tbuckley/cabot-search huggingface dataset:
(CDK) 4/6 inhibitors: An effective treatment for homologous recombination deficient (HRD) luminal breast cancers (BC)?
Authors: Lucas Gouvêa, Elizabeth Santos, Marcelle Cesca, Mario Machado Lopes, Nathalia Soldi, Viviane Primo Basilio De Souza, Fabricio Braga, Eduardda B. Silva, Izabella Ferreira, Victor Bertoli, Thaissa Fernandes, Amanda Carneiro, Juliana Rosa Chinelato, Roberto Novello
Journal: Journal of Clinical Oncology (2024)

e13100 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) still represents the best 1st-line choice for hormone receptor (HR) positive(+)/HER2 negative(-) metastatic breast cancer (MBC) patients (pts). Approximately 8% of pts with HR+ BC harbors germline BRCA mutation (g BRCAmt). The interaction between Cyclin/CDK pathway, endocrine receptor (ER) and Breast Cancer gene 1/2 (BRCA1/2) is complex and evidence reported so far, await confirmation in the context of future randomized clinical trials. So far, limited data exist about treatment effectiveness of CDK4/6i in homologous recombination deficiency (HRD) Luminal BC. A current frequent question in clinical practice is which additional adjuvant therapy to prioritize for luminal BRCA tumors (tu), considering the approval of both CDK4/6i andpoly ADP ribose polymerase (PARP) inhibitors in this scenario. Considering potential impacts of genetic instability in tu biology, such as potential loss of Rb protein related to Loss of Heterozygosity (LOH) of BRCA2 as a primary resistance mechanism in CDK4/6i, we sought to analyze the clinical results of that drug in tu with genetic instability. Methods: We retrospectively analyzed real-world outcomes of CDK4/6i performance in HR+/HER2- MBC treated in a single institution, with focus in clinical outcomes of HRD BC. germline HR genes status and somatic phosphatidylinositol 3-kinase (PIK3CA) status were also analyzed. Results: A total of 384 consecutive MBC pts treated with CDK4/6i were included in this study. The most used CDK4/6i was palbociclib (40,6%), followed by ribociclib (29,8%) and abemaciclib (29,2%). Considering the whole cohort PFSm 30months (95%IC 26-34) and OSm were 56 months (95%IC 52-60) No differences in PFS or OS was observed among the 3 CDK4/6i. Median age of the cohort was 60 years old. 38.5% were premenopause Pts and 59.9% were postmenopause. A total of 149 (39%) pts performed germline screening. Between 19 pts with gHR mt, 12 were BRCA1/2 mt (just one BRCA1). The other were: 2 PALB2, 2 CHEK2, 1 ATM, 1 RAD51D, 1 RAD51C mt. So far, no differences in PFS ou OS was observed in the presence of BRCA 1/2 or other gHR mt. Nevertheless, PIK3CA mt was tested in 142 pts, 51 were positives. That mt was a predictor of worse OS (55m; 95%IC 45-65) x 63m (95%IC 56-69), p 0,019. Conclusions: The results of this real-world study suggest that treatment outcomes with CDK4/6i may be worse in pts with HRD tu due to potential differences in tu biology. Future exploration in larger samples of patients who have had biomarker testing is ongoing. Patients with Pik3CA mt treated with CDK4/6i presented worse clinical outcomes.
Safety profile of sacituzumab govitecan in patients with breast cancer: A systematic review and meta-analysis.
Authors: Maria Inez Dacoregio, Isabella Michelon, Caio Castro, Francisco Cezar A. Moraes, Lis Victoria Ravani, Guilherme Rossato de Almeida, Maysa Vilbert, Ricardo L. Costa
Journal: Journal of Clinical Oncology (2024)

e13106 Background: Sacituzumab govitecan (SG), a first-in-class TROP-2-directed antibody conjugated to a topoisomerase inhibitor, has shown antitumor activity across various breast cancer (BC) subtypes. Following SG approval for metastatic triple negative breast cancer (TNBC) and its broad use, understanding SG’ safety profile is crucial. Hence, we conducted a systematic review and meta-analysis to evaluate the safety and tolerability of SG in patients with BC. Methods: We comprehensively searched PubMed, Embase, and Cochrane databases, and ASCO and ESMO websites for clinical trials assessing the safety of SG in BC patients. Outcomes of interest included treatment-related adverse events (TRAEs) of any grade, grade 3/4, adverse events (AEs) leading to death, and AEs leading to SG dose reduction or discontinuation. All analyses were performed in R software (v.4.2.2) using random effects models. Heterogeneity was assessed using I 2 test. Results: A total of 1,325 patients from six studies – three randomized clinical trials (RCTs) and three non-RCTs – were included. Median age of population ranged from 47 to 56 years. Most had metastatic disease (86%, n=1187), and triple-negative BC (48.6%, n=670). Regarding therapies, 798 patients received SG and 527 had treatment of physician's choice (TPC). In the pooled analysis of 748 patients on SG, the overall risk of AEs was 100% (95% CI 99-100%). The estimated risk of the most common all grade AEs were neutropenia (66%), anemia (44%), nausea (56%), vomiting (30%), fatigue (46%), constipation (17%), diarrhea (45%), and alopecia (46%), as described (Table). The risk of grade 3/4 AEs among 748 patients on SG was 55% (95% CI 36-74%). Neutropenia was the most important grade ≥3 AE, with a estimated frequency of 47%; followed by anemia and diarrhea, with an incidence of at 9% and 7%, respectively. The incidence of all other grade 3/4 AEs (e.g. anemia, vomiting, leukopenia, fatigue, constipation, and diarrhea) was below 10%. Dose reduction and discontinuation were observed in 14.4% and 2.9% of patients, respectively. Toxicity-related deaths occurred in six patients (0.4%). In a comparative sensitivity analysis of RCTs only, SG had significantly higher toxicity than TCPs, all grade AEs (OR 12.30 95%CI 1.68-89.87, p=0.01), and grade &gt;3 AEs (OR 1.69 95%CI 1.25-2.28, p=0.0006). Conclusions: In this systematic review and meta-analysis, SG was associated with a high incidence of AEs. Neutropenia is a notable and potentially serious adverse event. Toxicity associated with SG may be addressed through close monitoring and early management. [Table: see text]
Investigating the outcome of vascular emboli in patients with breast cancer.
Authors: Tafenzi Hassan Abdelilah, Farah Choulli, Ismail Essadi, Rhizlane Belbaraka
Journal: Journal of Clinical Oncology (2024)

e13116 Background: Vascular emboli (VE) represent a critical event in breast cancer pathophysiology. Despite their clinical relevance, their relative impact on breast cancer outcomes remains underexplored. In this study, we delve into comparing the survival outcomes and recurrence rates of patients with and without VE in patients with breast cancer (BC) and adjust for other patient-related variables. Methods: This study was designed based on a retrospective cohort of pathologically confirmed de novo, local, or metastatic recurrence BC female patients diagnosed between 2020 and 2022 and aged &gt; 18 years. Kaplan-Meier curves and Cox proportional hazards models were used to estimate the effect of vascular emboli on survival and recurrence while controlling other reviewed demographic, clinic, pathologic, and therapeutic features following a course of adjuvant or neo-adjuvant treatments. Results: A total of 501 patients were eligible for this study (216 patients without VE vs. 285 patients with VE). The median follow-up was 274 (IQR: 195–523) days. In the group of patients with positive VE, the median age at diagnosis was 49 years, and the median progression-free survival (mPFS) was 881 (95% CI: 856, 1555) days; Patients with bilateral BC have a poorer mPFS of 515 (95% CI: 411, Not Estimable [NE]), while right BC was associated with a better outcome of 1,035 (95% CI: 869, NE) days (p = 0.001). Moreover, patients with positive hormonal receptors (HR &gt;=10%) who benefited from endocrine therapies have a better PFS of 974 (95% CI: 872, NE) days compared to those with negative HR (&lt;10%) of 656 (95% CI: 586, NE) days (p = 0.02). In addition to the molecular profile, TNBC was associated with poorer survival 579 (95% CI: 553, NE), compared to RH-/HER2+ 675 (95% CI: 635, NE), RH+/HER2- 935 (95% CI: 777, NE), and RH+/HER2+ 1,133 (95% CI: 856, NE) days (p &lt; 0.001). Surgery was associated with better mPFS (935 (95% CI: 869, NE) days compared to neo-adjuvant or palliative patients 856 (95% CI: 635, NE) (p = 0.002). In the group of patients with negative VE, the median age was 48 years. The mPFS was 852 (95% CI: 789–996) days. Patients presented with positive lymph (N2) have a worse PFS of 611 (95% CI: 505, NE) days; in addition, patients with HER2=0 have a worse PFS of 775 (95% CI: 595, 1,320) days compared to HER2 1+ or non-amplified HER2 2+ 928 (95% CI: 840, NE) days, while no statistically significant differences between patients who received different treatment options (HER2 TKI, chemotherapy, radiotherapy, and endocrine therapy) were found. Conclusions: These findings emphasize the importance of considering VE status and hormonal receptor expression in tailoring treatment strategies for BC patients. Identifying high-risk individuals who may benefit from aggressive or novel therapies remains crucial for improving outcomes. Further research is warranted to validate these results and guide clinical decision-making.
CNS efficacy of trastuzumab deruxtecan in metastatic breast cancer: A single-institution, real-world analysis.
Authors: XiaojiE Zhang, Kay T. Yeung
Journal: Journal of Clinical Oncology (2024)

e13117 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that revolutionized the management of patients with HER2+ (HER2 FISH+, IHC 3+) and HER2 low (HER2 FISH-, IHC 1+/2+) metastatic breast cancer (MBC). Studies have shown that T-DXd may induce antitumor activity in HER2+ MBC with brain metastases (BM). However, data is limited on the central nervous system (CNS) efficacy of T-DXd in HER2 low disease. The only report thus far is from the HER2 low cohorts in the DEBBRAH study with 12 patients showing an intracranial overall response rate (ORR-IC) of 50% and progression free survival (PFS) of 5.7 months. Here, we provide a real-world, retrospective analysis of the CNS efficacy of T-DXd in HER2+, HER2 low , and HER2 null MBC with BM. Methods: This is a single institution, retrospective analysis of patients with MBC with BM who received T-DXd between January 2020 and November 2023. Patients with HER2+, HER2 low , or HER2 null MBC and BM, treated or untreated at the time of T-DXd initiation, were included. All patients had baseline brain magnetic resonance imaging before T-DXd initiation. Efficacy analyses were performed using the RECIST 1.1 criteria to CNS target lesions by investigator assessment. ORR-IC and intracranial clinical benefit rate (CBR-IC) were reported. CNS PFS, defined as time until CNS progression or death of any cause, and overall survival (OS) were also evaluated. Results: 29 patients were included in the study: 10 (35%) had HER2+, 16 (55%) had HER2 low , and 3 (10%) had HER2 null disease. The patients had ECOG performance status ranging from 0 to 3, and received a median of 3 prior lines of therapy (range 1-8). At baseline, 3 patients (10%) had untreated BM, 6 (21%) had prior surgery, and 23 (79%) had prior radiation. 28 (97%) had concurrent extra-cranial metastases. Best CNS response and duration of response are listed in the table below. ORR-IC was 10% overall and 6% in HER2 low group. CBR-IC was 58% overall and 50% in HER2 low group. Median OS in all patients was 65 weeks. Median CNS PFS was not statistically different in the overall group (24 weeks) compared to the HER2 low group (21 weeks) with p=0.4661 via log rank test. Conclusions: This is the first real-world study reporting the CNS efficacy of T-DXd in patients with MBC across HER2 expression levels. The CNS efficacy of T-DXd in our institutional experience was similar in HER2+ and HER2 low MBC, and was much lower than previously reported in prospective clinical trials. Performance status, extent of prior treatment, and systemic disease burden likely contributed to this difference. Larger cohort and prospective studies on patients with HER2 low MBC with BM are warranted. [Table: see text]
Prognostic factors for patients with breast cancer brain metastasis after stereotactic radiotherapy.
Authors: Jie Xiong, Qiuchi Chen, Yanxia Zhao
Journal: Journal of Clinical Oncology (2024)

e13109 Background: Breast cancer (BC) is the most common cancer in females and BC brain metastasis (BCBM) is considered as the second most frequent brain metastasis. Numerous prognostic factors are associated with survival for patients with BCBMs. Here we investigated the clinical factors associated with overall survival (OS) and distant intracranial control (DIC) after stereotactic radiotherapy (SRT) for BCBM. Methods: The records of BCBM patients treated with SRT were collected from electronic database in Cancer Center, Union Hospital, Tongji medical college, Huazhong University of Science and Technology Hospital. Based on the univariate and multivariate Cox regression analysis, the prognostic significance of available variables was assessed. The nomogram was created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index, and the clinical benefits were evaluated through clinical decision curve analysis (DCA). Results: 101 BCBM patients receiving SRT were analyzed in this study, and 5 patients were excluded with other primary malignancies or missing data. Median observation time was 15.0 months, and median OS was 22.0 months. OS rate was 71.5% in 1 year, 45.8% in 2 years, and 32.8% in 3 years. DIC was 49.8% in 1 year, 26.6% in 2 years, and 18.3% in 3 years. Multivariable analysis identified prognostic factors for OS including number of the brain metastasis, molecular subtypes type, brain metastasis as the first metastasis site, Karnofsky performance status (KPS), and receiving systemic therapy after SRT. KPS&lt;80, triple-negative subtype, the existence of extracranial metastases, the existence of lung metastases were associated with decreased DIC. Selected by the Akaike information criterion (AIC), the nomogram model contains age, KPS, histological subtype, number of brain metastases, brain metastasis as first metastasis site, PTV size, liver metastases, albumin and neutrophils. The calibration curve for probability of survival showed high consistencies between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.823, and the bias-corrected C-index generated by bootstrap validation with 1,000 resamples was 0.772, which was statistically higher than the C-index values of the other systems: Recursive partitioning analysis (RPA) (0.627), Graded prognostic assessment (GPA) (0.637), Breast-specific Graded Prognostic Assessment (breast-GPA) (0.699). BCBM patients receiving SRT were divided into four risk groups: I group (risk score &lt; 150), II group (150≤risk score&lt; 220), III group (220≤risk score&lt;290) and IV group (risk score≥290). The Kaplan‐Meier OS curves showed great discrimination among the four risk groups. Conclusions: The proposed nomogram resulted in a more-accurate prognostic prediction for BCBM patients receiving SRT.
Novel organoid platform for drug screening of patients with breast cancer.
Authors: Shian-Jiun Shih, Ruobo Zhang, Yi Chun Han, Mark D. Pegram, Ying C. Chang
Journal: Journal of Clinical Oncology (2024)

e13125 Background: Marketed methods are available for in vitro organoid growth for the purpose of translational science, evaluation of drug efficacy and patient treatment predictivity, but require needle biopsy of the tumor which is invasive to the patient. Non-invasive methods exist for isolating circulating tumor cells (CTC) from blood but require large volumes due to their low frequency (&lt;1 in 10 5 -10 6 PBMCs). Low CTC recovery limits the number of downstream analyses. To overcome these obstacles, Cellentia is introducing a novel in vitro system called R 3 CE (Rapid, Reproducible, Rare Cell Expansion), developed by AcroCyte Therapeutics Inc. (Taiwan), to the US market. The advantage of R 3 CE is that blood is used to generate viable representative cells of the patient’s tumor which can be expanded and banked, thus the number of characterization assays is flexible. The R 3 CE method allows for extensive drug screening within a rapid timeframe to inform patient treatment. This poster will show drug screening results on organoids derived from blood of breast cancer patients, and R 3 CE method transfer to Cellentia. Methods: For patient drug screening, 0.5 mL of peripheral blood was drawn from stage IV breast cancer patients. Cells were seeded onto proprietary plates, cultured for several days, passaged and screened for drug resistance or susceptibility to Cisplatin, Paclitaxel, 5-FU, Vinorelbine, and Gemcitabine by assessing the relative viability from luminescent measurements of drug treated organoids normalized to a mock control. For R 3 CE method transfer, frozen breast cancer organoids were thawed and seeded onto proprietary plates, grown for several days and used in the drug screen as described above. Results: Blood from five breast cancer patients (Patients A-E) were grown into organoids and used for screening drugs listed (Table). Relative viabilities were calculated. A threshold was set at 10% where relative viabilities above or below 10% showed the organoids were resistant (R) or susceptible (S) to killing by the drug candidate, respectively. The results of the R 3 CE drug test were compared to the clinical (Clin) outcome for each patient (clinical outcome is unknown (U) in some instances) and shown (Table). The drug test and the clinical outcome showed 100% concordance. Cellentia executed drug screening with the same drug panel utilizing frozen breast cancer organoids in the R 3 CE platform and demonstrated susceptibility in the drug screening. Conclusions: R 3 CE platform showed promising results as a personalized drug screening tool for breast cancer patients. Frozen breast cancer organoids for drug screening demonstrated successful method transfer to Cellentia. [Table: see text]
Tagging large CNV blocks in wheat boosts digitalization of germplasm resources by ultra-low-coverage sequencing
Authors: Jianxia Niu, Wenxi Wang, Zihao Wang, Zhe Chen, Xiaoyu Zhang, Zhen Qin, Lingfeng Miao, Zhengzhao Yang, Chaojie Xie, Mingming Xin, Huiru Peng, Yingyin Yao, Jie Liu, Zhongfu Ni, Qixin Sun, Weilong Guo
Journal: Genome biology (2024)

Abstract Background The massive structural variations and frequent introgression highly contribute to the genetic diversity of wheat, while the huge and complex genome of polyploid wheat hinders efficient genotyping of abundant varieties towards accurate identification, management, and exploitation of germplasm resources. Results We develop a novel workflow that identifies 1240 high-quality large copy number variation blocks (CNVb) in wheat at the pan-genome level, demonstrating that CNVb can serve as an ideal DNA fingerprinting marker for discriminating massive varieties, with the accuracy validated by PCR assay. We then construct a digitalized genotyping CNVb map across 1599 global wheat accessions. Key CNVb markers are linked with trait-associated introgressions, such as the 1RS·1BL translocation and 2N v S translocation, and the beneficial alleles, such as the end-use quality allele Glu-D1d (Dx5 + Dy10) and the semi-dwarf r-e-z allele. Furthermore, we demonstrate that these tagged CNVb markers promote a stable and cost-effective strategy for evaluating wheat germplasm resources with ultra-low-coverage sequencing data, competing with SNP array for applications such as evaluating new varieties, efficient management of collections in gene banks, and describing wheat germplasm resources in a digitalized manner. We also develop a user-friendly interactive platform, WheatCNVb ( http://wheat.cau.edu.cn/WheatCNVb/ ), for exploring the CNVb profiles over ever-increasing wheat accessions, and also propose a QR-code-like representation of individual digital CNVb fingerprint. This platform also allows uploading new CNVb profiles for comparison with stored varieties. Conclusions The CNVb-based approach provides a low-cost and high-throughput genotyping strategy for enabling digitalized wheat germplasm management and modern breeding with precise and practical decision-making.
Safety analysis for BH009 vs docetaxel from a bioavailability study.
Authors: Qun Sun, Xiaohua Wei, Haihua Jiang
Journal: Journal of Clinical Oncology (2024)

e13129 Background: BH009 is a novel polysorbate 80-free formulation of docetaxel (DXT) that could eliminate hypersensitivity reactions associated with polysorbate 80. In a bioavailability study of BH009 vs docetaxel (Taxotere), we reported that the ratios for the total DXT and free-DXT fraction C max , AUC 0-t , and AUC 0-∞ of BH009 and docetaxel were within 80% to 125% (90% confidence intervals). Here, we report the safety analysis from the same study population. Methods: This multicenter, randomized, open-label, 2-way crossover study compared the pharmacokinetics and safety of BH009 and docetaxel (Winthrop docetaxel injection, an authorized generic of Taxotere). A total of 46 patients with breast, head and neck, lung, stomach, ovarian, or cervical cancers were randomized, of which 43 patients were treated with BH009 and 44 patients were treated with docetaxel. Patients received a single dose of 75 mg/m 2 BH009 or Taxotere IV over 60 min, with ≥21-d washout between doses. Safety evaluation included treatment-emergent adverse events (TEAEs) and serious adverse events. Results: In all, 198 TEAEs were reported during the study: 94 after the administration of BH009 and 104 after the administration of docetaxel. No serious adverse events or deaths occurred. The only grade 3/4 toxicities that occurred for both arms during this study were hematologic. Overall, the incidence of grade 3/4 hematologic toxicity was significantly lower in the BH009 group than in the docetaxel group (2.3% vs 15.9%). Only one patient in BH009 arm experienced grade 3 anemia; no additional grade 3/4 hematologic adverse events were seen in the BH009 group. The incidence of grade 3/4 leukopenia, neutropenia, and lymphopenia in the Taxotere group was 6.8%, 4.6%, and 2.3%, respectively. The overall safety profile in the BH009 group was better than that in the Taxotere group. Conclusions: A better safety profile was observed in the study when BH009 group was compared to docetaxel group in grade 3/4 hematologic toxicity. Clinical trial information: NCT04889599 . [Table: see text]
Author Correction: Self-supervised learning of accelerometer data provides new insights for sleep and its association with mortality
Authors: Hang Yuan, Tatiana Plekhanova, Rosemary Walmsley, Amy C. Reynolds, Kathleen J. Maddison, Maja Bucan, Philip Gehrman, Alex Rowlands, David W. Ray, Derrick Bennett, Joanne McVeigh, Leon Straker, Peter Eastwood, Simon D. Kyle, Aiden Doherty
Journal: npj Digital Medicine (2024)

In this Article the authors have corrected a data cleaning issue.Specifically, some devices (older version of Actigraph) used to collect the wrist-worn accelerometer data for the study could enter sleep mode when the movement detected was low.Based on this, they filtered out the data affected by the sleep mode, only considering data without discontinuity in the data stream.However, another study in their group found this criterion insufficient because when the device enters sleep mode, values from the last timestamp are recorded for the entire second to the device, making it a continuous data stream.Therefore, all the data with repeated values for over one second were filtered out.The impact of the issue was limited to 205 out of 1448 nights of training data.After retraining on the clean dataset, preliminary results show that it enhances the reported sleep staging performance.These changes do not affect the core findings of the research.