bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human phase I/II safety and preliminary efficacy of PM1032, a bispecific antibody targeting CLDN18.2 and 4-1BB, in patients with advanced solid tumors.
Authors: Guo Ye , Wu Lihua , Li Yong , Wen Jinhua , Xue Junli , Wang Zhuoyi , Li Pu , Zhao Wei , Liu Jingfeng , Rao Xi , Li Qun , Xue Liqiong , Ge Xiaoxiao , Lin Fengjuan , Tang Wenbo , Zhou Jiuli 
Published: June 2024

2662 Background: PM1032 is an anti-CLDN18.2 x 4-1BB bispecific antibody that activates immune cells, such as T and NK cells, via CLDN18.2-mediated crosslinking of 4-1BB. Potent anti-tumor efficacy is facilitated with limited toxicity as immune activation is only stimulated in the context of CLDN18.2 expression on target cells. Here, we present the preliminary safety and efficacy results from an ongoing Phase I/II trial, which is a first-in-human (FIH), dose-escalation, and expansion study of PM1032 in patients (pts) with advanced solid tumors. Methods: This FIH study of PM1032 with adults with previously treated, advanced or metastatic solid tumors includes dose escalation (3+3 design; regardless of CLDN18.2 expression) and dose expansion stages (CLDN18.2+ gastrointestinal (GI) cancers). During the dose escalation stage, PM1032 was administered at doses of 0.3, 1, 3, 5, 8 and 12 mg/kg for the assessment of drug limiting toxicity (DLT) after 3 weeks, followed by administration Q2W until disease progression (PD) or observations of intolerable toxicity. Responses were evaluated according to RECIST 1.1. Adverse events (AEs) were graded using CTCAE v5.0. CLDN18.2 positivity was defined as ≥1% of tumor cells with ≥1+ signal intensity by immunohistochemistry. Results: As of January 12, 2024, a total of 30 pts received PM1032 (18 pts during dose escalation and 12 pts during dose expansion) with no DLTs observed (median age 54y; most pts had ≥2 metastatic sites). CLDN18.2 expression was evaluable in 80% of the pts and 66.7% were positive. The most common tumor types were GI cancers including 14 gastric and gastroesophageal junction cancers (GC/GEJ), 10 pancreatic adenocarcinoma (PDAC) and 5 other GI cancers. All pts had ≥1 line of prior therapy and 17 pts (56.7%) had prior immunotherapy. TRAEs occurred in 22 subjects (73.3%), and ≥ Grade 3 TRAEs occurred in 3 subjects (10%). The most common TRAEs were nausea (20%) and aspartate transaminase increase (16.7%). Among a total of 16 CLDN18.2+ pts enrolled at the 5, 8, and 12 mg/kg dose levels who completed at least one tumor evaluation, 2 pts achieved PR, 7 pts had SD and 3 pts were Non-CR/Non-PD. Additionally, the ORR was 20% in 10 measurable and evaluable CLDN18.2+ GC/GEJ pts. The longest treatment duration was 18 months and 5 pts had treatment durations ≥ 6 months. Pharmacokinetics (AUC0-336h & Cmax) were dose-proportional across the dose ranges of 0.3 mg/kg – 12 mg/kg with a terminal half-life of 6.0~10.1 days. Conclusions: PM1032 was well-tolerated up to 12 mg/kg Q2W and demonstrated preliminary anti-tumor activity in CLDN18.2+ tumors. Further development of PM1032 as a monotherapy and/or combination therapy for CLDN18.2-positive cancers is planned. Clinical trial information: NCT05839106 .
Phase I trial of hypoxia-responsive CEA CAR-T cell therapy in patients with heavily pretreated solid tumor via intraperitoneal or intravenous transfusion.
Authors: Zhang Hangyu , Yang Zhi , Zhu Xudong , Li Jie , Gao Yang , Zhang Yingzi , Tong Zhou , Fu Qihan , Bao Xuanwen , Li Bin , Zhang Qianzhen , Shen Junjie , Zheng Yi , Liu Lulu , Zhao Peng , Qian Cheng , Fang Weijia 
Published: June 2024

3514 Background: Chimeric antigen receptor (CAR) T cell therapy has been successful in hematologic malignancies but not in solid tumors. Homing capacity and tumor microenvironment are key issues to limit CAR-T efficacy to solid tumors. Our previous study has shown that hypoxia-responsive CAR-T cells exhibit reduced exhaustion and enhanced efficacy in solid tumors (Cancer Res 2024). Here, we aimed to optimize the administration route by comparing safety and efficacy of our newly established CEA CAR-T through intraperitoneal (I.P.) and intravenous (I.V.) infusions in solid tumor patients who failed to standard therapy. Methods: In this phase I, open-label, dose-escalation clinical trial, eligible patients were CEA positive and relapsed or refractory to at least second-line treatment. CAR-T cells was administered via I.P. or I.V. with dose escalation including low dose of 1-3 x106 CAR+/kg and high dose of 4-6 x106 CAR+/kg. Adverse events were graded by CTCAE 5.0. Tumor responses were evaluated using RECIST 1.1. Results: Between June 2022 to Jan 2024,40 pts were enrolled and infused CAR-T cells, including 35 CRC pts, 3 GC pts, 1 NSCLC pts and 1 BTC pts. There were 16 pts in the I.P. group and 24 pts in the I.V. group. CRS was observed in 62.5% of the pts at grade 1-2, and no ICANS or treatment related death was reported. Grade 1-2 mucositis was reported in 25% of the patients. Immune-mediated diarrhea and colitis of all grades occurred in 32.5% of the patients, including 17.5% grade 3 events. And 100% of patients experienced grade 3-4 hematologic toxicity. In terms of efficacy, the I.P. group displayed a higher objective response rate (ORR) of 25% (4/16), compared to 8% (2/24) in the I.V. group, alongside a superior disease control rate (DCR) of 88% (14/16) in I.P. compared to 67% (16/24) in I.V. group. Notably, within the high-dose group receiving I.P. infusion, the ORR increased to 28.5%. Moreover, the responded patients in the high-dose group all had sustained tumor remission for more than 5 months, including one patient who had a 76% target lesions regression at six months follow up. CAR-T cells demonstrated robust expansion in both the I.P. and I.V. groups, while no significant difference was found in maximum concentration. Conclusions: The CEA CAR-T cell therapy had acceptable toxicity via I.P. or I.V. infusion. We have observed a promising antitumor potential by I.P. infusion and a prolonged tumor remission in high-dose group. Further investigation is needed to highlight these findings and the corresponding mechanisms. Clinical trial information: NCT05396300 . [Table: see text]
Spatially resolved multi-region proteomics for prediction of clinical outcome in deficient mismatch repair metastatic colorectal cancer treated with PD-1 blockade.
Authors: Saberzadeh Ardestani Bahar , Liu Zhenglong , Stein Mariam I , Sherman Will , Graham Rondell P. , Trussoni Christy , Ordog Tamas , Sinicrope Frank A. 
Published: June 2024

3520 Background: In patients with metastatic colorectal cancer (CRC) and deficient DNA mismatch repair (dMMR), we previously found transcriptomic signatures reflecting stromal compartment composition and proliferative capacity that can predict the efficacy of immune checkpoint blockade (ICB). To identify proteomic markers of response and/or resistance to ICB, we performed spatially resolved proteomic analysis of the tumor microenvironment. Methods: Patients with surgically resected, primary dMMR metastatic CRCs received pembrolizumab (Mayo Clinic, N=30). In FFPE tissues, Digital Spatial Profiling of 71 proteins was performed using panels covering immune cells, immune activation, cell death, PI3/AKT signaling, MAPK signaling, and pan-tumor markers (GeoMx nCounter). In ten regions of interest/slide (~600 µm2) at the tumor invasive margin, protein expression was determined in four cellular compartments: epithelium (panCK+), immune cells (CD45+; leucocyte common antigen), stroma (panCK-), and nonimmune stroma (panCK-/CD45-). After normalization, protein abundance per compartment was analyzed by response (RECIST 1.1) [OmicVerse Python]. Differentially expressed proteins (binary) were examined by progression-free survival (PFS) using multivariable Cox regression with covariate adjustment (Lifelines Python). Results: Pre-treatment panels including 71 proteins were analyzed by treatment response and PFS after PD-1 inhibition. Proteins found to be significantly associated with response (p< 0.01) and PFS are described. Across all compartments, responders showed upregulation of NK cells and T cell subsets (CD3+, CD4+, CD8+), and ICOS; strongest association was found for CD4+: HRadj: 0.16; 95%CI: 0.08-0.31; p< 0.001. Nonresponders showed higher phospho-JNK (HRadj: 2.09; 95%CI: 1.28-3.42; p=0.003) and SMA. In the epithelial compartment, upregulation of the Treg marker CD25 and reduced caspase-9 were observed in responders. Among responders, the stromal compartment was highly enriched in HLA-DR, dendritic cells (CD11c), PD-L1, immune activation markers (CD40, CD44, CD80, CD27), CD95/Fas, and GZMB. In the stromal compartment, downregulation of BCL6 and phospho-GSK3B was observed in responders. The immune compartment of responders showed increased beta2-microglobulin and Ki-67, while the non-immune stromal compartment showed increase in the macrophage marker CD68. Importantly, proteins found to be upregulated in responders were significantly and independently associated with longer PFS whereas the opposite was true for nonresponders. Conclusions: In metastatic dMMR CRCs, spatially defined protein markers were significantly associated with anti-PD-1 response, and independently associated with patient PFS (strongest predictive utility for CD4 in immune stroma and phospho-JNK in epithelium).
Financial toxicity and unmet essential needs in patients with gastrointestinal cancer.
Authors: Lapen Kaitlyn , Dee Edward Christopher Christopher , Thom Bridgette , Aviki Emeline Mariam , Chino Fumiko 
Published: June 2024

3527 Background: Patients with gastrointestinal (GI) cancers face complex, multimodality treatment and often experience financial toxicity (FT), which can negatively affect both psychosocial and oncologic outcomes. Despite increased recognition of the role of the social determinants of health in driving cancer disparities, best practices in screening for FT and assessment of unmet essential needs in this population is still unknown. Methods: From 6/2022-8/2023, cross-sectional FT assessments were conducted at a comprehensive cancer center for all patients with gastrointestinal cancers. The Comprehensive Score for Financial Toxicity (COST) assessed FT; ability to meet essential needs, financial concerns, and quality of life (QOL) were also queried. Multivariate linear and logistic regression tested for predictors of FT and unmet needs and were adjusted for patient and clinical characteristics. Results: There were 8,335 patients with GI cancers who completed the FT and essential needs assessment. Mean age was 63.0 years (SD 12.6) and 76% were non-Hispanic white (NHW). GI subsites were most commonly colon (29%), rectum (21%), and pancreas (18%). 54% had active cancer treatment (chemotherapy, radiation, or surgery) within 120 days of assessment. Mean COST score was 24.3 (SD 10.7; scale 0-44, lower scores indicate worse FT). 63% had COST <26 diagnostic of FT. Regression analysis found greater FT was associated with non-NHW race/ethnicity (β 4.43, P<0.001), advanced disease [stage III (β 1.34, P<0.001), stage IV (β 1.68, P<0.001)], and recent treatment (β 3.23, P<0.001). Patients ≥65 years had lower FT (β -3.67, p<0.001). 28% reported difficulty meeting an essential need including paying for transportation (12%), housing (12%), food (11%), and medications (11%). Regression analysis found unmet needs were associated with non-NHW race/ethnicity (OR 2.34, 95% CI 2.09-2.62, p<0.001), advanced disease [stage III (OR 1.28, 95% CI 1.09-1.49, p=0.002), stage IV (OR 1.27, 95% CI 1.08-1.49, p=0.003)] and recent treatment (OR 1.25, 95% CI 1.12-1.39, p<0.001). FT and unmet needs did not vary significantly by disease subsite. 26% reported using savings to pay for cancer treatment; an additional 7% had no savings to begin with. 10% took less medications than prescribed due to cost. Mean QOL score was 7.2 [(SD 2.0) 0 “as bad as it can be” to 10 “as good as it can be”]. Regression analyses found greater FT was associated with lower QOL (β -0.98, p<0.001), increased amount of savings to pay for treatment (β 0.48, p<0.001), and taking less medications than prescribed due to cost (β 0.11, p<0.001). Conclusions: Screening for FT and essential needs is possible in a diverse cohort of patients with GI cancers. Over half were identified to have FT and over one fourth had unmet essential needs. Identifying and addressing the financial burdens of cancer treatment and essential needs may improve QOL, medication adherence, and cancer survivorship.
Consensus molecular subtypes (CMS) as prognostic and predictive biomarkers of RAS wild-type (WT) metastatic colorectal cancer (mCRC): Pooled analysis of the randomized trials FIRE-1, FIRE-3, XELAVIRI, and PanaMa.
Authors: Stahler Arndt , Modest Dominik Paul , Stintzing Sebastian , Held Swantje , Fischer von Weikersthal Ludwig , Müller Lothar , Graeven Ullrich , Decker Thomas , Heintges Tobias , Kahl Christoph , Scheithauer Werner , Kiani Alexander , Kaiser Florian , Schwaner Ingo , Fruehauf Stefan , Karthaus Meinolf , Trarbach Tanja , Klauschen Frederik , Horst David , Heinemann Volker 
Published: June 2024

3529 Background: CMS were associated with prognostic relevance in RAS WT mCRC, while their role as predictive biomarker is debatable. We aimed to assess the predictive impact of CMS on treatment with anti-EGFR vs. anti-VEGF antibodies vs. cytotoxic treatment alone in a pooled analysis. Methods: Available CMS data (called by predictedCMS method) of the randomized controlled trials FIRE-1 (FUFIRI vs. mIrOx); FIRE-3 (FOLFIRI+ cetuximab vs. bevacizumab), XELAVIRI (sequential vs. initially combined FOLFIRI+bevacizumab) and PanaMa (FOLFOX+panitumumab followed by FU/FA +/- panitumumab) of RAS WT mCRC were included. Non-evaluable CMS were excluded. Kaplan-Meier estimated overall survival (OS) and progression-free survival (PFS). Uni- and multivariate Cox regression analysis (including all baseline characteristics) was used to calculate hazard ratio (HR) and 95% confidence interval (95% CI). Results: 1147 tumors had available CMS data and 746 (65.0%) were RAS wild-type (WT): CMS1, n=89; CMS2, n=346; CMS3, n=71; CMS4, n=240. CMS were significant prognostic biomarkers in terms of PFS (median months, CMS1, 6.7; CMS2, 11.1; CMS3, 8.1; CMS4, 10.0, P<0.001) and OS (median months: CMS1, 14.8; CMS2, 28.7; CMS3, 19.5; CMS4, 26.5; P<0.001). CMS remained significant in a multivariate backward elimination Cox regression analysis including all baseline characteristic variables and BRAF status with regard to PFS ( P=0.03) and OS ( P=0.04) Interaction of CMS and treatment was significant regarding OS ( P<0.001) and PFS ( P=0.001). The longest OS was observed using anti-VEGF antibodies in CMS1 and anti-EGFR antibodies in CMS2 or CMS4 RAS WT tumors (Table). Conclusions: CMS were confirmed as prognostic biomarkers and might contain predictive information for the choice of anti-EGFR or anti-VEGF antibodies in RAS WT mCRC. Prospective validation remains mandatory. [Table: see text]
Receptor expression testing of the synchronous axillary nodal metastasis in early-stage breast cancer: Comparison of primary tumor and its draining nodes.
Authors: Abdallah Mahmoud , Tirona Maria Tria , Nwanwene Kemnasom , Khatri Jai Kumar , Sidda Adarsh , Biglow Layana Roslyn , Eldib Howide , Mahdi Ahmad 
Published: June 2024

e12542 Background: Early stage (Stage I-III) human epidermal receptor -2 (HER2) positive and triple negative breast cancers (TNBC) tend to behave more aggressively than hormone positive breast cancers with higher and earlier incidences of recurrences. Oftentimes, testing for receptor subtypes is done only on the primary tumor and not on the synchronous axillary metastasis, with the assumption that the axillary metastasis is congruous to the primary lesion. Current guidelines also do not specify a requisite to do this testing. Information about the receptor expression types is fundamental for the treatment of breast cancer. We aimed to determine if there is significant discordance between the primary and ipsilateral axillary metastasis in early-stage breast cancer. Methods: We conducted a retrospective analysis via electronic medical record review of a large institutional database from 2008 to 2020. Sample for this study included all patients with a diagnosis of early-stage breast cancer (Stage I - III) with triple negative or HER2 positive tumors. Data on demographics, comorbidities, receptor status, staging, and mortality were collected. Results: Electronic charts from 448 patients were reviewed. 140 patients had axillary node positive disease. 40 (29%) of the 140 patients underwent testing for receptors subtypes on both primary and axillary nodal metastasis. 8 (20%) of the 40 patients had discordance in their receptor subtype expressed in their respective axillary nodal metastasis. 32 (80%) of the 40 patients had axillary receptor expression congruous to the primary tumor. At the time of our review, there was no statistically significant mortality between discordant compared to concordant group (13% vs 20%; p=0.54). 2 patients were lost to follow up. Conclusions: Our data suggests that one in every five axillary metastatic breast cancers can have receptor subtypes discordant compared to the receptors expressed on the primary tumor. Knowledge about any such discordance between the primary and respective axillary metastasis has a consequential impact on the treatment approach for early-stage breast cancer. This is especially true if the patient’s nodal metastatic lesions indeed prove HER2 receptor positivity or do not express any receptors (TNBC). Consequently, patients may be being deprived of benefits from advances in treatment of these cancers, such as targeted therapies towards HER2 receptor, hormonal treatments when indicated, or the utilization of neoadjuvant chemotherapy. A strong case can be thus made to revise current standards to include receptor testing on all primary and synchronous axillary metastasis. Further testing is needed to validate our findings.
Degradation of estrogen receptor α induced by ionizing radiation contributes to senescence of ER+ breast cancer cells.
Authors: Wang Jufang , Li Hongyan , Zhang Hong 
Published: June 2024

e12544 Background: According to the clinical and pathological characteristics, breast cancer is usually classified into estrogen receptor positive (ER+), human epidermal growth factor receptor 2 positive and triple negative. Among them, ER+ breast cancer accounts for more than two-thirds of total breast cancer. Nowadays, both ionizing radiation and endocrine therapy are used for the treatment of ER+ breast cancer. In our previous studies, it was found that significant cellular senescence and reduction of endogenous estradiol (E2) were induced by carbon ion or X-ray exposure in ER+ breast cancer cells. However, the underlying mechanism remains unclear. Methods: Two human ER+ breast cancer cell lines, MCF7 and T47D, were chosen to investigate the senescence-associated indications after 1-10 Gy of X-ray exposure. Since the elevated estrogen receptor α (ERα) is the most significant characteristic of ER+ breast cancer, the levels of ERα were detected by qRT-PCR and West Blotting analysis. In addition, MCF7 tumors were established in BALB/C nude mice and discerned using immunohistochemistry after local exposure of tumors to 2 Gy of X-rays. Results: It was confirmed that the cell survival decreased in a dose-dependent manner after 1-10 Gy of X-ray exposure in both cell lines. Increased p21 protein expression which was considered as a senescence biomarker and enhanced senescence-associated β-galactosidase activity were also observed after X-ray exposure. Meanwhile, distinct cell cycle arrest was induced by 2 Gy of X-rays in T47D cells or by 8 Gy of X-rays in MCF7 cells, implying that T47D cells were prone to enter senescence. Furthermore, both the mRNA levels and protein levels of ERα were significantly decreased at 24 hours in the two cell lines when the exposure dose was up to 4 Gy of X-rays. Reduction of glucocorticoid-regulated kinase 3 (SGK3), a transcriptional target for ERα, was also observed in both cell lines, in according with the reported SGK3-dependent survival mediated by ERα/E2 dimer in ER+ breast cancer cells. In vitro experiments, the results verified the ERα degradation and the proliferating inhibition indicated by suppression of Ki67 protein in MCF7 tumor after 2 Gy exposure. Conclusions: These findings reveal that the degradation of estrogen receptor α induced by ionizing radiation contributes to the senescence of ER+ breast cancer cells and thereby inhibits the tumor growth. The results provide a potential therapeutic strategy to enhance the radiosensitivity of ER+ breast cancer cells through regulations of ERα or ERα-regulated kinase SGK3 in radiotherapy.
The correlation between Ki 67 and Oncotype Dx on HR+, HER2- early breast cancer management: Insights of molecular testing.
Authors: Campoverde Leticia , Camacho Felipe , Sanchez Adriana , Lugo Paulina 
Published: June 2024

e12546 Background: Elevated Ki-67 expression serves as an indicator of tumoral proliferation in breast cancer (BC) and is used in Ecuador for survival estimation, recurrence risk assessment, and guiding chemotherapy decisions. The Oncotype DX Breast Recurrence Score (ODX RS) is a validated 21-gene assay for hormone receptor-positive, HER2-negative invasive BC. It predicts chemotherapy benefits and the risk of distant recurrence over 10 years and is a mortality indicator. ODX RS has the potential to reduce the need for chemotherapy, alleviate financial burdens, and enhance clinical outcomes. Despite conflicting evidence on the significance of Ki-67 in the ODX RS, there is a lack of exploration within Latin populations. This study aims to compare the correlation of immunohistochemical (IHC) measured Ki-67 to the ODX RS in the Ecuadorian population. Methods: A retrospective analysis included women with early BC who underwent ODX RS testing in Ecuador from May 2020 to January 2023. Inclusion criteria: early BC (T1-T3/N0-N1a); IHC estrogen receptor (ER) positive; HER2 negative; and availability of tumor size, grade, lymph node status, and Ki67 proliferation index data. Exclusion criteria: patients with recurrent BC, incomplete pathology, or lacking IHC data. Patients were categorized into low (≤5%), intermediate (6%–29%), and high Ki67 expression groups (≥30%). Using the statistical software SPSS, the correlation between ODX scores and Ki-67 expression was analyzed using Pearson’s correlation coefficient. For risk stratification groups, Spearman's correlation was employed. Results: Among 77 patients undergoing Oncotype DX testing, 64 (with a mean age of 55) met the inclusion criteria. Eighty-six percent of cases were invasive ductal carcinomas (IDC). Seventeen percent exhibited low Ki-67 expression, 61% intermediate, and 20% high. No statistically significant correlation was found between IHC Ki-67 expression and ODX RS (r=0.051; p=0.69), neither when stratified by categories (r=0.086; p=0.50). A subanalysis based on risk categories showed 82% correspondence in the low Ki-67 group, 18% in the intermediate group, and 31% in the high Ki-67 group. No significant correlation was observed when stratified by histological types (invasive ductal carcinoma and invasive lobular carcinoma), nor by sample origin (core biopsy, excisional biopsy). Conclusions: There was no correlation between IHC Ki-67 expression and ODX risk scores in this study involving Ecuadorian patients. Our findings emphasize that IHC Ki-67 expression should not be the sole determinant for guiding therapeutic decisions and predicting recurrence in early breast cancer.[Table: see text]