bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying mutations in ctDNA to predict antibody-drug conjugate response in breast cancer.
Authors: Chinea Luis , Chan Isaac , Chang Hannah 
Published: June 2024

e13074 Background: Metastatic breast cancer (mBC) is a complex disease, and outcomes remain poor because new therapies are needed. A new class of drugs, antibody-drug conjugate (ADC), has shown effectiveness across all breast cancer subtypes. Yet FDA- approval for these therapies is restricted only to HER2 and triple-negative subtypes. Therefore, we urgently need to identify which patients, regardless of subtype, will respond to ADCs. The advent of circulating tumor DNA (ctDNA) offers a unique noninvasive method to capture breast cancer (BC) heterogeneity. Recently, ctDNA testing has been employed in clinical practice to guide targeted therapies for mBC, particularly in cases of hormone receptor positive (HR+) disease with mutations in PIK3CA and ESR1. The clinical implications to predict response to ADC therapy in BC remains unclear. Here we test the hypothesis that ctDNA can detect mutations that predict response to novel ADCs. Methods: We analyzed a subset of patients from the Dallas Metastatic Breast Cancer Study comprised of patients with mBC who underwent ctDNA testing using the Tempus xF liquid biopsy ctDNA sequencing panel. The data was analyzed from a single academic medical center between the initial year of ctDNA collection in 2019 to 2023. We identified detectable mutations from patients and addressed a relationship by using Metascape. Relevant signaling pathways were identified: APOBEC, ErbB signaling, p53 and Ras-MAPK pathway. Patients with triple negative, HER2, and HR BC were examined for ADC response and associated mutations. Survival analyses were estimated using Kaplan-Meier and Gehan Breslow Wilcoxon test for statistical analysis. Results: We identified 43 patients with HR+ mBC who had at least one mutation within the Ras-MAPK pathway and 10 of 43 received ADC therapy. Median survival of patients who received ADC therapy 58 months (n=10) vs not receiving ADC therapy 33 months (n=33) (p < 0.05). Of the ten patients who received ADC treatment, 60% had 1+ HER2 staining on tissue biopsy. 70% of patients received Trastuzumab deruxtecan (T-DXd) and 30% received Sacituzumab govitecan (SG). SG was given to patients with negative HER2 staining on biopsy. Patients with at least one mutation within ABOBEC, ErbB signaling, and p53 pathways did not have statistically significant differences in mOS. Conclusions: In HR+ mBC, detection of mutated genes associated with the Ras-MAPK pathway by ctDNA was associated with a more favorable response when treated with ADCs. These findings are exciting because HR+ BCs are being targeted with ADCs regardless of HER2 or TROP2 expression, highlighting the need for new biomarkers to distinguish which HR+ patients to treat. Our retrospective analysis findings are limited by the number of patients with ctDNA testing and also timing of testing. Further studies are needed to solidify the observed correlation between Ras-MAPK pathway mutations and favorable response to ADC treatment.
Early tumor response in first‐line palbociclib plus AI in Chinese women with HR+/HER2- advanced breast cancer: Primary analysis of a multicenter, prospective real-world study.
Authors: Cao Wen-Ming , Li Xiaolin , Xu Zhengyang , Lu Haiqi , Chen Zhanhong , Chen Junqing , Wang Xiaojia , Hu Hai , Ye Weiwu , Wang Rong 
Published: June 2024

e13078 Background: The CDK4/6 inhibitors (CDK4/6i) and aromatase inhibitors (AIs) regimen is the first-line standard for HR+/HER2- advanced breast cancer. Despite this, high-risk patients often receive combination chemotherapy for quicker disease control, a practice supported by anecdotal evidence of the efficacy of the CDK4/6i and AI combination but lacking rigorous research validation. Early tumor shrinkage (ETS), a prognostic marker in colorectal cancer, remains undefined in HR+ breast cancer. This study (NCT04858997) aims to investigate the early effectiveness of the CDK4/6i and AI combination through ETS, addressing a significant gap in the literature. Methods: This study enrolled HR+/HER2- advanced breast cancer patients diagnosed between April 2021 and October 2023, who were treatment-naïve for their advanced disease and consented to palbociclib and AI therapy. Participants underwent CT scans to evaluate treatment response at baseline, week 4, week 12, and every 12 weeks thereafter. The study primarily investigated ETS, defined herein as a ≥10% reduction in the sum of diameters of target lesions by week 4. Secondary endpoints encompassed TTR, ORR, and PFS. Results: The study enrolled 30 patients with a median age of 55 years (range 29-76); 30% were premenopausal, and 40% presented with ≥3 metastatic sites. Visceral metastases were observed in 53.3% of the cohort (N=16). ETS was achieved in 73.3% of patients at the first assessment 4 weeks post-treatment initiation, with 68.8% in patients with visceral metastases and 78.8% in those without. The mTTR=3 months, differing between patients with visceral metastases (6 months) and those without (3 months). The overall response rate (ORR) was 63.3%. The ETS outcomes predict the best response in patients, with 77.3% reaching ETS eventually achieving partial or complete response (PR/CR), compared to only 25% of those not reaching ETS. Conclusions: This study validates the CDK4/6i and AI combination's early effectiveness in HR+/HER2- advanced breast cancer, showing that 4-week treatment responses predict best of response outcomes. Achieving ETS is closely linked to a higher likelihood of therapeutic success, underscoring its value as a prognostic marker for informed therapy choices.
Dose escalation and expansion results from the phase I study of F0024, a trophoblast cell-surface antigen 2 (TROP2) antibody-drug conjugate (ADC), in patients (pts) with advanced solid tumors.
Authors: Du Yiqun , Meng Yanchun , Wang Jingfen , Wang Ying , Wu Fan , Chen Yu , Chen Lilin , Qing Lihua , Qiao Yaya , Liu Kezhen , Sun Wenyi , Li Xiaowen , Zhang Jian 
Published: June 2024

e13131 Background: F0024 is an antibody-drug conjugate (ADC) targeting Trop-2, an intracellular calcium signaling transducer overexpressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. We assessed its safety and efficacy in patients with advanced solid tumors, mainly in triple negative breast cancer (TNBC). Methods: PTs with unresectable solid tumors refractory to/relapsed from standard treatment received F0024 on days 1 and 8 of 21-day treatment cycles. Primary objectives include maximum tolerated dose (MTD) identification, safety, and tolerability and secondary objectives include efficacy, pharmacokinetics, and incidence of anti-drug antibodies against F0024. Pts were eligible regardless of TROP2 level. Results: As of October 8, 2023, 62 pts were treated with≥1 dose of F0024. 21 pts were treated during dose escalation at 2.5 (n = 1), 5.0 (n = 3), 7.5 (n = 3), 10 (n = 4), 12 (n = 8), and 15 (n = 2) mg/kg and 41 pts with TNBC were treated in dose expansion at 10.0 (n = 30) and 12.0 (n = 11) mg/kg. 32 pts (51.6%) discontinued (20 (32.2%) due to disease progression per RECIST v1.1). Treatment emergent adverse events (TEAEs) regardless of causality were reported in 61 of 62 pts (98.4%; 34 pts [54.8%] experienced ≥grade 3, 9 pts [14.5%] had serious adverse events). Treatment related adverse events (TRAEs) were reported in 61 of 62 pts (98.4%; 32 pts [51.6%] experienced ≥grade 3, 4 pts [6.5%] had serious adverse events). The most common grade 3 TRAE were neutropenia (45.2%), leukopenia (33.9%), febrile neutropenia (4.8%), anemia (4.8%), and maculo-papular rash (4.8%). A total of 17 responses have been observed at the dose of 5.0 mg/kg or greater. 34 TNBC pts were dosed at 10 and 19 were dosed at 12 mg/kg with exposure to a median of 11.5 (1.0-26.0) and 4.0 (1.0-21.0) doses. 11 partial responses were achieved in 29 efficacy-evaluable TNBC pts at 10 mg/kg leading to an overall response rate (ORR) of 37.9% (95% CI 20.7% - 57.7%). The disease control rate of 10 mg/kg is 79.3% (95% CI 60.3%-92.0%). 5 escalation pts and 25 expansion pts remain on trial. Updated trial details/results will be presented. Conclusions: In this first-in-human study of F0024, treatment was generally well tolerated and MTD was not yet reached up to 12 mg/kg. F0024 demonstrated encouraging preliminary antitumor activity in heavily pretreated TNBC pts, especially in 10 and 12 mg/kg. Clinical trial information: NCT05174637 .
Learning from Black patients with TNBC to implement equitable cancer care.
Authors: Leach Virginia , Regnante Jeanne , Karmo Maimah , Wittig Lizzie , Cooper Goff Shanda , Peoples Krista 
Published: June 2024

e13141 Background: Black women are at higher risk of being diagnosed with the breast cancer sub-type Triple-Negative Breast Cancer (TNBC) than their white peers. This is the first patient experience survey for Black women diagnosed with TNBC. Tigerlily Foundation (TLF) conducted a TNBC survey of BIack women to understand the patient experience throughout the cancer continuum of care. Methods: The survey instrument received an IRB exception and included 40 questions organized by the seven themes: Demographics, Self-Detection/Early Assessment, Screening to Diagnosis, Diagnosis to Treatment, Post Treatment and Palliative Care/Survivorship, Emotional Trauma and Mental Health, and Trust/Bias. Data collection occurred between December 2022 and January 2023. Two methodological approaches influenced this unique study design: 1) a Health Literate and Culturally Sensitive approach and 2) a Trusted Outreach approach. The survey was sent to leaders of patient-based organizations who distributed the survey with their community members. Results: All participants (N = 106) racially identified as Black women diagnosed with TNBC. The age of participants ranged from 25–71. Participants were not always given information to manage their expectations before or after the screening process, as 38% reported they did not receive such information, while 45% reported they did. The number of times participants required diagnostic imaging ranged from only once (24%), two-three times (41%), four-five times (17%), or greater than six times (11%). Biopsies also varied among participants from one (25%), two-three times (40%), four-five times (15%), or greater than six times (8%). Many participants experienced a diagnosis change, and 57% were initially diagnosed with a different breast cancer subtype, while 24% were initially diagnosed with TNBC. Most of the participants stated their doctor seemed knowledgeable working with them as a newly diagnosed TNBC patient (55%), many were unsure if their doctor seemed knowledgeable working with them as a newly diagnosed TNBC patient (30%), and others said their doctor did not seem knowledgeable (18%). The range of follow-up care received varied. The follow-up care identified was palliative care services (including mental health services, nutrition consultation, etc.) (32%), risk management (11%), high-risk tracking and education program (28%), survivorship support (42%), other services (4%), and no follow-up care services (5%). Conclusions: Prospective implementation science is needed to ensure equitable care standards are sustainably provided to Black women. It is imperative to understand the cancer care continuum from the perspective of the patients from what they think of the care received and care they would have liked to receive. TLF successfully reached Black TNBC patients to share their authentic experiences and provided a framework for other research institutions and patient advocacy groups to do the same.
Identifying and addressing real-world challenges to triple-negative breast cancer (TNBC) care: A quality improvement initiative.
Authors: McKinnon Kelly E. , Bardia Aditya , Alemar Jose , Dewald Ilona , Storey Janet , Dooyema Samuel , Carter Jeffrey D. , Heggen Cherilyn 
Published: June 2024

e13143 Background: Recent introduction of novel therapies into advanced TNBC management has greatly increased complexity of care. This study aimed to identify real-world challenges and practice gaps in evidence-based treatment for TNBC in the community oncology setting. Methods: In March-August 2023, 48 health care providers (HCPs) at 4 US community oncology clinics completed surveys on practice gaps and challenges related to care delivery, treatment selection, adverse event management, and shared decision making (SDM) in TNBC. HCPs (n=47) then participated in audit/feedback (AF) sessions to review clinical evidence and develop clinic-specific action plans to address identified gaps. Follow-up surveys evaluated the impact of real-world clinical practice changes stemming from the initiative. Results: HCPs reported sequencing of therapies across multiple lines of treatment, coordinating care and care transitions, and providing patient-centered supportive care as their top 3 challenges. They also reported challenges with managing adverse events, particularly neutropenia (46%) and cardiotoxicity (25%). Most HCPs (~70%) reported providing nutritional support services, healthy lifestyle counseling, and financial counseling, while distress screening, quality of life assessment, and end-of-life counseling were less frequently used (~40%). Two-thirds of HCPs said that they often or always engaged in SDM with their patients, with top barriers identified as lack of time, patients’ low health literacy, and lack of support staff. Changes that were considered most likely to improve care were improved collaboration across interprofessional teams (31%) and improved follow-up and monitoring for early signs of recurrence/progression (21%). When asked about support necessary to for changes across their healthcare system, HCPs selected improved workflows/protocols to support collaboration across disciplines (tumor boards, specialty care teams, etc) as their top resource need. After the AF sessions, action plans included use of new communication channels to discuss patient side effects or confirm plans for biomarker testing, improved treatment sequencing protocols, workflow standardization for patients transitioning to specialty care teams, and implementation of checkpoints to ensure continued patient engagement and timely identification of adverse events. On a follow-up survey, clinics reported they had improved follow-up and monitoring for adverse events (83%) and were engaging patients more frequently in SDM (67%). Conclusions: Community oncology clinics face multiple ongoing challenges that may be impeding the ability to integrate newer therapies into TNBC management. Further research on multidisciplinary communication, collaboration, and needed workflow changes has the potential to improve care for patients with TNBC.
Effect of AURKA targeting on nuclear PD-L1 and the efficacy of immune checkpoint inhibitors in triple-negative breast cancer.
Authors: Takchi Andrew , D'assoro Antonino Bonaventura 
Published: June 2024

e13153 Background: Aurora-A mitotic kinase (AURKA) plays a role in Triple Negative Breast Cancer (TNBC) progression through activation of epithelial to mesenchymal transition (EMT)-mediated cancer cell plasticity. Cancer cells that undergo EMT acquire a CD44high/CD24low and/or ALDHhigh cancer stem-like phenotype (Cancer Stem Cells) characterized by intrinsic drug resistance. Cancer Stem Cells (CSCs) shows high PD-L1 expression that induces tumor immune escape through CD8+ T-cells exhaustion. Significantly, “undraggable” nuclear PD-L1 may play a key role in induction of immune therapy resistance and cancer cell plasticity. Methods: (1) TNBC Models: MDA-MB 231, unique MDA-MB 231/LM Durvalumab resistant (DUV-R) and TNBC-M40 cells established from metastatic PDXs; (2) In Vitro Studies: TNBC cells were treated with the AURKA inhibitor alisertib (50nM). PD-L1 expression was evaluated by immunoblotting. Apoptosis was measured by immunofluorescence using Cleaved-PARP antibodies. To assess stemness capacity, TNBC cells were cultured under non-adherent conditions to form mammospheres. ALDH activity (functional stemness marker) was measured using the Aldefluor Kit. (3) In Vivo Studies: 1x106 MDA-MB 231/LM cells were injected into the mammary fat pad of humanized NSG-CD34+ female mice. Animals were treated with anti-PD-L1 ICI atezolizumab (20 mg/Kg) and alisertib (25 mg/Kg) as monotherapy or in combination. 1x106 MDA-MB 231/LM cells were also injected into the mammary fat pad of humanized NSG-CD34+ female mice and treated with durvalumab (20 mg/Kg) to develop durvalumab-resistant models. PD-L1, CD44, Vimentin expression and tumor infiltration of CD8+ T-cells were assessed by immunofluorescence. Results: Treatment of MDA-MB 231/LM xenografts with alisertib decreased the levels of CD44 and PD-L1 expression and increased CD8+ T-cells tumor infiltration. Because PD-L1 genetic targeting enhanced in vitro alisertib-induced apoptosis, MDA-MB 231/LM xenografts were treated with alisertib and the anti-PD-L1 ICI atezolizumab. Com- bination of atezolizumab and alisertib resulted in the reduced expression of the EMT marker vimentin that was linked to lack of organ metastasis. Combination of atezolizumab and alisertib also induced a significant reduction of ALDHHigh CSC in ex-vivo 3D-Organoids established from TNBC-M40 cells. MDA-MB 231/LM DUV-R cells showed increased nuclear PD-L1 compared to parental cells. The combination of alisertib with Immune Checkpoint Inhibitors (ICIs) induced apoptosis of MDA-MB 231/LM DUV-R cells through down-regulation of intra-tumoral nuclear PD-L1 expression. Conclusions: This study provides innovative pre-clinical rationale for combining AURKA inhibitors with ICIs to reduce “ undruggable” nuclear PD-L1 expression and impair cancer cell plasticity of metastatic TNBCs that currently have limited effective therapeutic options.
A meta-analysis of the difference in response to trastuzumab-deruxtecan (T-DXd) based on HER2 immunohistochemistry (IHC) in HER2 low metastatic breast cancer (mBC).
Authors: Ashok Kumar Prashanth , Sandhu Michael , Sravanthi Metlapalli Venkata , Suresh Kumar Vishnu Charan , Benjamin Sam 
Published: June 2024

e13164 Background: HER2 low BC have an IHC staining of 1+ or 2+ with negative fluorescence in situ hybridization (ISH). Although T-DXd is approved for this, difference in activity between 1+ and 2+ is uncertain. Methods: A systematic search with controlled vocabulary encompassing BC and T-DXd was conducted in PubMed, Embase, Scopus, and Cochrane on November 11 2023 with no search restrictions. 2318 records were identified and duplicates were removed using Mendeley. The remaining 1189 records were imported into Rayyan, and the titles were screened independently by 2 reviewers. 47/75 full texts were relevant, of which 4 [3 clinical trials, 1 retrospective study] were included for analysis. Only studies that provided outcome data for HER2 1+ and 2+ ISH- were included. RevMan was used to analyze the Risk Ratio (RR) and Odds Ratio (OR) with 95% Confidence Interval (CI), derived from Random Effects (RE) model with Mantel-Haenszel (MH) method. Pooled proportions (PP) were determined using OpenMeta. Results: There were a total of 264 patients in 1+ and 204 in 2+ISH-. Median age was 57 years. All studies had pre-treated mBC. T-DXd dose was at least 5.4 mg/kg every 3 weeks. Visual inspection of our funnel plots revealed no bias. PP (3/4 studies) for patients achieving an Objective Response Rate (ORR) [Complete Response (CR)+Partial Response (PR)] was 42.9% (31.6-54.2%) in 1+ and 38% (26.3-49.7%) in 2+. The median Progression free survival (2/4 studies) was 8.6 (1+) and 7.95 (2+) months respectively. RE RR (3/4 studies) for Progressive Disease (PD) showed no difference between 1+ and 2+ [0.93 (0.80, 1.10), p=0.4, I²=0%]. Similarly, RE OR (3/4 studies) for Disease Control Rate (DCR) [CR+PR+Stable disease (SD)] [1.20 (0.78, 1.85), p=0.41, I²=0%], ORR [1.17 (0.58, 2.34), p=0.66, I²=0%], and PR [1.05 (0.52, 2.11), p=0.89, I²=0%] showed no significant difference between 1+ and 2+ (Table). Conclusions: Our results indicate no difference in response to T-DXd between 1+ and 2+, solidifying its role as a treatment option in HER2 low mBC. Limited number and heterogeneity between studies are limitations of our study, which ought to be addressed in future trials through clear subgroup stratification between 1+ and 2+. [Table: see text]
Everolimus for advanced breast cancer: Is the histological subtype important?
Authors: Vargas Alicia , Flores Paco Pablo , De La Haba Juan , Morales-Estevez Cristina , Rodríguez-Alonso Beatriz , Porras Ignacio , de la Cruz-Merino Luis , Muñoz Clara , Lorente Margarita , González Flores Encarnación , Sanchez-Rovira Pedro , Arenas Rafael , Armenta Ana , Aranda Enrique 
Published: June 2024

e13165 Background: Invasive lobular (L) breast carcinomas (BC), which account for up to 15% of all BC, had particularly histopathological characteristics: tends to be estrogen/progesterone receptor positive and HER2-neu negative and as such are treated with endocrine therapy (ET). It had been demonstrated a frequent activation of PI3K–AKT–mTOR signaling in LBCs, suggesting this pathway to be a promising therapeutic target for LBC. Interestingly, in some of these patients, the subsequent use of a mTOR inhibitor (everolimus) combined with an ET produced greater clinical benefits. Our aim is to evaluate the efficacy of everolimus in advanced BC (ABC) in the usual clinical practice, focusing on LBC. Methods: We retrospectively analyzed 147 women with ABC from four Spanish hospitals who were treated with everolimus (Ev) in second or successive lines of treatment between 2014-2023. We performed a descriptive statistical analysis of the clinicopathological variables and calculated the investigator-assessed time to treatment failure (TTF), defined as the interval from initiation of treatment to its premature discontinuation (because of progression disease (PD) or toxicity), as well as its association using Kaplan-Meier test. Survival curves were analyzed using long-rank test. Finally, we analyzed the subgroup of those with everolimus TTF (TTF2) longer than previous line TTF (TTF1) by Xi2 test. Results: With a median (m) age of 59, 21 (14%) patients (pts) were diagnosed with advanced LBC. The histopathological characteristics of the pts are shown (Table). Treatment had to be stopped in 24 pts due to toxicity (oral mucositis 21%), and the rest was due to PD or exitus. The response rate (stabilization, partial and complete response (CR)) was 49% with 4% of CR. The overall m of TTF2 was 9,1 months, while the TTF1 m was 9,5 months. Analyzing by histology, TTF2 m was 18.16 months in LBC vs 7.85 in ductal BC (p=0.01). Contrary to expectations, 40 pts (27,2%) had a longer TTF2 compared with TTF1 (p>0.001). When analyzing this subgroup we found 9 pts with LBC and 27 DBC (p>0,05). 26 pts (65%) had not received previous line with HT (p=0.005). On the other hand, when analyzing the subgroup of pts with LBC, up to 47.36% of pts had TTF2>TTF1. Conclusions: The use of everolimus in pts with LBC appears to be more effective than in DBC according to the results reported in our series and its use in initial hormonal lines may be reconsidered. However, we need more prospective studies differentiating histologies to demonstrate our results for others Pi3k inhibitors. [Table: see text]