bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extracellular vesicle-derived non-coding RNAs to predict outcome in patients with triple-negative breast cancer (TNBC) with residual disease (RD).
Authors: Stecklein Shane R , Koestler Devin , Yellapu Nanda K , Yoder Rachel , Kimler Bruce F. , Staley Joshua M. , Schmitt Zachary , Khan Qamar J. , O'Dea Anne , Nye Lauren Elizabeth , Elia Manana , Heldstab Jaimie , Home Trisha , Hyter Stephen , Isakova Kamilla , Pathak Harsh B , Godwin Andrew K. , Sharma Priyanka 
Published: June 2023

578 Background: TNBC patients with RD after neoadjuvant systemic therapy (NAST) have high risk of recurrence. Biomarkers to risk-stratify patients with RD could individualize adjuvant therapy and inform adjuvant therapy trials. We aim to investigate the impact of circulating extracellular vesicle (EV)-derived non-coding RNAs (exo-ncRNAs) on outcomes in TNBC patients with RD. Methods: The study population included 79 TNBC patients with RD post-NAST and available end-of- treatment plasma samples enrolled in an IRB-approved multisite prospective registry. EVs and their associated exo-ncRNAs were isolated by membrane affinity spin columns (Qiagen exoRNeasy). Exo-ncRNA was subjected to next-generation sequencing (Qiagen QIAseq miRNA library kit). N=47 served as a discovery cohort and N=32 served as validation cohort. With inclusion of transcripts expressed in ≥ 80% of samples, there were 1,123 normalized reads/sample. Hazard ratios and C-statistics for event-free survival (EFS) were computed for each exo-ncRNA. We report exo-ncRNAs that were significantly associated with EFS in both the discovery and validation cohorts. Results: Patient and tumor characteristics were balanced in discovery and validation cohorts. Three exo-ncRNAs were associated with increased recurrence risk in both the discovery dataset ( miR-200a-3p, HR=1.39, 95%CI 1.01-1.89, P=0.04, C-stat=0.55; miR-203a-3p, HR=1.77, 95%CI 1.15-2.73, P=0.01, C-stat=0.59; and miR-7845-5p, HR=1.53, 95%CI 1.15-2.05, P=0.004, C-stat=0.62) and the validation dataset ( miR-200a-3p, HR=1.83, 95%CI 1.24-2.72, P=0.003, C-stat=0.76; miR-203a-3p, HR=1.78, 95%CI 1.10-2.87, P=0.02, C-stat=0.67; and miR-7845-5p, HR=2.06, 95%CI 1.06-4.01, P=0.03, C-stat=0.52). Using the miRNA Target Prediction Database (miRDB), we identified 1,088, 1,352, and 387 predicted targets for miR-200a-3p, miR-203a-3p, and miR-7845-5p, respectively. Amongst 2,827 prediction events there were 2,526 unique target mRNAs. 2,235 mRNAs were targets for one candidate miRNAs, 281 mRNAs were predicted targets for two candidate miRNAs, and 10 mRNAs were predicted as targets for all three candidate miRNAs. Conclusions: The expression of miR-200a-3p, miR-203a-3p, and miR-7845-5p in plasma-derived EVs in TNBC patients with RD after NAST is associated with increased risk of recurrence. We identified ten mRNAs that are predicted targets of all three of these miRNAs. If validated in additional cohorts these exo-ncRNAs could be used in a liquid-biopsy assay to identify high-risk patients with RD who could benefit from adjuvant treatment intensification. [Table: see text]
Differential genomic and transcriptomic analysis of invasive lobular and ductal carcinomas.
Authors: Mouabbi Jason A , Meric-Bernstam Funda , Khorkova Svetlana , Turova Polina , Kotlov Nikita , Chernyshov Konstantin , Kushnarev Vladimir , Love Anna , Clayton Patrick , Nomie Krystle , Fowler Nathan , Tripathy Debu 
Published: June 2023

579 Background: Invasive lobular carcinoma (ILC) is more aggressive than hormone receptor (HR)-positive invasive ductal carcinoma (IDC). However, in practice, ILC and IDC are often treated in a similar fashion with endocrine therapy and chemotherapy. Identifying novel biomarkers, genetic alterations, transcriptomic features, and tumor microenvironment (TME) variations could initiate the development of personalized treatment plans for patients with ILC. Methods: We collected ILC and luminal (non-basal/non-HER2) IDC samples from four datasets (TCGA, METABRIC, RATHER PMC4700448, and UQCCR PMC31263747) and performed differential expression and gene set enrichment analyses, revealing novel genomic, transcriptomic, and TME differences. Using methods from Bagaev et al., we quantified the activity of 29 functional gene expression signatures with single sample gene set enrichment analysis before clustering the samples into five TME subtypes; statistical significance was measured with the Mann-Whitney U test. Differential expression analysis of RNA-Seq data was completed using DESeq2. Further, we analyzed the frequency of specific biomarkers to identify potential therapeutic options. Mutations and biomarker enrichment were assessed using the chi-squared test. Results: We analyzed 1,735 samples (1,442 luminal IDCs and 293 ILCs). CDH1 mutations were more prevalent in ILC samples (56%) compared to IDC samples (6%). Of the 44% of ILC samples with wild-type CDH1, 90% had low CDH1 expression. Inference models showed differences in transcription factors expression between ILC and IDC. ILC had significantly higher expression of TFAP2B, SOCS2, NOSTRIN, THBS4, SCUBE2, and GDF9 and lower expression of CDCA4, PSMG1, LMOD1, and SLC7A5 (adj p < 0.0001 for all genes). Analysis of the TME showed that 44% of ILC samples were immune enriched with high PDL1, CTLA4, and LAG3 expression. In comparison, approximately 30% of ILC samples contained enhanced vascularization and expressed high VEGFA, PDGFRA, and PDGFRB. Finally, compared to luminal IDC, ILC tend to have a statistically significant higher TROP2 expression, similar to that seen in basal subtype. Conclusions: ILC and IDC expressed distinct genomic alterations, gene expression, transcriptomic features, TMEs, and biomarkers. These differences can be used as a blueprint to tailor ILC phenotype-specific interventional clinical trials.
Use of machine learning to predict pathological complete response using multi-modal data from I-SPY2 clinical trials.
Authors: Ahmed Fahad Shabbir 
Published: June 2023

592 Background: The objective of the current analysis of the I-SPY 2 data from multiple breast cancer clinical trials for stages II and III cancers was to look at the possibility of developing a machine learning algorithm to predict pathological complete response using multimodal data. Methods: Imagining, clinical and biomarkers data form the I-SPY 2 trial was used in this analysis. Four different experiments were designed for to assess different data pre-processing and machine learning methods mainly deep neural networks (DNN) and random forest (RF) classifiers. Experiment 1 and 3 use DNNs while Experiment 2 and 4 used RFs; more over the first two experiments used data that was continuous in nature from the point of view of pre-performed imaging analysis while in later two experiments we had binarized all the variables using a median cutoff for high vs low values. The variables used were treatment recieved, HER2/neu receptor status, hormone receptor status, age, ethnicity, gynecological history, MRI feature data. All models were evaluated using robust testing methods that included sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), accuracies (training and test sets), area-under the receiver-operator curve and F1-Score. Results: From a total of 985 patients with clinical data we used 384 that had multi-feature MRI data. Time series data for the initial scan (T0) and a scan 3 weeks later (T1). The final comparative analysis showed the best model among the 4 experiment the best performing algorithms for this analysis was random forests using median cutoffs with a best F1-score (0.43), specificity (86.4%), PPV (47.8%), accuracies (train sets, 100%; test sets, 75%), and AUROCs (0.78, 0.56-0.73). Conclusions: The use of machine learning to predict pathological complete response using multimodal data shows good potential as a digital biomarker. However, these results need further validation before a clinical tool is available for the clinicians. [Table: see text]
Association of HER2/CEP17 ratio with pCR after HER2-directed neoadjuvant treatments in the phase III NeoALTTO trial.
Authors: Singer Christian F. , König Franz , Kacerovsky-Strobl Stephanie , Danzinger Sabine , Brunner Christine , Suppan Christoph , Deutschmann Christine , Balic Marija , Greil Richard , Egle Daniel , de Azambuja Evandro , Di Cosimo Serena , Gnant Michael 
Published: June 2023

600 Background: HER2-directed therapies are approved for the treatment of patients with HER2-positive invasive breast cancer as defined by HER2 protein overexpression, or HER2 gene amplification based on HER2/chromosome enumeration probe (CEP17) ratio ≥ 2.2. Above this accepted HER2 status determination, however, it is still unknown whether the efficacy of HER2-directed therapy in early breast cancer increases with increasing HER2/CEP17 ratios. Therefore, the purpose of the presented work is to evaluate whether quantitative assessment of the HER2/CEP17 ratio predicts pathological complete response (pCR) and event-free survival (EFS) of patients treated with neo-adjuvant HER2-based regimen in the prospective phase III NeoALTTO trial. Methods: 455 women with HER2-positive early breast cancer, who had received neo-adjuvant trastuzumab and/or lapatinib for 6 weeks and then together with 12 cycles of weekly paclitaxel were included in this analysis. The HER2/CEP17 ratio in the primary tumor samples was correlated with pCR and survival outcome. Results: The Median HER2/CEP17 ratio in NeoALTTO was 5.1 (range: 1.1 – 100.0), and ratios were not associated with age, hormone receptor status, or any of the other clinicopathological variables analyzed. The log HER2/CEP17 ratio significantly predicted for pCR in both uni-variate (OR: 1.83; 95% CI: 1.11 - 3.01, p = 0.0176) and multivariate analysis (OR: 1.79; 95% CI: 1.07 - 2.99, p = 0.0257). Higher HER2/CEP17 ratios were, however, not associated with improved EFS (adjusted HR = 0.79; p = 0.3537). A pCR prediction model which included HER2/CEP17 ratio, treatment arm, and hormone receptor status improved the predictive strength of treatment arm alone from a ROC AUC value of 0.60 to 0.69. Conclusions: In patients treated with HER2-based neoadjuvant therapy, quantitative analysis of the readily available pre-treatment HER2/CEP17 ratio by FISH is predictive of pCR but not EFS.
Induction chemotherapy plus radiotherapy alone versus cisplatin-based concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: An open-label, non-inferiority, randomized phase 3 trial.
Authors: Chen MingYuan , Huang Peiyu , Chen Xuyin , Ding Xi , Ling Guo , Mo Hao-Yuan , Duan Chongyang , Ling Li , Zou Xiong , Liu You-Ping , You Rui , Xie Yulong , Cao Jingyu , Liu Sihan , Wang Zimeng , Yang Qi , Qiu Fang , Hua Yijun , Cao Kajia , Luo Dong-Hua 
Published: June 2023

6001 Background: Cisplatin-based concurrent chemoradiotherapy (CCRT) has long been regarded as standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) due to its favorable local control. However, concurrent platinum is associated with intolerable toxicities and ineffective in preventing distant metastasis. Since IMRT enhances the local control and induction chemotherapy (IC) decreases the risk of distant failure, it is worth exploring whether IC plus IMRT alone regimen could replace CCRT for patients with LA-NPC. Methods: This open-label, phase 3, non-inferiority clinical trial was conducted from June 12, 2015 to April 30, 2019. Patients with stage T1-4N2-3 or T3-4N0-1 M0 NPC were randomly assigned (1:1) to receive gemcitabine (1000 mg/m²) and cisplatin (80 mg/m²) IC for 2 cycles followed by IMRT alone or IMRT plus concomitant weekly cisplatin (40 mg/m²) up to 7 cycles. 2-year failure-free survival was set as primary endpoint and non-inferiority margin of 10% was established. Efficacy analysis and safety analysis were dividedly performed in the intention-to-treat and safety population. Results: A total of 249 patients were enrolled, including 124 patients in IC group and 125 patients in CCRT group. Median follow-up time was 60 months (IQR, 48-71). 2-year failure-free survival was 90.2% in IC group versus 86.3% in CCRT group, with an HR of 0.818 (95% CI, 0.479-1.397) and absolute difference of 3.9% (1-sided 95%CI, -4.2 to 11.9). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. Compared with CCRT group, fewer grade ≥3 AEs occurred in IC group (47.5% vs 61.5%, p = 0.015), including leucopenia, anemia, mucositis, nausea and dysphagia. The IC group had significantly better QoL during and short periods after IMRT, including domains of global health status, physical functioning, fatigue, nausea and vomiting, pain, and appetite loss. Conclusions: For LA-NPC, gemcitabine and cisplatin induction chemotherapy plus IMRT alone was not inferior in 2-year failure-free survival to concurrent chemoradiotherapy. Clinical trial information: NCT02460887 .
A phase Ib/II study of GFH018 in combination with toripalimab in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC).
Authors: Mai Hai-Qiang , Guo Ye , Yang Muh-Hwa , Yang Kunyu , Chen Li-Tzong , Mun Hui , Yang Yan , Wang Shuang , Zhu Huaqiang , Shen Haige , Wang Yu 
Published: June 2023

6026 Background: The transformed growth factor beta (TGF-β) signaling pathway is dysregulated in carcinogenesis. In NPC patients, upregulation of TGF-β pathway is correlated with disease stage or phenotype due to Epstein-Barr virus (EBV) infection. GFH018, a novel TGF-βRI inhibitor, can inhibit tumor growth through inhibiting the activity of TGF-βRI kinase to block the signal transduction of TGF-β and modulate the tumor immune microenvironment. Preclinical studies showed that GFH018 in combination with PD-1/PD-L1 monoclonal antibody can significantly inhibit tumor growth synergistically. Here we report the preliminary results of combining GFH018 and Toripalimab treating R/M NPC patients (pts). Methods: This is a phase Ib/II study to evaluate the safety and efficacy of the combination of GFH018 and Toripalimab in pts with advanced solid tumors. Patients with RM NPC were enrolled to receive GFH018 80mg twice a day (BID) 14-day-on/14-day-off in combination with Toripalimab 3mg/kg every two weeks. Tumor assessment was performed every 8 weeks per Response Evaluation Criteria in Solid Tumor (RECIST) 1.1. Results: As of 31 Dec 2022, 32 pts with R/M NPC who had progressed on at least one prior line therapy were enrolled. Sixteen (50%) had received ≥3 lines of prior therapies, and 19 (59.4%) had previously received immune checkpoint inhibitors (ICIs) and platinum-based chemotherapies. The median duration of study drug exposure was 7 weeks. Twenty-five pts (78.1%) experienced treatment-related adverse events (TRAEs) of any grades, and 11 pts (34.4%) had ≥ Grade 3. The most common TRAEs (occurring in ≥ 3 pts) were anaemia (n = 6, 18.8%), hyponatraemia (n = 6, 18.8%), rash (n = 6, 18.8%), fatigue (n = 4, 12.5%), white blood cell count decreased (n = 4, 12.5%), aspartate aminotransferase increased (n = 3, 9.4%), back pain (n = 3, 9.4%), decreased appetite (n = 3, 9.4%), hypokalaemia (n = 3, 9.4%), and hypothyroidism (n = 3, 9.4%). As of 18 Jan 2023, among the 27 pts with post-baseline tumor assessments, 8 achieved partial response (PR), and 5 stable disease (SD); the overall response rate (ORR) was 29.6%, and disease control rate (DCR) was 48.1%. Six PR and 2 SD were observed among the 12 pts without prior treatment of ICIs; the ORR was 50%, and DCR was 66.7%. Four pts discontinued treatment without any post-baseline tumor assessments due to AEs or withdrawal of consent, and 1 patient is premature for tumor assessment. Conclusions: GFH018 combined Toripalimab was well tolerated and demonstrated preliminary efficacy in pts with R/M NPC. Specifically, in pts who had not previously received ICIs, promising antitumor activity was observed supporting further investigation to this group of pts. Clinical trial information: NCT04914286 .
Final results from TACTI-002 Part C: A phase II study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in patients with metastatic 2nd line head and neck squamous cell carcinoma unselected for PD-L1.
Authors: Doger de Spéville Bernard , Felip Enriqueta , Forster Martin , Majem Margarita , Bajaj Pawan , Peguero Julio Antonio , Carcereny Enric , Krebs Matthew G , Mukherjee Uma , Mueller Christian , Triebel Frederic 
Published: June 2023

6029 Background: Eftilagimod alpha (E), a soluble LAG-3 protein, acts as an MHC class II agonist triggering activation of antigen-presenting cells (APC) and CD8 T-cells. Using efti to enhance patients’ immunity may lead to stronger anti-tumor responses than observed with pembrolizumab (P) alone. We report final results from Part C of the TACTI-002 trial (NCT03625323) where 2nd line metastatic head and neck squamous cell carcinoma (HNSCC) patients (pts) unselected for PD-L1 were treated with E + P. Methods: Pts with metastatic HNSCC, unselected for PD-L1 expression with disease progression on or after 1st line platinum-based therapy (± cetuximab) were enrolled. Primary endpoint (EP) was objective response rate (ORR) by iRECIST. Other EPs included tolerability, progression free survival (PFS), duration of response (DoR), and overall survival (OS). Pts received E (30 mg SC Q2W for eight 3-week cycles and then Q3W up to 1 yr) with P (200 mg IV Q3W up to 2 yrs). Imaging was performed Q9W. PD-L1 was retrospectively assessed using the IHC 22C3 kit. The study was approved by ethic committees and institutional review boards. Results: 39 pts were enrolled between Mar 2019-Jan 2021 (cut-off Jul 2022) with HNSCC of oropharynx (38%), oral cavity (32%), hypopharynx (19%) and larynx (16%). Median age was 63 yrs (48-84 yrs) and 90% were male. ECOG PS was 0 and 1 in 35% and 65% of pts. Two pts were excluded from efficacy results due to fatal COVID-19 prior to their first post-baseline scan. The primary EP, ORR by iRECIST, was 30% with 14% complete responders (see table). ORR by RECIST 1.1 was comparable (24%). Median PFS by iRECIST was 2.1 mo with 32% of pts progression-free at 6 mo. Median OS was 8.7 mo with 46% alive at 12 mo. Median DoR by iRECIST was not reached with 17 mo min FU. Responses were seen in all PD-L1 subgroups (see table). ORR, 6-mo PFS, 12-mo OS rates for PD-L1 CPS ≥20 were 60%, 53%, 73% with a median OS of 15.5 months. Two pts (5%) discontinued due to adverse events (AE) (fatigue and arthralgia [each grade 2]; pneumonitis [grade 3]) that were related to study treatment (efti and/or pembro). The most common (≥15%) AEs were hypothyroidism (21%), asthenia (21%), cough (18%), anemia (18%), weight decrease (18%), and fatigue (15%). Conclusions: Efti + pembrolizumab is safe, showing encouraging antitumor activity in platinum and partially cetuximab pre-treated, 2nd line HNSCC patients. TACTI-003 (NCT04811027) a randomized study in 1st line HNSCC is currently recruiting. Response by iRECIST: Clinical trial information: NCT03625323 . [Table: see text]
Results from two phase II studies of SI-B001, an EGFR×HER3 bispecific antibody, with/without chemotherapy in patients (pts) with recurrent and metastatic head and neck squamous cell carcinoma (HNSCC).
Authors: Xue Liqiong , Yang Kunyu , Fang Meiyu , Ma Xuelei , Zou Wen , Ding Muran , Wang Zhaoxiang , Peng Yujia , Xiao Sa , Wang Hongwei , Zhu Hai , Olivo Martin Sebastian , Zhu Yi , Guo Ye 
Published: June 2023

6037 Background: SI-B001 is an EGFR×HER3 bispecific antibody. We present the efficacy and safety results from two ongoing studies of SI-B001, S209 and S206, in recurrent and metastatic HNSCC. Methods: S209 included pts with recurrent and metastatic HNSCC progressed on prior anti-PD-1/L1 plus platinum-based chemotherapy (PBC). Pts were treated with SI-B001 16mg/kg IV QW. S206 included pts with recurrent and metastatic HNSCC progressed on prior anti-PD-1/L1 with or without PBC and received no more than two lines of treatment. Pts enrolled in S206 were divided into two groups: Group A, pts without prior exposure to paclitaxel were treated with SI-B001 (12mg/kg IV QW) plus paclitaxel (80mg/m2 IV QW); Group B, pts with prior exposure to paclitaxel were treated with SI-B001 (12mg/kg IV QW) plus docetaxel (35mg/m2 IV D1D8D15 Q4W). The study endpoints of the two studies were identical. The primary endpoint was objective response rate (ORR) by investigator per RECIST v1.1. Secondary endpoints were ORR by independent central review, progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall Survival (OS), and safety. Results: As of Dec 31, 2022, 11 pts in S209 received SI-B001. Pts had a median of 4 prior lines of therapy. In 9 out of 11 pts who have at least 1 post baseline tumor assessment in S209, ORR (n/N) was 22.2% (2/9), mPFS [95%CI] was 2.7 [1.8-7.9] mo. 29 pts in S206 received SI-B001 plus chemotherapy, including 19 pts in Group A and 10 pts in Group B. In 22 pts who had at least 1 post baseline tumor assessment, ORR was 45.5% (10/22), mPFS was 5.1 [3.7-5.6] mo. 1 nasal sinus cancer pt enrolled had stable disease (SD). 14 out of the 18 pts who have at least 1 post baseline tumor assessment in Group A, ORR was 64.3% (9/14) mPFS was 5.6 [5.1-6.3] mo. 8 out of 10 pts who have at least 1 post baseline tumor assessment in Group B, ORR was 12.5% (1/8), mPFS was 1.9 [1.2-3.7] mo. The most common grade 3 and above treatment-related adverse events (TRAEs) in S209 was Hypomagnesaemia (9%). The most common grade 3+ TRAEs in S206 were rash (16%), anaemia (8%) and white blood cell count decreased (8%). No SI-B001 drug-related deaths occurred in either study. Conclusions: SI-B001 plus paclitaxel demonstrated potential improvements in ORR and DCR compared with SI-B001 monotherapy in recurrent and metastatic HNSCC. The toxicity of SI-B001 plus chemotherapy in HNSCC is manageable and tolerable. Clinical trial information: NCT05044897 ; NCT05054439 . [Table: see text]