bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of neratinib on HER2 mRNA stability via hsa-miR-23a-5p and efficacy of CDK4/6 inhibitors in HER2-low breast cancer.
Authors: Chen Liushan , Ye Lingling , Liang Yuqi , Zuo Qian , Hu Yuyu , Guo Qianqian , Chen Qianjun 
Published: June 2024

e12550 Background: Traditional HER2-negative breast cancer sometimes includes HER2-low components, and CDK4/6 inhibitors are the first- and second-line treatments for advanced HER2-low breast cancer. Nonetheless, little is understood about how the stability of HER2 mRNA in HER2-low breast cancer affects the effectiveness of CDK4/6 inhibitor therapy and the associated intervention techniques. Methods: In order to investigate the impact of HER2-low on the effectiveness of CDK4/6 inhibitor in treating breast cancer, we first used HER2-0 and HER2-low breast cancer cells/mice as the study object and assessed the anti-proliferation effect of CDK4/6 inhibitor using CCK8 technique and monoclonal formation experiment. Second, we increased the treatment of anti-HER2 inhibitor neratinib and assessed its impact on the efficacy of HER2 low breast cancer CDK4/6 inhibitors. By reducing the expression of HER2 in HER2 low breast cancer cells, we analyzed and determined whether HER2 is the primary pathway that influences the poor efficacy of HER2 low breast cancer CDK4/6 inhibitors; At last, actinomycin D was used to detect the mRNA stability of HER2 in the treatment of HER2-low breast cancer by neratinib against CDK4/6 inhibitors, and then microRNA sequencing and luciferase reporter gene detection technology were used. To investigate the specific mechanism of action of neratinib on the mRNA stability of HER2 in the treatment of HER2-low breast cancer by CDK4/6 inhibitors. Results: Our study found that treatment with CDK4/6 inhibitors was significantly less effective against HER2-low breast cancer compared to HER2-0 subtype (P=0.005). Notably, in HER2-low subtype cells, HER2 knockdown significantly inhibited cell proliferation (P<0.001), G1 phase cell cycle arrest (P=0.001), and downregulated cyclin D1 expression and CDK4 protein levels (P=0.007, P=0.003). Second, it was found that in the cell and animal models of HER2-low breast cancer, the addition of the CDK4/6 inhibitor drug neratinib effectively reduced the stability of HER2 mRNA (P=0.001), inhibited the cell cycle of G1 phase (P=0.005). In addition, we observed that lowering the dose of neratinib to 1/2 (20 mg/kg) remained effective and well tolerated (P=0.002). Finally, we found that neratinib can reduce the mRNA stability of HER2 by binding hsa-miR-23a-5p to the 3'UTR region of HER2 (P<0.001), thereby improving the efficacy of CDK4/6 inhibitors in HER2-low breast cancer. Conclusions: We found that low expression of HER2 reduced the efficacy of CDK4/6 inhibitors in HER2-low breast cancer; Neratinib reduces the mRNA stability of HER2 by binding hsa-miR-23a-5p to the 3 'UTR region of HER2, thereby improving the efficacy of CDK4/6 inhibitors in HER2-low breast cancer. These findings provide a tolerable and effective two-drug combination regimen for patients with clinical HER2-low breast cancer.
Immune subtyping of ER-positive, PR-negative and HER2-negative breast cancers by immunohistochemistry: Molecular basis and clinical relevance.
Authors: Zhang Huimin , Zhao Yuting , Xie Peiling , Chen Heyan 
Published: June 2024

e12553 Background: The diversity and plasticity behind ER+/PR−/HER2− breast cancer (BC) remain underexplored. In our previous work, an immune subtype classification for ER+/PR-/HER2- BC with RNA-seq data was established to distinguish between immune-hot and -cold tumors to provide guidance for immune checkpoint inhibitor (ICI) therapy. However, considering the economic costs, the clinical application of sequencing methods is limited. This study aimed to identify biomarkers of the immune subtype classification and develop a diagnostic procedure for ER+/PR-/HER2- BC immune subtyping based on the immunohistochemistry (IHC) technique, thereby identifying candidates of ICI therapy and refining treatment strategies for ER+/PR-/HER2- BC. Methods: RNA-seq data for 411 patients diagnosed with ER+/PR-/HER2- BC were obtained from the METABRIC database (METABRIC cohort). The immune subtype classification was established by consensus clustering with 1480 immune-related genes. Biomarkers for each immune subtype were identified from differentially expressed genes and validated using logistic regression and ROC curve analysis. Validation of the immune classification was conducted using RNA-seq data from the GEO and TCGA databases. Transcriptomic gene chip sequencing was performed on surgical specimens from 15 ER+/PR-/HER2- BC patients in our center (Chip cohort) to classify the immune subtypes. Biomarkers identified were validated and a diagnostic procedure was designed using IHC techniques. Results: In the METABRIC cohort, immune subtypes including Clusters 1-5 were established. Five biomarkers including DCN, SPP1, CXCL9, STC2, and SRGAP1 were identified, with the AUC values of ROC curves being 0.90, 0.82, 0.99, 0.70, and 0.89, respectively. Notably, Cluster 3 exhibited higher infiltration of CD8+ T cells, B cells, and M1 macrophages, with a greater association with immune activation pathways, thus being defined as the immune-hot subtype. Cluster 1, also showing a moderate immune cell infiltration, was characterized by a more pronounced stromal infiltration. In the Chip cohort, IHC revealed that Cluster 3 exhibited the highest levels of CD8+ T cell and B cell infiltration as well as PD-L1 expression, suggesting a potential benefit from ICI therapy. In contrast, Cluster 1 demonstrated the most extensive infiltration of endothelial and fibroblast cells. The other subtypes were characterized by a suppressed immune microenvironment, especially in Cluster 2, where an infiltration of SPP1+ macrophages was observed. A diagnostic procedure was designed with the biomarkers using IHC techniques. Conclusions: This study validated the immune subtype classification for ER+/PR-/HER2- BC. An easy-to-use IHC-based diagnostic procedure was developed, facilitating the identification of potential ICI therapy candidates in clinical practice at a lower cost.
Deliberate inclusion of multiple co-correlated gene target sets during discovery for improved biomarker translation to a clinical assay in early-stage breast cancer.
Authors: Cormier-May Elizabeth , Colbus Michael , Keiser Martin J 
Published: June 2024

e12560 Background: Co-correlation between gene targets provides a more robust, and often nonlinear, understanding of human biology, resulting in more accurate and reliable diagnostics. When translating from discovery to a clinical assay, detectability of promising targets often hinders diagnostic development. Translating a single set of co-correlated targets becomes more challenging, as the success of the program is dependent on the interrelationship between all targets and the ability of the entire set to translate clinically. Given target translation uncertainty, we hypothesized that the deliberate inclusion of multiple independent sets of co-correlated targets during discovery could bridge the gap between promising biology and a clinically viable assay. We set out to discover and clinically validate multiple sets of co-correlated targets required for noninvasive breast cancer detection. Methods: Nonlinear statistical methods were repeatedly applied to microarray gene expression profiles from peripheral blood (PBMCs) obtained from 140 patients with and without breast cancer. Four independent cohorts were used for subsequent studies to assess efficacy and reproducibility of discovered targets. In total, five independent sets of highly efficacious co-correlated targets, totaling 26 unique genes, were discovered and analytically validated across the five patient cohorts (n=357). A sixth independent cohort of 197 plasma samples (breast cancer n=116, controls n=81) was obtained and used to clinically translate and validate the 26 targets using real-time qPCR (qPCR). Results: qPCR revealed strong and reproducible clinical signal from 8/26 previously discovered targets (Table). To evaluate the efficacy of the targets, an 8-gene signature was trained on the PBMC discovery cohort, achieving >99% sensitivity, 83% specificity, indicating a promising classifier could be trained from the 8 qPCR targets. During CLIA validation of the assay, in normalized qPCR data from 87 patients, the 8-gene assay achieved a statistically significant >99% sensitivity, 89% specificity in stage I breast cancer. Conclusions: Given the performance observed from the 8-gene qPCR assay, we conclude that the deliberate inclusion of multiple sets of co-correlated targets, including those considered mathematically redundant during discovery, contributed to the success of a clinically viable assay for the detection of early-stage breast cancer in plasma. [Table: see text]
Overall survival in patients with HER2-low breast cancer at a reference hospital in Mexico.
Authors: Rubio-Anguiano Brenda Lorena , Valencia-Cedillo Raquel , Grajales Rocio 
Published: June 2024

e12578 Background: Breast cancer is the most diagnosed cancer in women. The 5-year overall survival (OS) rate in early-stage disease is 97% while in advanced disease is 36%. HER2 is a growth receptor involved in cell survival and proliferation. An overexpression of this protein leads to a more aggressive behavior; however, with targeted therapies, OS has improved. Recently, a new classification has been developed for tumors previously known as HER2-negative: HER2-low; which are those with IHC 1+ or 2+/ISH negative. It is believed that in these types of tumors, the signaling pathways of the HER2-positive subtype are also activated. There are conflicting studies on the prognostic impact of this subgroup. Currently, there is availability of anti-HER2 treatment for patients in advanced stages, as described in the DESTINY-Breast04 study, which changes the treatment paradigm for this pathology. Methods: The aim of this study is to determine overall survival in patients with HER2-low breast cancer. A retrospective, analytical, observational cohort was performed. Patients diagnosed with HER2-negative/low breast cancer, treated at the UMAE Oncology Hospital of the CMN Siglo XXI, from January 2018 to December 2022, were included. OS and disease-free survival (DFS) were calculated using Kaplan-Meier curves, and the impact of HER2-low expression on OS and DFS was assessed using log-rank analysis. The prognostic analysis of the complete model was performed using a Cox proportional hazards model. Results: We included 213 patients. The median age was 57 years. Ninety-five patients were HER2-low (44.6%), and 118 were HER2-negative (55.4%). Seventy-six percent had positive hormone receptor (HR) status. Patients with HR+/HER2-negative were 84 (52.2%), and HR+/HER2-low were 77 (47.8%). Among HR-negative status, the majority were HER2-negative (65.4%). When comparing HER2-negative and HER2-low, no statistically significant differences were found, with a 48-month overall survival of 70% for HER2-negative compared to 87.1% for HER2-low (p= 0.5700). OS analysis in the HER2-low group, comparing HR+ vs. HR-, a statistically significant difference at 48 months of 98.31% vs. 49.17% (p <0.0001), respectively, was found. Regarding DFS, a comparison between HR+ against HR-, it was 79.53% vs. 37.14%, respectively (p= 0.0002). The DFS analysis revealed that, among the variables studied, lymphovascular invasion (LVI) and HR+ status showed a statistically significant association with time to recurrence. Particularly, the presence of HR positivity was associated with a significant 82.6% reduction in the risk of recurrence. Conclusions: HER2 status alone (negative or low) did not offer a clear distinction in terms of OS or DFS. Nevertheless, it was observed a difference in OS and DFS outcomes favoring the HR-positive group when examining HR status among individuals with HER2-low, though this finding requires validation in a larger population.
Retrospective observational study of patients with luminal breast cancer in early stages: 10-year follow-up—Which luminal breast cancer relapse?
Authors: Puertas Andrea , Herruzo Cabrera Ismael , Ríos Pozo Maria Belén 
Published: June 2024

e12586 Background: Luminal BC is a heterogeneous group of breast cancer (1), with molecular signatures of better prognoses and others of worse prognoses being found. Prosigna test provide the molecular BC subtype, an individualized prognostic score called “ROR score”. Our main objective is to analyze in 10 years which Luminal early BC patients have local and distant relapses. See if there is a correlation between ROR and relapse. As second objective is select this group of patients who relapse and analyze the presence of CAF S1 for a future study. Methods: We performed a retrospective observational study from the two main hospitals in Málaga (Spain) We included 415 women 43-79 years with EBC defined as T1 or T2 primary breast cancer <30 mm in the largest dimension) node negative. Molecular BC subtype analyzed by IHC and genomic platform Prosigna) The patients were treated with breast-conserving surgery with clear excision margins hypofractionated radiotherapy and adjuvant endocrine therapy. We followed them from 2014 to the present. Results: 415 patients. We made genetic platform Prosigna to all of them luminal A 55%, Luminal B 37%, Basal like 4.8% and Her2 3.6%. The median follow-up was 9.1 years. The cumulative incidence of recurrence in Luminal BC was 2.29% (44.4% locoregional 55.55% distant recurrence). In 55.55% of the patients that relapsed had a Prosigna test with high ROR score, in 11.11% of the patients that relapsed had a Prosigna test with an intermediate ROR score and in 33.33 of the patients that relapsed had a Prosigna test with a low ROR score. Conclusions: In our study the cumulative incidence of recurrence in Luminal BC was 2.29 % and the ROR score provided a good estimate of the risk of relapse. Currently we use genomic platforms as Prosigna to estimate the ROR and adapt treatments to the risk. However, until now there is no biological or translational study focusing on T1N0 luminal BC. Subsequently, there exists a real need for new strategies to determine the long-term prognosis of these patients. We selected a group of patients to analyze the presence of CAF S1 fibroblast for a future study. Distant recurrence in T1N0 Luminal BC is strongly associated with the presence of CAF-S1 fibroblast The determination of CAF-S1 could more accurately predict recurrence in this subgroup of patients and could be a target for future treatments.
Axillary lymph nodes pCR (apCR) versus breast pCR (bpCR): A meta-analysis involving 10,723 patients.
Authors: pu shengyu , Chen Heyan , Zhang Huimin , He Jianjun , Hao Na 
Published: June 2024

e12630 Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) may improve the long-term survival of patients with breast cancer, as scored by disease-free survival (DFS) and overall survival (OS). Axillary lymph node pCR (apCR) is an important prognostic factor and may influence surgical de-escalation strategies; however, there is insufficient evidence to confirm that apCR produces a better prognosis than breast pCR (bpCR). The study aimed to perform a meta-analysis to assess the effect of apCR on survival compared with bpCR. Methods: We searched Cochrane Library, Web of Science, PubMed, Embase, and Clinical Trials.gov for breast cancer clinical trials with NAC. For included studies, we extracted the following data for analysis: study details, characteristics of participants, and survival data. Outcome data were reported as hazard ratios (HRs) and 95% confidence interval (CI) to measure the association between pCR and DFS, and OS. An I² test and subgroup analyses were performed to assess statistical heterogeneity in the included studies. Egger’s test and Begg’s funnel plot were used to determine potential publication bias. Results: We obtained data from 12 studies with 10,723 patients. Those patients with apCR had significantly better DFS than those with bpCR (HR=0.67, 95% CI, 0.60-0.76, P<0.00001), and no significant heterogeneity was observed between studies (I2=0%). As for OS, the HR significantly supported apCR (HR=0.72, 95% CI, 0.60-0.86, P=0.0002). There was no significant heterogeneity between studies (I2=35%). Subgroup analyses of each variable did not alter the results. Egger's test and Begg’s funnel plots indicated no significant publication bias in this analysis. Conclusions: This meta-analysis demonstrated that apCR is strongly associated with better DFS and OS than bpCR. This finding suggests that apCR has the potential to be an early surrogate endpoint for long-term prognosis.
Efficacy and safety of recombinant humanized anti-HER2 antibody-MMAE conjugate (RC48) in neoadjuvant for HER2-positive breast cancer: A single-arm phase II study.
Authors: Yang Jixin , Yang Yuqing , Wen Xinxin , Wu Jiang , Yu Jing , Wang Lei , Hu Wenyu , Xu Dongdong , Luo Jialing , Ma Wen , Li Nanlin ,   Xijing Hospital
Published: June 2024

e12636 Background: Breast cancer patients who achieve pCR after neoadjuvant therapy have a relatively good prognosis. Whether antibody‐drug conjugates (ADCs) can replace traditional chemotherapy combined with dual-target therapy in neoadjuvant therapy still needs to be explored. RC48 is a novel recombinant human anti-HER2 monoclonal antibody conjugated with a microtubule inhibitor (MMAE) via a cleavable linker, which can effectively kill HER2-positive tumors as well as tumors with low or heterogeneous HER2 expression through the bystander effect. The purpose of this study was to evaluate the efficacy and safety of RC48 in neoadjuvant treatment of HER2-positive breast cancer. Methods: Patients with HER2-positive breast cancer (size>20mm) or confirmed axillary lymph node metastasis were eligible and received RC48 at a dose of 2.5mg/kg alone every 2 weeks for 6 cycles followed by surgery. EC was administered postoperatively every 21 days for 4 cycles. Trastuzumab combined with pertuzumab was administered for 1 year in the adjuvant setting. The primary endpoints were ORR and pCR rates. Results: 23 patients had been enrolled, and all of them had completed surgical treatment. The median age was 45(38-70) years. The current results showed that 13.0% (3/23) achieved pCR, 78.3% (18/23) achieved PR, and 8.7% (2/23) experienced PD. The ORR was 91.3%. 42% (5/12) of patients with initially positive axillary lymph nodes turned negative after surgery. 11.8% (2/17) HR-/HER2+ patients achieved pCR. According to the proportion of target lesion reduction, patients were divided into mild response (0-50%) and moderate-to-severe response (51%-100%). In the HR-/HER2+ subtype group, 23.5% (4/17) had a mild response, and 76.5% (13/17) had a moderate-to-severe response. 6 patients with HR+ have been enrolled, and 16.7% (1/6) of them achieved pCR. All of HR+ subtypes had a moderate-to-severe response. No relevant serious (grade 3/4) toxicity has been reported. Conclusions: The present data showed an acceptable pCR rate with RC48 in HER2-positive breast cancer. Although the pCR rate was lower than the traditional chemotherapy combined with targeted therapy, the effect of rapid reduction of tumor volume was better (the moderate-severe remission rate was 82.6%). For HR+/HER2+ breast cancer, the ORR in this study reached 100%, indicating that the novel ADC had a significant inhibitory effect on the crosstalk between ER and HER2. And it was expected that the Destiny Breast 11 study would show similar results. This scheme had a good negative conversion rate for patients with positive axillary lymph nodes. Finally, RC48 provided a neoadjuvant treatment option with low toxicity and high patient compliance for HER2-positive breast cancer. Clinical trial information: NCT05134519 .
Trends over time in liquid biopsy testing in patients with metastatic breast cancer (MBC) across the Mayo Clinic enterprise.
Authors: Yadav Sumeet Kumar , Rajput Sanjna , Samineni Thoshik , Thompson Kevin , Tang Xiaojia , Leon-Ferre Roberto Antonio , O'Sullivan Ciara Catherine , Peethambaram Prema P. , Advani Pooja Prem , Sideras Kostandinos , Chumsri Saranya , Gill Paula , Ticku Jonathan , Anderson Karen S. , Ernst Brenda , Northfelt Donald W. , Haddad Tufia C. , Goetz Matthew P. , Kalari Krishna Rani , Giridhar Karthik 
Published: June 2024

e13036 Background: In January 2023, the FDA approved elacestrant for ESR1-mutated, ER+/HER2- MBC based on a companion diagnostic cell free (cf)DNA test (Guardant Health). In this study, we analyze the trends of liquid biopsy utilization at Mayo Clinic (MC) over a 3 year period to understand the impact of this drug approval on testing patterns and identify emergent alterations in patients (pts) with MBC. Methods: We extracted clinically performed Guardant 360 and Guardant 360 CDx ordered at MC sites in Rochester (MN), Florida (FL), Arizona (AZ), and across 9 additional Mayo Clinic Health System (MCHS) sites. Pts with MBC were identified using the EMR and analyzing visit diagnosis codes and staging information. Shifts in testing patterns were analyzed over a 3 year period from January 1, 2021 - December 31, 2023. Data was collected on the number of tests, serial testing, frequency of pathogenic mutations, and emergent mutations in ESR1 and PIK3CA. Chi-square test was used to compare the categorical values. Results: Between 2021-2023, 2,741 pts with MBC were seen across all sites. A total of 408 cfDNA tests were performed in 370 unique patients with MBC. Most pts (90%) had 1 test performed. The proportion of pts with MBC tested was 85/1350 (6.3%) in 2021, 77/1495 (5.2%) in 2022, and 208/1558 (13.4%) in 2023. The increased proportion of pts tested in 2023 was statistically significant compared to prior years (p<0.0001), while no difference was observed between 2021 and 2022 (p 0.19). Testing patterns varied by site, with FL ordering the highest number of tests, followed by MN and AZ. Of the 34 providers practicing during the entire period seeing more than 10 MBC pts, the number of providers ordering Guardant testing increased from 15/34 (2021) and 14/34 (2022) to 20/34 (2023), though not statistically significant (p 0.15). Of the 41% with EMR-documented staging available, testing was highest in the ER+/HER2- (81.3%) subtype, followed by TNBC (13.6%) and then HER2+ (5.2%). The most commonly identified mutations identified in the first testing were PIK3CA (41.1%), TP53 (40.5%), ESR1 (30.5%), and ATM (13.2%). D538G (8.0%), Y537N (4.4%), and Y537S (3.5%) were frequent emergent mutations seen in ESR1. Conclusions: We observed an increase in cfDNA testing at the start of 2023 which aligns with the FDA approval of elacestrant. We observed variation by site and individual providers that warrants further exploration to improve cfDNA testing in MBC pts at Mayo Clinic.