bluuebunny/crossref_metadata_2025 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]
Targeted genotyping for recurring variants in cancer susceptibility genes in non-Ashkenazi Jewish patients with breast cancer diagnosed ≥ 50 years.
Authors: Bernstein-Molho Rinat , Abu Shhada Narmeen , Laitman Yael , Netzer Iris , Shoval Shelly , Friedman Eitan
Published: June 2024

e12547

Background: Several recurring pathogenic variants (PVs) in BRCA1/BRCA2 and additional cancer susceptibility genes are described in ethnically diverse Israeli population. Since 2019 testing for these recurring PVs is reimbursed unselectively for all breast cancer (BC) patients in Israel, while extended multi-gene panel testing is reimbursed based on specific clinical criteria. We aimed to evaluate the yield of genotyping for these recurring PVs in non-Ashkenazi Jewish BC patients diagnosed ≥ 50 years. Methods: Clinical and genotyping data of all BC patients undergoing oncogenetic counseling at the Oncology institute at Sheba medical center from June 2017 to December 2023 were reviewed. Results: Of 2706 BC patients (mean age at diagnosis 54 years; range, 20-92 years) counseled, 515 patients of non-Ashkenazi Jewish (all 4 grandparents) descent, diagnosed ≥ 50 years of age were genotyped, 55 with triple-negative BC (TNBC) and 460 with non-TNBC. One of the recurring PVs in BRCA1/BRCA2 were detected in 12.7% (7/55) of TNBC patients and 0.65% (3/460) in non-TNBC. One patient with non-TNBC had PMS2 PV. Low-penetrance variants (not all in BC related genes) were found in 2.5% of genotyped TNBC and in 3.7% of non-TNBC patients, including CHEK2 c.499G>A (n=3), APC c.3920T>A (n=4), and heterozygous MUTYH c.1187G>A (n=5). Following first-pass genotyping, 146 patients performed multigene panel testing, none carried a BRCA1/BRCA2 PV, and only 5/127 non-TNBC (3.9%) harbored PVs in CHEK2 (n=2), ATM c.103C>T (n=2) and NBN (n=1). Conclusions: The observed low rates of PV detection in non-Ashkenazi Jewish non-TNBC cases older than 50 years at diagnosis, mostly for clinically insignificant variants, questions the justification of unselected genotyping in this subset of patients.
FKBP10-inhibited β-catenin ubiquitination in the malignant transformation of breast epithelial cells.
Authors: Chen Wei-xian , Zhu Bei , Shao Quan-feng , Zheng Lin
Published: June 2024

e12580

Background: Current model of breast cancer (BCa) progression suggests a linear and three-stage process from normal epithelial tissue to ductal carcinoma in situ (DCIS), and then invasive ductal carcinoma (IDC). Since the detailed mechanisms for BCa oncogenesis remain largely unclear and there is still a lack of root-cause level interventions, exploring the underlying molecular alterations during three-stage process of BCa carcinogenesis is urgently needed. Methods: Three-stage specimens from the very same patients were collected. High-throughput sequencing was applied to obtain the differentially expressed genes among normal, DCIS, and IDC samples. Expression level and prognostic value of the selected gene were evaluated by PCR, western blot, tissue chip, and bioinformatics analysis. MCF10DCIS and MCF10Ca cell lines were respectively used to establish DCIS and IDC tumor models in breast epithelial cell-specific gene knockout mice. Patient-matched DCIS and IDC organoids were also constructed. Signaling pathways associated with malignant transformation of breast epithelial cells were detected by using high-throughput sequencing in mouse models and organoids. Protein binding was evaluated by protein mass spectrometry and co-immunoprecipitation. Results: By using high-throughput sequencing, we found that FKBP10 levels were gradually increased in three-stage specimens from the very same patients and were associated with poor prognosis. By establishing DCIS and IDC models in FKBP10flox/floxCre+/- and FKBP10flox/floxCre-/- control mice, we confirmed that FKBP10 deficiency could suppress BCa formation. Besides, FKBP10 knockdown could reduce oncogenic potentials in patient-matched DCIS and IDC organoids. Wnt/β-catenin signaling pathway was related to malignant transformation of breast epithelial cells, when MCF10DCIS+FKBP10flox/floxCre+/- model, MCF10Ca+FKBP10flox/floxCre+/- model, FKBP10-knockdown DCIS and IDC organoids, and their corresponding controls were comprehensively compared. Moreover, FKBP10 was found to inhibit β-catenin ubiquitination with the help of deubiquitinase Trim13, thus activating Wnt/β-catenin signaling pathway and accelerating malignant transformation of breast epithelial cells. Increased level of β-catenin was able to promote FKBP10 expression in a feedback loop. We also confirmed that exosome-loaded FKBP10-targeting peptide could suppress tumor growth both in vitro and in vivo. Conclusions: FKBP10-inhibited β-catenin ubiquitination was responsible in the malignant transformation from normal tissue to DCIS, and then IDC. Our study would uncover novel regulatory mechanisms of FKBP10 in three-stage process of BCa carcinogenesis and provide a new therapeutic approach for clinical treatment.
Pathological complete response rate to anthracycline versus non−anthracycline based chemotherapy regimens in localized and regional HER2 neu positive breast cancer.
Authors: Halaweh Osama M. , AlAbbad Maram , Alshehri Abdulrahman , Alsubait Saud , AlDaabil Riyadh , Abushullaih Samer
Published: June 2024

e12632

Background: Debate over the need of anthracycline as part of neoadjuvant chemotherapy in HER2-neu early breast cancer was addressed in many trials with results favoring similar outcomes with or without anthracycline. This was not adopted fully in Saudi Arabia because of concern regarding ethnic differences in response to treatment. We conducted this retrospective analysis to evaluate if there is any difference in pathological complete response rate (PCR) in patients with early HER2-neu positive breast cancer depending on neoadjuvant chemotherapy regimen. Methods: Patients with HER2-neu positive early breast cancer who were treated with neoadjuvant chemotherapy at Johns Hopkins Aramco Healthcare (JHAH) facility between the year 2018 and 2022 were all evaluated for pathological subtype, HER2-neu status and type of neoadjuvant chemotherapy administered. Pathological response status was evaluated in all patients and PCR was measured to see if there was any difference depending on the use of anthracycline (AC) or non-anthracycline (non-AC) based chemotherapy regimen. Patient demographics, tumor characteristics, clinical stage, treatments and outcomes were collected via JHAH’s oncology registry. Categorical variables are reported as frequencies and percentages. The association between chemotherapy regimen AC vs non-AC based and PCR was analyzed using Fisher Exact Test. p-value <0.05 was considered statistically significant. Analyses were conducted using JMP version 15. Results: In this study 59 HER2-neu positive early breast cancer patients were identified. We examined their clinical characteristics and treatment outcomes. Median age was 57. The most prevalent histology was invasive carcinoma of no special type (79.66%), Estrogen receptor positivity was observed in 72.88% of patients, while progesterone receptor positivity was seen in 62.71% of cases. Majority of patients were alive (96.61%) at the time of data collection. There was no significant difference in clinical stage in both groups. The association between chemotherapy type and pathological response was assessed. Among patients receiving AC chemotherapy (n=29), 55.17% achieved PCR, while for patients receiving Non-AC chemotherapy (n=30), the PCR rate was 50%. However, this difference was not statistically significant (p-value = 0.8). Conclusions: In our cohort of HER-neu positive early breast cancer patients who received neoadjuvant therapy there seems to be no significant difference in PCR with AC or Non-AC based chemotherapy regimens. This is concordant with the international trends.
Trastuzumab-induced cardiotoxicity in patients with metastatic HER2-positive breast cancer treated at a reference hospital in Mexico.
Authors: Leocachin-Parra Daniela Leticia , Bocardo-Galvan Jessica Berenice , Grajales Rocio , Carrillo-Estrada Montserrat
Published: June 2024

e13032

Background: In Mexico, breast cancer represents the leading cause of cancer-related death in women, and up to 52% is diagnosed at a metastatic stage. Up to 20-25% of women with breast cancer have overexpression of the human epidermal growth factor receptor 2 (HER2) which is associated with an aggressive behavior. The most relevant adverse effect associated with therapy targeting this receptor is an increase of up to 4 times in the rate of myocardial dysfunction. There is limited research in the Mexican population, especially in the metastatic context. This review is intended to be conducted in the national population, including patients with HER2-positive metastatic breast cancer who have received trastuzumab treatment, to determine the main characteristics of such myocardial dysfunction using the definition of cardiac dysfunction proposed by the International Cardio-Oncology Society (ICOS) in 2021, as well as its current prevalence. Methods: Observational, descriptive, cross-sectional, retrospective study. Medical records of patients diagnosed with metastatic HER2-positive breast cancer between January 2017 and December 2022, who received trastuzumab and had a determination of left ventricular ejection fraction (LVEF) before treatment and at least two LVEF determinations during treatment to determine the presence or absence of cardiotoxicity. LVEF could have been determined by MUGA (Multigated Acquisition Scan) or by echocardiogram. Results: A total of 103 patients were included, with a mean age of 55 years. The found prevalence of cardiotoxicity was 30.09%. Among the most frequent clinical characteristics of these patients were obesity in 32.2% [n= 10], smoking habit in 12.9% [n= 4], and type 2 diabetes in 9.7% [n= 3]. The diagnosis of de novo metastatic disease was 48.4% [n= 15]. A history of ischemic heart disease was present in 3.2% [n= 1], and a frequency of 12.9% [n= 4] of patients with borderline LVEF (50-54%) was reported at baseline, with only 3.2% [n= 1] documented with a baseline LVEF < 50%. The median number of trastuzumab cycles administered during follow-up was 14 cycles, anthracycline therapy was documented in most patients, and previous exposure to thoracic and/or mediastinal radiotherapy with a dose exceeding 30 Gy was found in 35.5% [n= 11]. Referral to cardiology and/or cardio-oncology service was 51.6% [n= 16]. Discontinuation of anti-HER2 treatment was carried out in 3 patients (2.9%). Conclusions: We demonstrated a prevalence of cardiotoxicity from anti-HER2 agents in our population similar to that reported in the international literature. Multicenter studies are necessary to define the prevalence more accurately in the Mexican population, as well as prospective studies to demonstrate the association between cardiovascular risk factors and clinical characteristics with the development of cancer therapy-related cardiac dysfunction.
Expanding multiple features of extracranial metastasis to predict survival for patients with breast cancer brain metastasis: A population-based retrospective analysis.
Authors: Xu Hangcheng , Wang Yan , Sa Qiang , Wu Yun , Zhou Yiran , Wang Jiayu , Xu Binghe
Published: June 2024

e13038

Background: Breast cancer brain metastasis (BCBM) is associated with poor survival outcomes and reduced quality of life. The Graded Prognostic Assessment (GPA) score model serves as a well-established tool for predicting the prognosis of BCBM. Notably, the presence of extracranial metastasis (ECM) is considered as a significant prognostic factor in the breast GPA. This study aims to further refine this factor to enhance the prognostic prediction for BCBM. Methods: This study included all inpatients diagnosed with BCBM at the Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS), from January 2010 to July 2021. The subsets were categorized by the presence, number, location, and control status of ECM. Baseline clinicopathological characteristics were documented and compared among subgroups. The primary endpoint was overall survival (OS) after the diagnosis of BCBM. We used the Kaplan–Meier method with log-rank test to compare the survival outcomes. Cox regression analyses were conducted to identify significant prognostic factors, which were then incorporated into a new Breast-GPA model. Results: A total of 286 patients with BCBM were included in the study. Kaplan–Meier survival curves suggested that patients without ECM when diagnosed with BCBM showed better survival (p=0.0068). In the subgroups with ECM, more than 3 organs involved, both bone and visceral metastasis and progressive ECM portended dismal OS (p=0.0032, 0.0014 and 0.00054). Multivariate analysis (MVA) demonstrated that the presence, number, and control status of ECM significantly influenced OS after BCBM (p=0.01, 0.03, and 0.048, respectively). The specific location of ECM also had a significant impact on the long-term survival (p=0.0014). By modifying the current GPA model to include categories for '3 or fewer controlled ECM', the predictive accuracy of the newly established GPA model was further enhanced. Conclusions: More extracranial sites, both bone and visceral invasion and uncontrolled ECM were independent prognostic factors for dismal survival outcomes of BCBM patients.
Mutational landscape of HER-2 low breast cancer.
Authors: Vosoughi Elham , Nafissi Nellie , Mahadevan Aditya , Lee Seungshin , Mehta Rita S. , Parajuli Ritesh
Published: June 2024

e13040

Background: HER2-low breast cancer is defined as HER2 IHC score of 1+ or 2+/ISH- tumors. Anti-Her-2 therapies such as trastuzumab deruxtecan improve progression-free survival (PFS) and overall survival (OS) in patients with HER-2 low metastatic breast cancer. However, the mutational landscape of HER2-low BC is still not well defined. The aim of this study is to characterize the biological and clinicopathological landscape of HER2-low BC by next generation sequencing. Methods: We conducted a single institution, retrospective chart review of patients with metastatic breast cancer (MBC) from 1/2020 to 4/2023. We obtained Next generation sequencing data and correlated it with clinical outcomes. Patients with HER2 IHC score of 1+ or 2+/ISH- tumors referred as HER2-low, while with no HER2 IHC staining at all were referred as HER2-zero, and pts with HER2 IHC 3+ or HER2 IHC 2+/ISH+ referred as HER2+. Results: A total of 98 pts were enrolled:45 pts with HER2-low tumors, 29 pts with HER2+ and 24 pts with HER2-zero tumors. In the HER2-low cohort, 58% (26 pts) were initially diagnosed with loco regional disease while 42% presented with stage IV at diagnosis. On average patients were on 3 lines of therapy for metastatic disease (ranging between 1 to 12). Of those 35% received T-DXd. High Ki-67 proliferation (≥20), reported in 58% (26 pts). OS was 54.4 months, 95% CI [ 42.5,100.2]. In the HER2+ cohort, 31% of pts presented with stage IV at diagnosis. On average pts received 3 lines of therapy (ranging from 1 to 14). 69% of pts received T-DXd. High Ki-67 reported in 48% of pts. OS was 59.2 months, 95% CI [39.2,96,1]. In the HER2-zero, 62.5% of pts presented with stage IV. On average pts received 1 line of therapy (ranging between 1 to 5), 62% of pts had high Ki-67. OS of 41.6 months 95% CI [18.4, 77.9]. Conclusions: Although limited by the sample size, our data suggests that HER-2 low breast cancer tends to be more locally advanced or metastatic at the time of presentation. HER-2 low BC is associated with a higher Ki-67 index and tends to harbor more mutations. HER-2 low may not just be a target, but a unique biological entity and can be distinguished from HER2-Zero BC with higher prevalence of HR+ and other biomarkers and better OS. NGS data from a larger data set is required to better characterize HER-2 low breast cancer. We suggest that clinicians obtain NGS panel in all patients with HER-2 low MBC. [Table: see text]
Transcriptomic analysis of the tumor immune microenvironment (TIME) in patients with breast cancer with liver metastasis (BCLM).
Authors: Guo Weihua , Tan Jiayi , Chan Bryan , Mark Cynthia , Bitar Jin Sun , Bose Shikha , Pujara Vivek , Campbell Moray , Shiao Stephen Lawrence , Yuan Yuan
Published: June 2024

e13045

Background: Breast cancer with liver metastasis (BCLM) is a significant predictor of worse prognosis and poor overall survival. Liver specific homing of breast cancer is not well understood, and the tumor immune microenvironment (TIME) likely plays a critical role in the process of forming BCLM. This retrospective study was conducted to determine the clinical risk factors and transcriptomic biomarkers associated with BCLM. Methods: A retrospective single institute chart review was conducted. Patient, disease characteristics and treatment variables were reviewed. Liver metastasis specific survival (defined by overall survival time from the diagnosis of liver metastasis) were compared across three breast subtypes (i.e., ER+/HER2-, HER2+, and triple-negative (TN) breast cancer) using Kaplan-Meier curves. Next generation sequencing (NGS) via commercial platforms were then used to obtain transcriptomic data. Transcriptomic analysis including differential gene expression analysis, gene set enrichment analysis (GSEA), as well as gene deconvolution analysis with TIMER2.0 were conducted for comparison of transcriptomic profiles and immune compositions across the three breast cancer subtypes. Results: 176 patients with BCLM and available liver metastasis biopsy were identified through retrospective chart review. Liver metastasis specific survival was compared, HER2+ BCLM patients (n = 17) had the best outcome and TN BCLM patients (n = 46) had the worst outcome with ER+ BCLM patients (n = 112) in the middle (p < 0.0001, ER+ vs TNBC p < 0.0001, ER+ vs HER2+ p = 0.038, HER2+ vs TNBC p = 0.00011). Principle component analysis on the transcriptomic data of 30 liver metastatic samples revealed different expression profiles between ER+ (n = 20) and TN (n = 7) BCLM, while HER2+ (n = 3) BCLM did not shown statistical differences with either group. B cell mediated immunity was upregulated in TN BCLM compared to ER+HER2- BCLM by GSEA (normalized enrichment score = 2.35, adjusted P-value = 0.19). Consistently, plasma cells were relatively enriched in TN BCLM compared to ER+ and HER2+ BCLM (p = 0.037) based on CIBERSORT estimation. In contrast, monocytes and neutrophils were enriched in ER+ BCLM (p = 0.0093 & 0.018) based on TIMER2.0 estimation. Additional NGS analysis is currently underway for increased sample size. Conclusions: BCLM in TNBC was associated with significantly worse overall survival. TIME in TN BCLM enriched for genes associated with B cell mediated immunity while ER+ BCLM had more monocyte/neutrophil mediated immunity.
The association between age, toxicity and outcomes of abemaciclib treatment in HR+/HER2- metastatic breast cancer.
Authors: Ovcaricek Tanja , Matos Erika , Borstnar Simona , Ribnikar Domen , Grasic Kuhar Cvetka , Cankar Kaja
Published: June 2024

e13062

Background: The efficacy and safety of abemaciclib in patients (pts) with HR+/HER2− metastatic breast cancer (MBC) was demonstrated in the MONARCH clinical trials; however, real-world evidence is lacking, particularly in elderly pts. The dose reduction strategy used in the MONARCH trials has been shown to be an effective way of managing toxicity without compromising survival. Here, we provide real-world data on the efficacy and safety of abemaciclib treatment, focusing also on elderly pts with HR+/HER2− MBC and the association between abemaciclib dose reduction and survival. Methods: The efficacy and safety of abemaciclib in patients (pts) with HR+/HER2− metastatic breast cancer (MBC) was demonstrated in the MONARCH clinical trials; however, real-world evidence is lacking, particularly in elderly pts. The dose reduction strategy used in the MONARCH trials has been shown to be an effective way of managing toxicity without compromising survival. Here, we provide real-world data on the efficacy and safety of abemaciclib treatment, focusing also on elderly pts with HR+/HER2− MBC and the association between abemaciclib dose reduction and survival. Results: The median age of 134 pts was 62 yrs (IQR, 54-71), with 40 pts (29.9%) older than 70 yrs. Median rwPFS (mrwPFS) with abemaciclib + endocrine therapy in the ≥70 vs <70 age group was 15 vs 17 months (HR:1.1, 95% CI 0.70-1.76; p=0.65) and median OS (mOS) was 25 vs 34 months (HR:1.4, 95% CI 0.82-2.39, p=0.21). The most common rwAEs are shown (Table). Abemaciclib dose reductions occurred in 40% of pts ≥70 yrs of age compared to 28% of younger pts (χ2 (1)=1.98; p=0.22). There was no difference in mrwPFS between pts who had a dose reduction and those who did not (mrwPFS 15 vs 17 months (HR: 1.03, 95% CI 0.65-1.63, p=0.91) and mOS 28 vs 30 months (HR: 1.16, 95% CI 0.68-1.99; p=0.58)). Conclusions: The results of our study support the efficacy and safety of abemaciclib treatment in pts with HR+/HER2- MBC in real-world clinical practice. Age did not appear to be an important factor associated with higher rates of toxicity and similar efficacy of abemaciclib was demonstrated in the elderly pts population compared to younger pts. Importantly, abemaciclib dose reductions did not compromise survival. Clinical trial information: ERIDNPVO-0060/2022. [Table: see text]
Metastatic breast cancer in elderly women: A retrospective cohort study in Morocco.
Authors: Maadin Kaoutar , Mellas Nawfel , Benbrahim Zineb , Oualla Karima , Amaadour Lamiae , Arifi Samia
Published: June 2024

e13073

Background: Breast cancer (BC) stands as the predominant malignancy among women worldwide, presenting a significant global public health problem. In Morocco, it is the leading cause of cancer-related mortality in females. However, there exists a limited understanding of outcomes and treatment patterns for elderly patients with metastatic breast cancer (MBC) in our context. Methods: We conducted a retrospective cohort study at the Department of Medical Oncology, Hassan II University Hospital of Fez, focusing on 92 female patients aged 65 years or older diagnosed with MBC, between January 2012 and December 2016. The primary objectives were to estimate overall survival (OS) and progression-free survival (PFS), describe treatment patterns, and characterize the clinicopathological, and prognostic aspects of MBC in elderly women in Morocco. Results: The cohort’s median age was 70.88 (range, 65-88years) with 45.6% of patients aged of 65 to 69 years, 34.8% between 70 to 74 years old, and 19.6% over 75. Most patients (77.2%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 to 1, and only 33.7% had comorbidities. De novo stage IV constituted 59.8% of all cases. Metastatic recurrences represent 40.2% with 16.2% having recurrence within 12 months, and 83.8% having a recurrence interval exceeding 12 months. The median time to recurrence was 45.5 months. Invasive ductal carcinoma (IDC) was the predominant histological type (81.1%), with SBR grade II (51%) and grade III (21.7%). Metastases were observed in pleuropulmonary (78.3%), bone (56.5%), lymph nodes (33.7%) and liver (30.4%). With 71.7% having metastases in fewer than three sites, while 28.3% had metastases in three or more sites. Molecular profiling showed Luminal A (38%) and Luminal B (26.1%) subtypes as the most prevalent, followed by triple-negative (17.4%) and HER2+ (15.2%). Treatment modalities included chemotherapy (50%), hormone therapy (15.2%) or a combination of the two (17.4%), and anti-HER2 targeted (14.1%). Median OS was 37 months (95% CI: 16.86 - 57.13 months), and median PFS was 33.16 ± 4.1 months. Anti-HER2 therapy showed a significant association with survival (p = 0,05). Conclusions: This study highlights the characteristics, survival, and treatment modalities of elderly patients with MBC in Morocco. Despite the predominance of luminal BC an intriguing observation was the frequent use of chemotherapy as first line modality.