bluuebunny/crossref_metadata_2025_split huggingface dataset:
Co-occurrence of ESR1 and PIK3CA mutations in HR+/HER2- metastatic breast cancer: Incidence and outcomes with targeted therapy.
Authors: Dempsey Naomi , Bhatt Priya , Lewis Courtney , Tolman Dana , Chamorro Yolcar , Rubens Muni , Carcas Lauren , Sandoval-Leon Ana Cristina , Ahluwalia Manmeet Singh , Mahtani Reshma L. , Harpalani Natasha 
Published: June 2024

e13097 Background: ESR1 and PIK3CA mutations inform the use of targeted agents such as alpelisib (A), elacestrant (E), and capivasertib in patients (pts) with HR+/HER2- metastatic breast cancer (mBC). These mutations predict a worse prognosis and shorter response to endocrine therapy (ET). The prevalence of PIK3CA and ESR1 mutations detected via circulating tumor DNA (ctDNA) in mBC is about 35% and 33%, respectively, and the co-occurrence rate is 10-15%. Treatment outcomes with these targeted agents in pts with both mutations can inform sequencing decisions. Methods: We retrospectively analyzed pts treated at Miami Cancer Institute with HR+/HER2- mBC who underwent ctDNA testing (performed by Guardant360) between March 2019 and Jan 2024. The rate of co-occurring pathogenic ESR1 and PIK3CA mutations on a single sample was quantified. We report pt demographics, disease characteristics, and real world outcomes on A + ET and E in the co-mutated cohort. Results: Of the 626 pts who underwent ctDNA testing, 31.6% (n=198) had at least one PIK3CA mutation and 23.8% (n=149) had at least one ESR1 mutation. Co-mutations in both ESR1 and PIK3CA were found in 10.4% (n=65). In the co-mutated cohort, median age was 63, 84.6% were post-menopausal, and 58.5% were Hispanic. Most pts received prior CDK4/6 inhibitor (90.7%). A + ET was administered to 27 pts (41.5%) with a median of 2 prior lines of therapy (range 1-8). In these pts, 33.3% (n=9) achieved stable disease, 25.9% (n=7) partial response, 14.8% (n=4) progression, and 18.5% (n=5) discontinued due to toxicity prior to re-staging. E was administered to 12 pts (18.5%) with a median of 4 prior lines of therapy (range 1-13), with 4 pts still on treatment. None achieved stable disease or objective response, 66.7% (n=8) developed progression of disease as best response, and 33.3% (n=4) currently remain on treatment pending response evaluation. In the co-mutated cohort, only 4 received both A + ET and E, (3 received A first, 1 received E first). Pts treated with A + ET only (n=23) had a median time to next treatment (mTTNT) of 120 days (range 5-566) and those who received E only (n=8) had a mTTNT of 86 days (range 13-106) (Chi square=4.289, df = 1, p<0.05). The 4 pts who received both therapies were excluded from this mTNNT analysis. Conclusions: The rate of ESR1 and PIK3CA co-mutation in this cohort was consistent with the reported literature. mTTNT was significantly longer with A + ET compared to E, but real world outcomes on E remain immature with one-third of pts still on E at the time of analysis. A limitation of this study was the small sample size. Further analyses are warranted to clarify the optimal sequencing of these targeted therapies such as A, E, and capivasertib in pts with co-mutations in ESR1 and PIK3CA.
Frequency of dose reductions of abemaciclib in metastatic and early-stage hormone positive, HER2 negative breast cancer.
Authors: Ter-Zakarian Anna , Donovan Lauren N. , Nasraty Farah 
Published: June 2024

e13099 Background: Abemaciclib is a CDK4/6 inhibitor which in combination with endocrine therapy (ET) improves progression-free survival in hormone receptor (HR)-positive, HER2 negative advanced breast cancer, as well as invasive disease free-survival in high-risk early-stage breast cancer. However, abemaciclib is associated with adverse events which may limit treatment adherence. In this single-center study, we describe real-world safety outcomes of early-stage and advanced HR-positive, HER2 negative breast cancer patients prescribed abemaciclib in conjunction with ET. Specifically, we analyze the frequency of adverse events and dose reductions (DR). Methods: We conducted a retrospective study of patients treated at Scripps Clinic between 1/1/2019-1/1/2023 with HR-positive, HER2 negative breast cancer prescribed abemaciclib with ET. Primary analyses were performed to discern clinical characteristic differences between groups. Categorical variables were summarized as frequencies and compared between arms by Chi-Square tests or Fisher’s Exact Tests. All continuous variables were summarized as means and standard deviations and compared between arms by T-Tests if normally distributed or summarized as medians and compared between arms by Mann-Whitney Tests otherwise. Statistical significance was set to 0.05 and all analyses were conducted in R. Results: A total of 77 patients were analyzed including 62% in the adjuvant setting and 38% in the metastatic setting. 51% of patients required DR. Patients requiring DR were older relative to those not requiring DR (59 vs 52 years of age, p=0.019). Those requiring DR remained on abemaciclib longer relative to those without DR (509 vs 350 days, p=0.057). Among those requiring DR, there were higher rates of grades II-IV diarrhea (p<0.001) and Loperamide use (p=0.083). Those requiring DR also had higher rates of neutropenia (54% vs 29%, p=0.027), abdominal cramping (39% vs 8%, p=0.002), nausea (39% vs 13%, p=0.011), and fatigue (51% vs 32%, p=0.079). Among 9 patients who expired on abemaciclib, 7 were in the metastatic setting and 1 was linked to an adverse effect from abemaciclib; none required DR (24% vs 0%, p<0.001). Finally, patients in the adjuvant setting remained on abemaciclib longer relative to those in the metastatic setting (526 vs 281 days, p=0.01). 95% of patients experienced symptom improvement with DR (p<0.001). Conclusions: Our study describes real-world safety outcomes of patients with HR-positive, HER2 negative breast cancer treated with abemaciclib and ET. More than half of patients required DR. Those who reduced their abemaciclib dose had improvement of clinical symptoms and remained on therapy longer. Based on our findings and given the importance of adherence in treatment efficacy, a lower starting dose of abemaciclib may be a more tolerable strategy, especially among older patients who required more DR in our study.
Association between genetic susceptibility and mortality in triple-negative breast cancer.
Authors: Akpoviroro Ogheneyoma , Sauers Nathan Kyle , Uwandu Queeneth , Ekechukwu Ifunanya , Manyele Victoria , Castagne Myriam , Srinivasa Hema Malini , Sharma Namita 
Published: June 2024

e13130 Background: We sought to determine if positive germline genetic tests in patients with triple negative breast cancer (TNBC) was associated with mortality. Methods: Retrospective review. Inclusion criteria: female, 18-85, stage 1-3 TNBC, 2010-2015; 5-year follow-up period from date of cancer diagnosis, or follow-up until death if sooner. Results: Out of the total population of 219 patients, 37.9% (83/219) underwent genetic testing. All patients who underwent genetic testing were Caucasian; most were non-Hispanic (78/83, 94.0%). The average age of the population of patients who underwent genetic testing was 49.6; there were no differences in age between those with a positive genetic test (PT) versus(vs) a negative genetic test (NT) (p=0.963). The average ECOG score was 0.2 and this was similar between the PT and NT groups (p=0.725). The average tumor size was 25.3 and this was similar between PT and NT groups(p=0.992). Among those who underwent testing, a PT was observed in 22.9% (19/83) and a NT in 77.1% (64/83). Within the PT group, 15.8% (3/19) experienced recurrent disease, while 18.8% (12/64) in the NT group experienced recurrent disease (p=1.000).Within the PT group, 5.3% (1/19) were deceased compared with 28.1% (18/64) in the NT group (p=0.590). When recurrent versus nonrecurrent disease was compared regardless of genetic test results, 73.3% (11/15%) in the recurrence group were deceased, compared with 11.8% (8/68) in the non-recurrence group (p<0.001). When the genetic test population was stratified by recurrence, there was no association between genetic test results and living status in recurrent disease (p=0.154), or non-recurrent disease (p=0.183). Conclusions: Most patients who underwent genetic testing were Caucasian, and the average age of the cohort was approximately 49 years. Otherwise, the demographic characteristics were comparable between patients with a positive genetic test and those with a negative genetic test. Positive genetic test results were not associated with recurrent TNBC, or tumor size. However, the presence of recurrence was associated with a higher incidence of mortality, irrespective of genetic test results. Our study shows that genetic susceptibility to breast cancer was not associated with greater mortality. More has to be done to determine if racial disparities occur in offering genetic testing to racial minorities who meet criteria.
A propensity-matched cohort study of neoadjuvant immunotherapy combined with chemotherapy versus neoadjuvant chemotherapy for early-stage triple-negative breast cancer.
Authors: Zheng Chunhui , Wang Yongsheng , Qi Yingxue , Song Yunjie , Yin Xiangyu , Luo Ningning 
Published: June 2024

e13134 Background: Preferred neoadjuvant treatment (NAT) regimens for early-stage triple-negative breast cancer (TNBC) include anthracycline-cyclophosphamide and taxane-based chemotherapy. This study compared the efficacy, safety and biomarker exploration of camrelizumab combined with chemotherapy and chemotherapy as neoadjuvant treatment for early-stage TNBC. Methods: This study included 2 cohorts with different NAT regimens, matched (2:1) according to age, clinical T and N stage, and Ki-67 status. Patients in the immune combination chemotherapy (NIC) cohort were recruited from a phase II clinical trial (NCT04676997). NIC patients received intravenous camrelizumab at a dose of 200mg and simultaneous chemotherapy consisted of platinum-free drugs, or platinum containing drugs. Patients in the neoadjuvant chemotherapy (NAC) cohort regimen comprised 4 cycles of paclitaxel 175 mg/m2, and 4 cycles of epirubicin (90 mg/m2, d1, q2w) + cyclophosphamide (600 mg/m2, d1, q2w). The indicators of this study include pCR, breast pCR (bpCR), axillary lymph node dissection (ALND) rate, breast conserving surgery (BCS) rate and tumor immune microenvironment (TIME) analysis of gene expression profiling. Results: Of 252 eligible patients, 162 patients were identified in the analysis after propensity score matching (PSM). Compared with NAC alone, the addition of camrelizumab brought higher pCR rates (64.81% versus 37.04%, p<0.05), ALND rates (38.89% versus 12.96%, p<0.05) and comparable BCS rates (20.37% versus 15.74%, p<0.05). Gene expression analysis was performed on tumor tissue samples from 12 patients receiving NAC and 16 patients receiving NIC before and after NAT. The results showed that the TIME status of the NIC and NAC groups before treatment was basically the same. Moreover, we respectively compared the TIME status of patients with pCR and non_pCR in NIC and NAC before NAT. The results found that there were 9 significantly different signatures (p<0.05) between pCR and non_pCR patients in the NIC group, and 1 signature (p<0.05) in the NAC group, respectively. Notably, we found 8 signatures (B Cells, CD8 T Cells, TIS, IFN Gamma, Lymphoid, T Cell, APM, Immunoproteasome), that were scored significantly higher only in pCR patients in the NIC group compared with non-pCR patients, and 8 signatures could promote response to immunotherapy. The common difference signature between the two groups is Treg cells. Conclusions: In patients with early-stage TNBC, neoadjuvant treatment with camrelizumab plus chemotherapy significantly improved pCR with an acceptable safety profile. Differences in TIME may affect response to treatment regimens. Future validation in prospective randomized controlled trials with larger sample sizes is needed. Clinical trial information: NCT04676997 .
Unveiling the complexity: Liquid biopsy-based proteomic exploration of triple-negative breast cancer in women.
Authors: Zuccari Debora Aparecida Pires de Campos , Tamarindo Guilherme , Novais Adriana Alonso , Frigieri Barbara Maria , da Silveira Juliano Coelho , de Souza Fabiana Ferreira , Labate Carlos Alberto , Chuffa Luis Gustavo de Almeida 
Published: June 2024

e13138 Background: This groundbreaking study places a spotlight on breast cancer in women, with a specific emphasis on the challenging triple-negative breast cancer (TNBC) subtype. Delving into the intricate world of extracellular vesicles (EVs) from TNBC-diagnosed individuals, the research meticulously compares various conditions, including healthy controls, benign tumors, recurrent tumors, and those in remission. Employing cutting-edge techniques like liquid biopsy and LC-MS/MS, the study meticulously explores the proteomic profile of serum exosomes, aiming to pinpoint diagnostic and prognostic markers in breast cancer. Methods: In the initial phase, EVs were expertly isolated and characterized from blood plasma samples exclusively from women, utilizing state-of-the-art methods such as ultracentrifugation and nanoparticle tracking analysis (NTA). Despite applying rigorous statistical criteria, the study found no significant differences in EV concentrations and sizes among the diverse groups. However, the ensuing proteomic analysis uncovered 130 proteins, with Cystatin A and Histone H2A emerging as promising biomarkers for TNBC. To validate them, the study intricately tested tumor cell lines from distinct subtypes, representing luminal, triple-negative, and HER2 overexpressed. The examination of gene and protein expression through RT-qPCR and western blotting added a layer of depth to the research, unraveling the complexity of regulatory processes within cells and demonstrating a remarkable congruence between protein levels found in the proteomics from patients’ serum and in immortalized cell lines. Results: The proteomic analysis brought to light the absence of CSTA and HIST1H2A expression in benign tumor patients, varied levels in malignant tumor patients, and a substantial increase in TNBC patients pre-mastectomy. Validating these findings through western blotting further accentuated the potential of these proteins as distinguishing factors. Conclusions: In conclusion, this pioneering study not only underscores the immense potential of liquid biopsy-based proteomic analysis in identifying crucial diagnostic and prognostic markers in breast cancer but also sheds light on the intricate nuances of the challenging TNBC subtype. Our findings unveil valuable insights that pave the way for future personalized treatment strategies, marking a significant stride forward in breast cancer research.
Effect of transcription factor WT1 on triple-negative breast cancer metastasis through PFKFB4-mediated glycolysis.
Authors: Zhao Tingting , Zhou Yuqin , Wu Xiujuan , Peng Zaihui , Gao Pingping , Sun Na , Zhang Yi , Qi Xiaowei 
Published: June 2024

e13145 Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high probability of metastasis as well as a lack of specific targets and targeted therapeutics. Preliminary study suggested that Wilms' tumor gene 1 (WT1) is highly expressed in breast cancer patients with poor prognosis and may promote TNBC metastasis, but the underlying mechanism remains poorly defined. Methods: WT1 expression was evaluated by immunohistochemistry (IHC) in breast cancer patients. Kaplan–Meier survival analysis was performed to assess the prognostic significance of WT1 expression. WT1 was silenced in MDA-MB-231 and BT549 cells or overexpressed in HCC1806 cells. qRT-PCR and Western blot were used to detect the WT1 expression in tissues and cells. Wound healing assays, transwell assays and 3D spheroid assays were used to examine the migration and invasion abilities in TNBC cells. The lung metastasis model of mice was used to evaluate metastasis of TNBC in vivo. Chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) and transcriptome sequencing (RNA-seq) were performed to find PFKFB4, a downstream target gene for WT1. ChIP-PCR and dual-luciferase reporter assays were used to explore the transcriptional regulation of PFKFB4 by WT1. Seahorse XF glycolysis stress assay, glucose uptake assay, and lactate production assay were used to investigate the role of WT1 in regulating glycolysis metabolites. Results: WT1 was highly expressed in TNBC and correlated to poor prognosis in TNBC patients. Functional assays revealed that WT1 promoted TNBC cell metastasis in vitro and in vivo. Our mechanistic investigations demonstrated that WT1 promoted TNBC cells migration and invasion by transcriptionally activating the expression of PFKFB4.This action leaded to increased glycolytic capacity, glucose uptake, and lactate production in cancer cells, therefore promoting metastasis of TNBC. Clinically, the combined expression of WT1 and PFKFB4 provides a reliable predictive biomarker for the prognosis of TNBC patients. Conclusions: Our findings reveal a molecular mechanism of WT1 promoting TNBC metastasis, which provides new targets for the precision treatment of TNBC and new perspectives for the development of targeted metabolic anticancer drugs.
Activation of dendritic cells by a synthesized small molecule for breast cancer vaccination.
Authors: Wu Yuxuan , Yeh Yu-wen , Xiang Zou 
Published: June 2024

e13149 Background: Dendritic cell-based vaccination is a promising immunotherapy for treating various types of cancer. However, tumor-loaded dendritic cells alone have limited treatment efficacy. We have designed a small molecule mimicking the action of damage-associated molecular pattern molecules as an adjuvant for activating dendritic cells in vitro, which demonstrated augmented treatment efficacy. Methods: We aimed at exploring the roles of the synthesized small molecule in augmenting the efficacy of dendritic cell-based cancer vaccination to target triple negative breast cancer. Breast cancer mouse model is constructed using a 4T1 tumor cell line. Data were analyzed using a two-tailed unpaired t-test. Results: Mouse dendritic cells could be activated in vitro by the small molecule as an adjuvant evidenced by increased expression of MHC-I, MHC-II and CD40. Augmented motility of dendritic cells was also observed after treatment with the adjuvant. The signaling of NFkB is remarkably activated in dendritic cells by the adjuvant, which facilitates the maturation of dendritic cells. Engraftment of adjuvant-primed dendritic cells loaded with 4T1 tumor antigen into 4T1 tumor-bearing mice efficiently reduced the tumor size and improved survival, compared with the group treated with dendritic cells only. After injection of adjuvant-activated dendritic cells, both CD4 T cell and CD8 T cell populations were expanded in the spleen and lymph nodes draining the tumor sites. Furthermore, the adjuvant could promote the production of IFN-γ and IL-2, cytokines required for T cell activation and expansion. Next, splenocytes were obtained from individual mice after dendritic cell-based treatment. Upon re-encounter with the tumor antigen in vitro, remarkable expansion of T cell populations with a memory cell feature was confirmed in splenocytes derived from mice that received adjuvant-treated dendritic cells. Consistently, production of TNF-α, IFN-γ and granzyme B, was profoundly increased in these T cells associated with the adjuvant treatment. Conclusions: Our work suggests a novel dendritic cell-based cancer immunotherapy by using a small molecule mimicking the action of damage-associated molecular pattern molecules, which have documented immune potentiation activities.
Addition of IL-6 and phosphate to the m-EASIX score and detection of ICANS and CRS progression.
Authors: Barker Kenneth , Marco Tom , Husnain Muhammad , Katsanis Emmanuel 
Published: June 2024

e14511 Background: Cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS) can be severe complications of CAR-T infusion. Both syndromes have been associated with endothelial dysfunction which prompted prior use of a modified version of the Endothelial Activation and Stress Index (m-EASIX) to predict the occurrence of severe grades of ICANS and CRS. Recent studies have linked low phosphorous (P) levels to both syndromes, and IL-6 is a known mediator of both. Our study aimed to enhance early prediction of CRS and ICANS by integrating both P and IL-6 into the m-EASIX score. Methods: This retrospective study included 44 patients (26 male and 18 female) ranging from 42 to 86 years old with non-Hodgkin's lymphoma presenting to the University of Arizona Cancer Center for CAR-T treatment. P, CRP, IL-6, and LDH were recorded up to 7 days before and 14 days after CAR-T infusion. All platelet levels were recorded the day of infusion. Variations of the m-EASIX score as outlined in table 1 were then calculated. The values of P were cubed to ensure relative differences in P had proportional consistency to differences in other values. The scores were then used to generate ROC curves for the occurrence of CRS, ICANS, and the progression of CRS to grade ≥2 with CI generated through the Wilson/Brown method. Results: Of the 44 patients, 21 developed CRS alone, 12 developed ICANS+CRS, and 11 developed neither. 18 patients had progression of CRS to grade ≥2. The median day of onset for CRS, ICANS, and progression of CRS to grade ≥2 was 2, 5, and 4 days respectively. Day 3 post infusion yielded the highest values of area under the curve (AUC) with each variation of the m-EASIX score statistically significant with a p<0.001 as represented in table 1. The addition of P and IL-6 to the m-EASIX score increased AUC, sensitivity, and specificity for the occurrence of CRS, ICANS, and progression of CRS to grade ≥2. Conclusions: The inclusion of P and IL-6 in the m-EASIX score improved the sensitivity and specificity of detecting CRS, CRS progression, and the development of ICANS on the 3rd day post infusion. Larger scale studies investigating the efficacy of inclusion of P and IL-6 in the m-EASIX score in guiding early interventions to mitigate complications associated with CAR-T therapy are necessary. [Table: see text]