bluuebunny/crossref_metadata_2025 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]
Evolution of germline BRCA1/2 testing practices: A five-year comparative analysis among oncology providers and patients.
Authors: Effange Doreen , Buras Robert Richard , Gast Kelly C. , Larsen Haidle Joy , Shockney Lillie D. , Yung Rachel Lynn , Demirhan Kimberly , Kisiel Molly , Plotkin Elana
Published: June 2024

e13172

Background: The Association of Cancer Care Centers (ACCC) launched a quality improvement initiative in 2018 to address suboptimal germline BRCA1/2 testing rates and identify barriers impeding testing for patients with early-stage or metastatic breast cancer. Between 2018 and 2023, changes in clinical guidelines led to expanded testing criteria and increased referrals for genetic testing. A follow-up survey in 2023 aimed to assess changes in testing practices and challenges faced by cancer care teams, considering the evolving landscape of genetic testing and the impact of the COVID-19 pandemic. Methods: In 2018, a survey of 95 oncology providers was conducted to explore provider characteristics, testing characteristics, and challenges/barriers to germline BRCA 1/2 testing. The survey was conducted again in 2023 for comparative analysis with a response of 115 oncology providers. The surveys explored provider characteristics, testing practices, and challenges/barriers to germline BRCA1/2 testing. To comprehensively understand the patient's perspective, an additional survey was conducted in October 2023, involving 61 individuals recently diagnosed with breast cancer to evaluate the patient experience with germline BRCA 1/2 testing and subsequent follow-up. Results: The adoption of expanded testing criteria, which influenced changes in clinical guidelines, has led to a substantial increase in referrals for genetic testing. The utilization of genetic testing by medical oncologists experienced a notable surge with 64% of survey respondents in 2023 reporting that medical oncologists most often initiated tests for germline BRCA1/2 mutations, compared to 29% in 2018. Patients’ awareness and engagement were high, with 82% undergoing germline BRCA1/2 testing, 48% undergoing testing at diagnosis, 33% before treatment, and 13% during treatment. In 2023, 23% of providers reported routinely ordering germline BRCA1/2 testing for patients with early-stage breast cancer, marking a threefold increase from the 2018 survey results. For patients with metastatic breast cancer, 41% of providers routinely ordered BRCA mutation testing, a threefold increase from 14% in 2018. While testing rates improved, challenges and barriers persist such as patient concerns (47%), access to genetic counselors (42%), turnaround time for test results (36%), and reimbursement issues (28%). Conclusions: The comparative analysis revealed a moderate improvement in germline BRCA1/2 testing practices, with increased provider engagement and patient awareness. Despite progress, challenges persist, needing multi-pronged efforts to enhance testing uptake and distribute critical information on testing to patients. The results indicate positive trends but underscore the importance of addressing barriers for comprehensive patient care.
Antibody-drug conjugates (ADC) in patients with advanced/metastatic HER2-low expressing breast cancer: A systematic review and meta-analysis.
Authors: Michelon Isabella , Dacoregio Maria Inez , Vilbert Maysa , N. Priantti Jonathan , Castro Caio , Vian Lucas , Cavalcante Ludimila
Published: June 2024

e13174

Background: Historically, HER2-targeted therapies failed to improve survival of patients with HER2-low-expressing tumors. Recently, trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC), demonstrated superior outcomes compared with treatment of physician´s choice (TPC) in this population. Other ADCs have also shown encouraging results, including sacituzumab govitecan (SG), MRG002, and RC48-ADC. Hence, we performed a systematic review and meta-analysis to assess the effectiveness of ADCs in patients with HER2-low advanced/metastatic (a/m) breast cancer (BC). Methods: We searched PubMed, Embase, and Cochrane databases and ASCO, ESMO, and SABCS websites for studies evaluating ADCs on patients with HER2-low a/mBC. Outcomes of interest were objective response rate (ORR); disease control rate (DCR); clinical benefit rate (CBR); progression-free survival (PFS); and overall survival (OS). We used R software (v.4.2.2) and random effects models for all analyses. Heterogeneity was assessed using I2 test. Results: Overall, 12 studies were included (3 real-world studies and 9 clinical trials), with 1,292 HER2-low a/mBC patients, 378 received TPC, and 914 received ADCs. Most were treated with T-DXd (63%, n=572), SG (29%, n=268), MRG002 (6%, n=56), and RC48-ADC (2%, n=18). Median age ranged from 48.1 to 58 years, and follow-up from 9.5 to 18.4 months. Patients treated with T-DXd achieved a significantly higher ORR and DCR compared to those who received SG, RC48-ADC, and MRG002 (Table). CBR was numerically higher in patients on T-DXd than those on SG but did not reach a significant difference. Patients with HR-positive tumors treated with SG had an ORR of 45% (95% CI 23 – 67%), and patients with pure HER2-low treated with any ADC, had an ORR of 38% (95% CI 30 – 45%). In the pooled analysis of 3 RCTs, ADCs significantly prolonged PFS compared with TPC (n=963, HR: 0.44, 95% CI 0.32 – 0.61, I2 = 66%, p<0.001), and OS (n= 680, HR: 0.56, 95% CI 0.36 – 0.89, I2 = 73%, p=0.015). Patients on ADCs also achieved a greater anti-tumor response than TPC, including better ORR (OR: 4.18, 95% CI 2.40 - 7.28, I2 = 52%, p<0.001), DCR (OR: 2.82, 95% CI 2.06 - 3.85, I2 = 7%, p<0.001), and CBR (OR: 3.41, 95% CI 2.36 - 4.93, I2 = 25%, p<0.001). Conclusions: Our systematic review and meta-analysis supports the efficacy of ADCs in HER2-low a/mBC patients over TPC. Future studies should focus on bringing ADCs into earlier lines of therapy in this population.Anti-tumor activity of ADCs presented as overall % (95% CI). [Table: see text]
Low-dose radiation as a preconditioning regimen for dendritic cell vaccines.
Authors: Kwon Eric , Namen Shelby , Kang Solomon , Willoughby Colin , Zhang Kevin , Pandey Guarav , Yang Joanna Chensi , DeSelm Carl
Published: June 2024

e14519

Background: Dendritic cells are potent antigen-presenting cells that induce the adaptive immune system to protect against cancer. While anti-tumor immunity can be improved with dendritic cell vaccines, it is not fully known what approved preconditioning agents, if any, improve dendritic cell vaccine-induced antitumor T-cell response and tumor elimination. We explored the effect of low-dose radiation (LDR), cyclophosphamide, and paclitaxel as preconditioning regiments for a dendritic cell vaccine. Methods: KP tumors were engineered with ovalbumin and orthotopically injected subcutaneously (SQ) into the flank of wild type B6 mice. Preconditioning regiments of a control, LDR (2 Gy), cyclophosphamide (20mg/kg), LDR (2 Gy) + cyclophosphamide (20mg/kg), and paclitaxel (20mg/kg) were given on day 4. Bone marrow dendritic cells (DCs) were electroporated with ovalbumin peptide SIINFEKL and then one million cells were injected i.v. on day 5 and 8. Blood collection was done and ovalbumin-specific T-cell populations were examined by tetramer staining for SIINFEKL-specific TCR over time. Tumor size was measured over time and survival data was analyzed accordingly. Results: LDR effectively produced a significant increase in CD8+ SIINFEKL tetramer+ T-cell count per uL of blood compared to the non-preconditioned group. In addition, this LDR preconditioning regiment produced a significantly improved tumor response over time. The overall survival rate of subjects receiving LDR was significantly improved compared to all other groups. Conclusions: Here, we find that LDR is most effective as a preconditioning regimen prior to dendritic cell vaccination for inducing an antitumor T-cell response and achieving tumor control over time. LDR provides a promising method to supplement dendritic cell vaccination and potentially improve patient outcomes. Further study is needed to confirm its efficacy.
Analysis of proteomics based on LC-MS detection on the efficacy of immunocombined therapy for hepatocellular carcinoma.
Authors: Wang Nanya , Yan Yueqi , Wang Shibo , Liu Bo , Li Yu , Wang Ying
Published: June 2024

e14549

Background: Combined immunotherapy has become the preferred treatment for HCC. However, it faces challenges: possible serious adverse reactions, the low objective response rate, and the median overall survival is about 20 months, which is far from meeting the clinical treatment needs. There is still a lack of effective predictive biomarkers in clinical practice to screen the dominant population of combined immunotherapy. The purpose of this study is to use LC-MS to screen and identify differential metabolites between patients with different efficacy to help screen the dominant population of clinical immunotherapy. Methods: 38 HCC patients were included who were treated in the Tumor Center of the First Hospital of Jilin University from June 2020 to March 2022 and received combined immunotherapy. Sample collection and follow· -up, and collect basic clinical data. The enrolled patients underwent enhanced CT examination every 3 treatment cycles, and the efficacy of the patients was evaluated according to the solid tumor efficacy evaluation standard 1.1 (RECIST V1.1). The serum of patients before treatment was detected by LC-MS, and the difference of mass spectrometry data between patients with different curative effects was compared, and the differential metabolites were explored by proteomics analysis. Results: The best of response was partial response in 7 patients (22.6 %), stable disease in 6 patients, and progressive disease in 18 patients (58.1 %). Based on LC-MS proteomics analysis, differential metabolites between patients with different therapeutic effects were screened and identified, namely Q9Y275, Q56UQ5, P13611, and P30530 (P < 0.05). The relative abundance of Q9Y275, Q56UQ5, P13611 and P30530 in the disease control rate group was higher than that in the PD group. Conclusions: Based on LC-MS proteomics analysis, four types of differential metabolites between different populations of PLC patients receiving combined immunotherapy were screened and identified, namely Q9Y275, Q56UQ5, P13611 and P30530.
Novel TROP2-targeted CAR T cells with high specificity and sustained efficacy for solid tumors in animal models.
Authors: Liu Chih-Chun , Kuo Tzer-Min , Lai Jiann-Shiun , Lai Ming-Tain
Published: June 2024

e14563

Background: CAR T cell therapy, successful in hematological malignancies, encounters challenges against solid tumors due to immune exhaustion and senescence within the tumor microenvironment. The imperative need for an optimal tumor target antigen is evident in advancing CAR T therapy. TROP2, a membrane-associated glycoprotein, is highly expressed in diverse cancers, including cervical, bladder, esophageal, ovarian, and endometrial cancers. TROP2 overexpression, approaching 100% in cervical and hormone-resistant prostate cancer, correlates inversely with prognosis and survival, presenting TROP2 as a promising CAR T therapy target. This study engineered the novel TROP2 antibody R4702, featuring a distinct binding epitope from Sacituzumab and Datopotamab, to develop TROP2-specific CAR T cells and evaluated their efficacy against a spectrum of solid tumors. Methods: Expansion of CAR T Cells and Cytotoxicity: CAR T cells were created through lentivirus-mediated genetic engineering with the TROP2 antibody, followed by 10 days of expansion. T cell differentiation was evaluated, and luciferase-encoding target cells incubated with varying CAR T cell ratios overnight were quantified luciferase activity. In Vivo Efficacy and Persistence: CAR T cells were adoptively transferred into ASID mice with tumors. In vivo tumor imaging used luciferase activity, and calipers monitored tumor size weekly. CAR T cell persistence assessed their ability to suppress rechallenged tumor growth. Results: R4702, a novel TROP2-specific antibody, displayed high binding affinity to a distinct epitope. Post- ex vivo expansion, R4702 CAR T cells showed a substantial increase (100 to 200-fold) over 10 days, with a high expression level (50~80%) of R4702 CAR on T cells. Over 60% of R4702 CAR T cells displayed a less differentiated status, characterized by a CD62L+ population comprising TSCM and TCM. In vitro cytotoxicity revealed potent and specific efficacy against various TROP2-positive cancer cell lines, with no observed killing activity against TROP2-negative cells. In vivo efficacy of R4702 CAR T cells demonstrated 100% tumor growth inhibition within 30 days post-treatment across diverse xenograft models. Importantly, R4702 CAR T cells exhibited enduring anti-tumor efficacy against successive tumor challenges in xenograft models of pancreatic, gastric, NSCLC, TNBC, and ovarian cancers. In a head-to-head comparison with Sacituzumab and Datopotamab CAR T, R4702 demonstrated superior anti-tumor efficacy to Sacituzumab and comparable efficacy with Datopotamab in the BxPC-3 CDX model of pancreatic cancer. Conclusions: A novel TROP2-specific R4702 CAR T cell, developed, showcased robust tumor-killing capabilities. The anti-tumor activity persisted upon repeated tumor challenges across various xenograft models, underscoring the potential of R4702 CAR T cells as a promising therapeutic strategy.
Effect of RIPK3 on non-canonical PANoptosis to suppress anti-tumor immunity in lung cancer.
Authors: Zhong Hua , Yang Yv , Wang Yue , Wu Erpeng
Published: June 2024

e14565

Background: Hypoxia and glucose deprivation are common features of solid malignancies and considered the causes of tumor necrosis, while the molecular mechanisms of tumor cell death and its impact on tumor progression are not yet clear. PANoptosis is a newly recognized programmed cell death pathway, characterized by the simultaneous activation of necroptosis, apoptosis and pyroptosis. The canonical PANoptosis is controlled by an ASC-dependent multimeric protein complex named the PANoptosome. Methods: Using immunoblot and immunofluorescent analysis, we described the RIPK3 expression patterns and detected the programmed cell death markers in lung cancer tissues. We built a RIPK32×Fv-Flag-expressing PKLC cell line and identified the key molecules involved in tumor cell death by using MS analysis of RIPK3-immunoprecipitate. These molecules were confirmed by CRISPR-Cas9 mediated gene knockout. Then we analyzed the secretome by 4D-diaXLMS of cell death conditioned medium and identified a variety of DAMPs and cytokines released by PANoptotic tumor cells. Last, the differences of tumor growth and the immune microenvironment between wild-type and Ripk3 KO PKLC-CDX were compared. Results: Hypoxia and glucose deprivation could induce over expression of RIPK3 and mediated PANoptosis of tumor cells. The oligomerized RIPK3 rapidly recruits MLKL and mediates MLKL phosphorylation to induce necroptosis. Further aggregated RIPK3 can recruit RIPK1 and assembles with FADD and Caspase-8, causing Caspase-8 auto-cleavage. Active Caspase-8 can directly cleave caspase-3 and GSDMD to induce apoptosis and pyroptosis. The PANoptosis we described is initiated by RIPK3 and independent of ASC, which we termed non-canonical PANoptosis. We also found that Caspase-3, as an executor of apoptosis, is able to cleave RIPK3, RIPK1 and truncated GSDMD, negatively regulating PANoptotic cell death. Finally, we identified a variety of DAMPs released by PANoptotic tumor cells, which facilitate neutrophil differentiation and activation, promoting tumor progression by suppressing anti-tumor immunity. Conclusions: Hypoxia and glucose deprivation induce non-canonical PANoptosis that is initiated by RIPK3 and independent of ASC. The PANoptotic tumor cells suppress anti-tumor immunity through releasing DAMPs and cytokines to mediate neutrophil differentiation and activation, which promote lung cancer progression.
Pre-clinical safety and efficacy evaluation of sodium chloride nanoparticles for treating non-muscle invasive bladder cancer.
Authors: Gdowski Andrew , Kim Lucia , Lai Xining , Ma Xinrui , Raupp John , Zhan Shuyue , Beckabir Wolfgang , Sturdivant Michael , Wobker Sara Elizabeth , Li Zibo , Xie Jin , Kim William Y.
Published: June 2024

e14591

Background: Non-muscle invasive bladder cancer (NMIBC) presents a significant therapeutic challenge. Current treatment modalities such as BCG and intravesical chemotherapy given after transurethral resection of bladder tumors (TURBT), while effective, are associated with high cost burdens and are difficult for patients to tolerate due to side effects. This ultimately limits treatment regimen duration and decreases the effectiveness of the therapy which frequently leads to local recurrence. Sodium Chloride Nanoparticles (NaCl-NPs) have previously shown promise in preclinical models of intra-tumoral injection of various tumor types but has not been tested in more clinically relevant models of bladder cancer. In this study, we evaluate the safety and efficacy of NaCl-NPs as a local intravesical therapy for preventing tumor development in a preclinical murine model of bladder cancer. Methods: We conducted a dose escalation experiment via intravesical instillation of increasing doses of NaCl-NPs (300 ug/ml-2700 ug/ml, n=3 mice per group) to identify the maximum tolerated dose. Mice were treated on a weekly dosing schedule and toxicity was evaluated at day 35 as a composite of: evaluation of bladder histology with Hematoxylin and Eosin (H&E) staining by a board-certified pathologist, blood chemistry measurements, complete blood counts, as well as body weight measurement. Secondly, we assessed the efficacy of the nanoparticles through a tumor prevention experiment where MB49 bladder cancer cells were instilled in the murine bladder and shortly after treated with intravesical: 1.) Saline, 2.) Gemcitabine, or 3.) NaCl-NPs for 1 hour (n=18 per group). Mice were monitored for tumor development with 3D bladder ultrasound. In additional, overall survival (OS) was assessed. Results: The dose escalation study showed that there was no local or systemic toxicity in the NaCl-NP treated mice, even at the highest concentration (2700ug/ml). The tumor prevention study showed that mice treated with NaCl-NPs had a significant 2.55 fold reduction in tumors that developed at 4 weeks compared to saline (22% vs 56% respectively, p <0.05). This reduction was similar to that seen with intravesical gemcitabine, which is clinically, a standard of care intravesical chemotherapy. We also found an improvement in overall survival in the NaCl NP group with 70% of mice alive at 60 days compared to the other treatment groups (65% gemcitabine; 40% saline). Conclusions: Our findings suggest that NaCl-NPs could provide a safe and effective alternative therapy for preventing recurrence of NMIBC following transurethral resection of bladder tumors. This opens avenues for safer treatment protocols that can mitigate the side effects commonly seen in the management of early-stage bladder cancer.
Envafolimab plus chemotherapy as neoadjuvant therapy for resectable esophageal squamous cell carcinoma (ESCC): A prospective, single-arm, phase II study.
Authors: Zhao Jinbo , Yan Xiaolong , Bai Yuquan , Duan Hongtao , Jiang Tao
Published: June 2024

e14633

Background: Currently, chemotherapy plus PD-1 inhibitor immunotherapy has become a promising option in the neoadjuvant setting of resectable ESCC, nevertheless, the PD-ligand 1 (PD-L1) blockade-based combination has rarely been investigated to date. Envafolimab is the first and only globally approved subcutaneous (SC) PD-L1 inhibitor, which has shown satisfactory efficacy and safety profile in tumors. This Simon’s two-stage, phase II study explored the safety and feasibility of SC administration of envafolimab as an alternative to intravenous (IV) administration of PD-1/PD-L1 inhibitors in the neoadjuvant therapy of resectable ESCC. Here, we reported the results of the stage 1. Methods: In this Simon’s two-stage, phase II study, patients initially treated with locally advanced and resectable (stage II-IVA) ESCC were enrolled and received envafolimab (300mg, SC, day 1), albumin-bound paclitaxel (130mg/m2, IV, days 1 and 8), and carboplatin (AUC = 5, day 1) every 3 weeks for 3 cycles. The primary endpoints were safety and pathological complete response (pCR). A Simon’s two-stage design was utilized with following assumptions. Target accrual was 13 patients in the first stage (If 3 or more patients had pCR in stage 1, study could continue in stage 2), total 34 patients were enrolled in the stage 2. Secondary endpoints were major pathological response (MPR). Safety was assessed by adverse events (AEs) and postoperative complications. Results: Between October 2022 and April 2023, 13 (81.3%) of 16 enrolled patients completed neoadjuvant therapy and underwent surgery. All 13 (100%) surgical patients underwent successful R0 resection; of whom, 8 (61.5%) achieved pCR and 9 (69.2%) achieved MPR, respectively. Downstaging occurred in 10 (76.9%) of 13 patients. pCR and MPR were identified to be associated with tumor downstaging but not with PD-L1 expression. CPS levels in MPR and pCR group were significantly higher than that in Non- MPR and Non-pCR group. Grade 3-4 treatment-related AEs (TRAEs) and immune-related AEs (IrAEs) occurred in 12.5% and 37.5% of 16 patients, respectively. 10 (76.9%) of 13 patients reported postoperative complications. No treatment-related surgical delay or death occurred. Conclusions: Envafolimab plus chemotherapy as neoadjuvant therapy demonstrated promising antitumor activity for resectable ESCC with high rates of pCR, MPR and R0 resection, as well as acceptable tolerability. Based on the encouraging efficacy of our regimen in the first stage, we will continue the enrollment of patients in stage 2. Keywords: Esophageal squamous cell carcinoma; Envafolimab; Neoadjuvant therapy; Chemotherapy Clinical trial information: NCT05552651 .
Impact of time-of-day infusion of camrelizumab combined with chemotherapy on efficacy in advanced malignant tumors.
Authors: Sun Li-Yue , Xu Xian , Xu Quan-An , Xian Ke-Xin , Zeng Xin-Xin , Li Hua-Gen , Zhang Xu-Hui
Published: June 2024

e14634

Background: The combination of immune checkpoint inhibitors (ICIs) with chemotherapy has emerged as a standard first-line treatment strategy for advanced cancers. Camrelizumab and Tislelizumab, representative ICIs, have approval by the Chinese NMPA for first-line treatment of advanced cancers such as lung cancer and esophageal cancer. Previous studies have indicated that the timing of drug administration can influence the efficacy of ICIs. However, studies on the ICIs plus chemotherapy are lacking. Therefore, we conducted a retrospective study to explore the effect of the timing of infusion on patients with advanced cancer undergoing treatment with ICIs combined chemotherapy. Methods: We retrospectively enrolled a total of 253 patients diagnosed with advanced cancers between 2017 and 2023 in Guangdong Second Provincial General Hospital. Among these patients, 109 received camrelizumab (Cam cohort) plus chemotherapy and 65 received tislelizumab (Tis cohort) plus chemotherapy. Patients were grouped into morning (AM) and afternoon (PM) categories based on the timing of their ICIs administration (< 1 times versus ≥ 1 times after 16:00). The Response Evaluation Criteria in Solid Tumors Criteria V.1.1 was used to evaluate the response to treatment. The primary endpoint was progression-free survival (PFS). Results: The results consistently showed that the PM group had a longer PFS than the AM group in the overall patients (p < 0.01). In the Cam cohort, the PM group (n = 48) exhibited a longer PFS compared to the AM group (n = 61) (16.8 months vs. -, p = 0.02). However, no significant difference in PFS was observed among patients in the Tis cohort (AM vs. PM, n = 34 vs. n = 31, 16.1 months vs. -, p = 0.51). Subgroup analyses indicated that the PM group had a more favorable PFS treatment effect in most subgroups. The incidence of any Treatment Emerged Adverse Event (TEAE) (Cam cohort, AM vs. PM, 98.52% vs. 92.68%; Tis cohort, AM vs. PM, 97.05% vs. 100.00%) and grade 3 TEAEs (Cam cohort, AM vs. PM, 5.80% vs.7.30%; Tis cohort, AM vs.PM - vs. 12.90%) was similar in the Cam cohort and Tis cohort. The most common adverse events are anemia (Cam cohort vs. Tis cohort, 70.58% vs. 79.41%), thrombocytopenia (Cam cohort vs. Tis cohort, 54.41% vs. 58.82%) and lymphopenia (Cam cohort vs. Tis cohort, 44.11% vs. 44.11%). Conclusions: The findings of this study highlight a significant variation in daily rhythms among advanced cancer patients undergoing treatment with ICIs plus chemotherapy. Interestingly, a trend was observed in patients treated with camrelizumab, where those receiving treatment in the afternoon demonstrated a longer PFS. However, this trend was not observed in patients treated with tislelizumab. These results suggest that time-of-day infusion could potentially serve as a personalized strategy for patients treated with combination ICIs therapy.