and liver (30.4%). With 71.7% having metastases in fewer than three sites, while 28.3% had metastases in three or more sites. Molecular profiling showed Luminal A (38%) and Luminal B (26.1%) subtypes as the most prevalent, followed by triple-negative (17.4%) and HER2+ (15.2%). Treatment modalities included chemotherapy (50%), hormone therapy (15.2%) or a combination of the two (17.4%), and anti-HER2 targeted (14.1%). Median OS was 37 months (95% CI: 16.86 - 57.13 months), and median PFS was 33.16 ± 4.1 months. Anti-HER2 therapy showed a significant association with survival (p = 0,05). Conclusions: This study highlights the characteristics, survival, and treatment modalities of elderly patients with MBC in Morocco. Despite the predominance of luminal BC an intriguing observation was the frequent use of chemotherapy as first line modality.