bluuebunny/crossref_metadata_2025_split huggingface dataset:
A disease registry study to prospectively observe treatment patterns and outcomes in patients with HER2+ unresectable locally advanced or metastatic breast cancer (aBC): Interim results of the ESTHER study (NCT02393924).
Authors: Harper-Wynne Catherine , Owen James , Velikova Galina , Sutherland Stephanie , Jivulescu Mircea , Ring Alistair E. 
Published: June 2023

e13039 Background: Over the last decade the standard-of-care treatment for patients with HER2+ aBC has included anti-HER2 therapies often combined with chemotherapy. These approaches have shown efficacy in clinical trials which have recruited patients in restricted populations defined by lines of therapy and previous treatments. There are few data regarding the long-term outcomes of patients treated with these regimens, including those with brain metastases. We conducted a prospective, multicentre non-interventional study to observe anti-cancer treatment regimens and clinical outcomes in patients with HER2 positive aBC. Methods: Adult patients diagnosed with HER2-positive aBC within the last 6 months were included. No specific treatment approach or course was mandated by the protocol. Source data was taken from the patient’s chart and other medical records, then reported by means of an electronic data collection system. Data regarding treatment received, efficacy (progression-free and overall survival (PFS), response rates (RR) and development of CNS metastases) and safety (including cardiac toxicity) were captured. Results: Between February 2015 and April 2018, 311 eligible patients were recruited with median age 57 years (24-96). At diagnosis of aBC the most common distant metastatic sites were bone (n = 145;47%), liver (n=117;38%), lung (n=100;32%) and brain (n=21;7%). First line treatment was with pertuzumab (P)/trastuzumab(T)/chemotherapy (n=212;68%), T/chemotherapy (n=45;14%), other T combinations without P (n=19;6%), Trastuzumab Emtansine regimens without T or P (n=16;5%) (19; 5% other combinations). Patients’ status as of cut-off date for this analysis (28th Feb 2022, median follow-up 44.1 months) is shown. The median PFS of patients treated in the 1st, 2nd and 3rd lines was 26.7 months, 10.7 months and 8.6 months. At the time of this analysis an additional 60 patients (19%) had developed brain metastases during first line. The number of patients starting 2nd, 3rd and 4th line treatment with brain metastases were 28 (22%), 17 (40%), 7 (37%) respectively. Conclusions: In routine clinical practice, as reflected by this registry, at least 40% of patients who initiate first line therapy for advanced breast cancer do not proceed to 3rd line therapy, and brain metastases become increasingly common. These findings have implications for selection of optimal 2nd and 3rd line treatment. Clinical trial information: ISRCTN02393924 . [Table: see text]
Real world clinical outcomes of patients with HER2 positive metastatic breast cancer with central nervous system involvement treated with modern regimens.
Authors: Siegelmann-Danieli Nava , Livnat Idit , Ginsburg Roni , Yarden Adva , Apter Lior , Drori Michal , Drizon Anat , Chodick Gabriel , Sharman Moser Sarah 
Published: June 2023

e13040 Background: In 25-55% of Human epidermal growth factor receptor type 2 (HER2+) metastatic breast cancer (MBC) patients, central nervous system metastases will occur. Herein we describe treatment patterns and clinical outcomes in a modern series of patients with HER2+ MBC with brain metastases in a population based cohort of Maccabi Healthcare Services in Israel. Methods: Patients aged ≥18 years, who initiated first-line treatment for metastatic HER2 positive breast cancer between 1st January 2013 until 30th June 2021 and received brain surgery and/or irradiation were identified and followed until December 2021. The index date was fixed as the first day of first-line treatment. Time on treatment (ToT, as a surrogate for progression-free survival) and overall survival (OS) were determined. Results: A total of 61 patients with HER2+ MBC and brain metastases were identified. Median theoretical follow-up time was 6.2 years. The cohort consisted of 98.4% females, median age 50 years (IQR: 44-63), tumors were invasive ductal in 85% and in 57% were hormone receptor positive; ECOG performance status was 0-1 in 51% and missing in 32%. All patients initiated tratuzumab-pertuzumab-chemotherapy (TPC) combination, and second-line treatment was started in 72% during study follow up. Median ToT for first and second-line treatments were 16.9 months (95% CI: 13.9-27.7) and 7.92 months (5.6-10.9), respectively. In 15 patients (25%) brain metastases were diagnosed prior to TPC or within 6 months of treatment initiation, in 25 patients (41%) while on TPC treatment, and in 21 (34%) at later periods. Median OS was 45.5 months (35.4-71.2) from initiation of first-line treatment, and 36.3 months when brain metastases occurred upfront, 59.1 months when diagnosed while on TPC, and 40.8 months when diagnosed later. Median OS from brain metastases diagnosis was 25.1 months (17.0-34.6). Conclusions: We provide ToT (as surrogate for PFS) and OS on HER2+ MBC patients with brain metastases treated with upfront TPC in first line setting and mostly TDM1 in second line setting in a real-world setting. Outcome with newer anti-HER2 directed regimens for patients with brain metastases should consider clinical findings in this relatively modern series. [Table: see text]
Pyrotinib maleate for the treatment of brain metastases from HER2-positive solid tumours: A real-world study.
Authors: Wu Qichao , Wang Kuanyu , Sun Shibin , Ding Xiaosheng , Hua Yichun , Li Xiaoyan 
Published: June 2023

e13041 Background: Pyrotinib maleate is a small molecule, irreversible inhibitor of HER1, HER2 and HER4 tyrosine kinases developed in China. A number of clinical studies have confirmed the good efficacy in treating patients with HER2-positive solid tumours and HER2-positive breast cancer brain metastases. In this study, we ulteriorly explore the curative effect and safety of pyrotinib in HER2-positive solid tumours brain metastases treatment. Methods: Clinical data from 53 patients with HER2-positive solid tumor brain metastases enrolled were compiled and analyzed. The impact of whether pyrrolizidine was combined with chemotherapy, a large molecule TKI, and intracranial local radiotherapy on PFS and intracranial PFS in the enrolled patients is somewhat outlined. Results: From June 2021 to December 2022, according to 53 patients with HER2-positive solid tumor brain metastases availably measured intracranial metastases meeting RECIST 1.1 criteria at baseline, with the dosing regimen based on pyrotinib and the combination or intracranial radiation therapy following the clinician's choice. The recorded patients included 49 patients with breast cancer, 2 patients with lung adenocarcinoma, and 1 patient with gastric cancer. A total of 37 patients were HER2-positive by immunohistochemistry, 4 patients were HER-positive by genetic testing, 9 patients were HER2-positive by fluorescence in situ hybridization, and the remaining 3 patients had unknown HER2 status. A total of 27 patients had one or more radiation treatments for intracranial metastases, 39 patients with treatment regimens combining chemotherapy with pyrotinib, and 19 patients with combination of large molecule TKI. The selected 53 patients base in the study, had disease progression due to new intracranial metastases or enlarged intracranial metastases in 42. The mPFS was 12 months for all patients and 13 months for intracranial metastases. Further collated analysis has shown there was no significant difference in mPFS between subgroups according to age, method of HER2 detection, lines of therapy, whether or not combined with chemotherapy, and possibility of combining with large molecule TKI therapy. There was a remarkable difference in PFS between the combined intracranial radiation therapy group and the non-combined intracranial radiation therapy group (14.6 months vs. 11.4 months, p = 0.042). There was also a significant variance in intracranial PFS between the combined intracranial radiation treatment group and the non-combined intracranial radiation treatment group (15.8 months vs. 12.0 months, p = 0.023). Conclusions: Pivotally, pyrotinib has shown good clinical efficacy in patients with HER2-positive solid tumor brain metastases. The results of this study suggest that early intervention with intracranial local radiation therapy is utterly essential for HER2-positive patients with brain metastases at baseline.
Comparing digital and glass slide methods for determining the HER2-low and negative categories in breast cancer.
Authors: Xue Xuemin , Guo Changyuan , Ling Yun , Jia Rujing , Huang Wenting , Xi Yanfeng , Ying Jianming 
Published: June 2023

e13042 Background: The promising clinical use of anti-HER2 antibody–drug conjugates (ADCs) in patients with immunohistochemistry (IHC)-based HER2-Low (1+, and 2+/FISH−) breast cancer has been discovered recently. Thus, pathologists and clinicians are now under increasing pressure to discriminate HER2-low from HER2-0. Methods: This multi-institutional retrospective breast cancer study selected 60 cases of paired digital and glass slides with HER2-Low (IHC 1+, and 2+/FISH−) and HER2-0 according to the original pathology reports, including 20 cases per staining intensity. These cases were re-evaluated by 37 pathologists from three hospitals. After excluding those cases with HER2 ≥ 2+ confirmed by both digital and glass slides with ≥ 85% agreement across 37 pathologists, the remaining cases were reclassified into “HER2-Neg” and “HER2-Low” categories with ≥ 85% agreement. If a slide could not be placed into one of these two categories, it will be labeled “HER2-Ambiguous”. Results: After excluding 13 cases with HER2 ≥ 2+ confirmed by both digital and glass slides with ≥ 85% agreement, the remaining 47 cases were reclassified into “HER2-Neg”, “HER2-Ambiguous” and “HER2-Low” categories. Therefore, the Kappa value for these three categories between the digital and glass slides was 0.597 (p = 2.50e-07). Interestingly, our study demonstrated that a significantly higher proportion of HER2-Low cases were identified on digital slides (48.9%, 23/47) than on glass slides (38.3%, 18/47; BhapkarTest, p = 3.17e-04). Five of the twelve (41.7%) HER2-Ambiguous cases diagnosed using glass slides were reclassified as HER2-Low using digital slides. Conclusions: Our study indicated that, compared to glass slides, digital slides may tend to shift HER2-0 to HER2-low category, potentially increasing breast cancer patients access to anti-HER2 ADCs, although the clinical benefit and biological characteristics have not been fully investigated. Thus, further investigation is warranted.
ERBB2 (HER2) gene amplification concordance analysis of circulating tumor cells and tumor tissue in patients with breast cancer.
Authors: Yeung Kay T , Wang Yipeng , Jones Stephenie , Brandt Christopher , Muller-Cohn Judy , Muller Rolf , Dickerson Janet 
Published: June 2023

e13047 Background: HER2 targeted therapies, such as HER2 monoclonal antibodies, HER2 tyrosine kinase inhibitors, and HER2 antibody drug conjugates, are approved for the treatment of HER2-positive breast, gastric and colorectal cancers. However, inter- and intra-tumoral heterogeneity in HER2 status presented a significant challenge in identifying patients that may benefit from HER2-targeted therapies. Detection of ERBB2 amplification in Circulating Tumor Cells (CTCs) may circumvent tissue heterogeneity issues and effectively predict the response of patients to anti-HER2 agents as a non-invasive alternative approach. Methods: A twenty-four patient pilot study was designed to compare HER2 status of traditional needle biopsies to high sensitivity CTC based liquid biopsies. HER2 status was determined using immunohistochemistry (IHC) and Fluorescence in Situ Hybridization (FISH) for tissue samples and FISH analysis for CTCs. Currently 21 patient samples have been compared in this study. Results: CTCs with HER2 amplified signals were found in patients with stages 2, 3, or 4 breast cancers. Based on the biopsies of the primary tumor or metastatic disease, 6 patients (29%) had HER2-overexpressing as defined by either HER2 IHC 3+ or HER2 FISH amplified. Analysis of CTCs showed 100% concordance (HER2 amplification detected in CTCs) in these patients with HER2-overexpressing breast cancer. Furthermore, an additional 4 (19%) patients had HER2 amplification by CTC analysis but not on needle biopsy. Conclusions: Our finding demonstrates that LiquidScan can be used as a rapid analysis tool to evaluate HER2 amplification in CTCs. This approach can potentially help identify additional cohort of patients (HER2 non-amplified tumor / HER2 amplified CTCs) who may benefit from the new generation of HER2 targeted therapies. Studies are ongoing to include an expanded cohort of patients with early stage disease, as well as HER2-low disease, in order to evaluating dynamics of ERBB2 gene amplification, expression, and pathway activation while on active systemic therapy.
Gene expression comparison between primary aggressive luminal breast cancer and paired axillary and sentinel lymph node metastasis.
Authors: Li Jiyu , Chen Xiao , Wang Wenshan , Zhang Chi , Wang Huimin , Song Yunjie , Yin Xiangyu , Ma Xuejiao , Du Furong 
Published: June 2023

e13060 Background: More aggressive and therapy-resistant hormone receptor (HR)-positive breast cancer (hereafter luminal breast cancer, LBC) remains a great challenge. Few studies examine the genomics of axillary lymph node (ALN) metastasis in LBC. The aim of this study was to characterize and compare the mRNA expression patterns of primary breast cancers and paired ALN metastases. Methods: Aggressive pT1-2N2-3M0 LBC patients aged over 18 years who were treated at Shandong Provincial Hospital Affiliated to Shandong First Medical University and had available matched primary and metastatic tumor samples for gene expression analyses were retrospectively recruited. Bulk mRNA expression levels were determined by RNA sequencing (Illumina NovaSeq 6000 system) and calculated using featureCounts. Differential gene expression analysis was performed using DESeq2. All analyses were carried out with differentially expressed genes (DEGs) with an FDR <0.05. Changes of intrinsic subtypes from primary to metastatic disease were assessed. Results: Ten LBC patients with paired tumor samples were included. Compared with the primary tumor, ALN metastatic tumor had 1509 statistically significant DEGs, including 743 upregulated genes and 766 downregulated genes. Notably, there was an upregulation of genes related to immune response-activating signal transduction, T cell receptor signaling pathway, B cell receptor signaling pathway, and cytokine-cytokine receptor interaction in the ALN metastasis. The downregulation of genes were mainly enriched in the PI3K-Akt signaling pathway, ECM-receptor interaction, Wnt signaling pathway, and TGF-beta signaling pathway. Intrinsic subtype distribution in primary tumors was different from those in ALN metastatic tumors, such as Luminal A (30% vs. 50%), Luminal B (10% vs. 20%), HER2-enriched (20% vs. 10%), Basal-like (10% vs. 10%), and Normal-like (30% vs. 10%). These results suggest that LBC is a highly heterogeneous disease. Conclusions: In aggressive pT1-2N2-3M0 LBC, ALN metastases have a distinct gene expression profile and show upregulation of immune-related genes ( CR2, BLK, PAX5, CD19, FCRL1, TNFRSF13B). Genes associated with signaling pathways are involved in the development of breast cancer ( FST, TNN, LAMC3, SFRP2, FGF18), and are downregulated when compared to autologous primary cancer. These pathways are potential targeted pathways in the treatment of breast cancer. LBC cells metastatic to lymph nodes undergo a change to metastasize and survive in the new microenvironment, which may provide insights into the metastatic process. Besides, a switch towards more aggressive intrinsic subtype from primary to advanced disease is also observed.
First line combination of ribociclib and letrozole in patients (pts) with metastatic breast cancer (MBC): Focus on hepatic toxicity in the context of a real–world setting the Italian, multicenter Hermione–8 study.
Authors: Piazza Francesca , Bonelli Candida , Lui Stefania , di Nunzio Camilla , Collova Elena , Bozzoli Elisabetta , Vici Patrizia , Gebbia Vittorio , Valerio Maria Rosaria , Zustovich Fable , Vanella Paola , Coltelli Luigi , Pistelli Mirco , Giotta Francesco , Torri Valter , Cazzaniga Marina Elena 
Published: June 2023

e13064 Background: The introduction in the clinical practice of CDK4 / 6 inhibitors, in combination with endocrine therapy, has been a breakthrough in the therapeutic scenario of hormone receptor+ve/Human Epidermal growth Factor 2–ve (HR+/HER2–) MBC pts. However, despite the outstanding results in terms of OS and quality of life achieved up to now, it is important to consider that the highly selected population of clinical trials doesn’t always accurately predict the clinical impact of therapies in the general population, hence having real world data is an essential tool to guide physicians in daily clinical practice. Methods: In this observational, multicentre, prospective study, we evaluated the safety profile and the incidence of dose reductions, temporary interruptions and treatment discontinuation due to adverse events, in a real–world cohort of Italian pre or postmenopausal HR+/HER2– MBC pts who received a first line combination of ribociclib and letrozole. Results: A total of 78 MBC patients were included in the analysis. The median duration of treatment was 17 (1–61) months. At the time of ribociclib initiation, 13 (16.7%) pts already presented an altered transaminase value whereas liver metastases were present in 17 pts (21.8%). Ten (12.8%) pts experienced hepatic toxicity while on treatment. The median number of cycles for liver toxicity was 3 (1–18). The most common hepatic event was transaminase level increase in 7 (8.8%) pts. Such event occurred more frequently in the group of pts with normal baseline liver function. Hepatic toxicity was grade 1 in 3 (3.8%) pts, grade 2 in 3 (3.8%) pts, grade 3 in 3 (3.8%) pts and grade 4 in 1 (1.3%) pt. Dose reduction due to hepatic toxicity occurred in 3 (3.8%) pts, in particular one of them needed dose reduction from 600 mg to 400 mg, one from 600 mg to 200 mg whereas treatment discontinuation was applied in the last patient. Median time of treatment interruption due to hepatotoxicity was 29 (14–45) days and 3 (3.8 %) pts discontinued ribociclib due to adverse events. No deaths due to liver failure have been reported. Conclusions: Hermione–8 trial support a manageable safety profile of the combination ribociclib and letrozole in MBC patients treated in a real–world clinical setting, confirming toxicity profile in line with the results presented in the MONALEESA clinical trials. Dose reductions, temporary interruptions and discontinuation of treatment due to adverse events have been limited and seems comparable to the results from MONALEESA trials. [Table: see text]
Feasibility of treatment with another CDK4/6 inhibitor after severe ribociclib liver toxicity.
Authors: Zurcher Jean-Philippe , Goujon Morgan , Cottu Paul H. , Desmoulins Isabelle , Teixeira Luis , Mansi Laura , Meynard Guillaume , Dobi Erion , Rowinski Elise , Stacoffe Marion , Augereau Paule , Robert Marie , Mottaz Yann , Gaiffe Anaïs , Grandvuillemin Aurélie , Fleury Mapi , Dolcan Ana , Stravodimou Athina , Zaman Khalil , Curtit Elsa 
Published: June 2023

e13067 Background: Ribociclib is, for now, the only CDK4/6 inhibitor having demonstrated a statistically significant increase of overall survival in first-line in hormone receptor-positive, HER2-negative advanced breast cancer. One of the limiting toxicities of ribociclib is the occurrence of grade III/IV hepatobiliary toxicity in approximately 5% of patients. It contraindicates the reintroduction of the drug. Therapeutic options after this type of adverse event are challenging because there are very limited data regarding cross reactivity in risk for hepatic injury between ribociclib, palbociclib or abemaciclib. Methods: We describe a cohort of 28 patients who presented with grade III and/or IV ribociclib-induced hepatitis and who subsequently received another CDK4/6 inhibitor. Cases were collected from the French pharmacovigilance database and additional cases were obtained through institutional databases. Data were retrospectively obtained from patients’ reports. Results: Twenty-eight patients, from 11 centers, presented a grade III (71%, 20 patients) or a grade IV (29%, 8 patients) transaminase elevation with ribociclib. Median transaminase elevation was 12.3 x ULN (upper limit normal) for AST and 15.2 x ULN for ALT. This toxicity occurred within the first 6 months of treatment for all patients except one. Ribociclib was associated with letrozole in 21 patients, fulvestrant in 5 patients and anastrozole or exemestane in 2 patients. No acute liver failure occurred. All patients switched to another CDK4/6 inhibitor (23 patients - 82% - palbociclib and 5 - 18% - abemaciclib) without significant reoccurrence of liver toxicities. Four patients (14%) presented a transient grade 1 or 2 hepatic toxicity (all of them with palbociclib), 20 patients (71%) received the second CDK4/6 inhibitor at full dose. The median follow-up was 16 months. Conclusions: Treatment with palbociclib or abemaciclib after grade III or IV transaminase elevation due to ribociclib is feasible and none of the patients in this cohort exhibited reoccurrence of significant liver toxicity afterwards. Ribociclib liver toxicity occurs mainly during the first 6 months of treatment and takes several months to recover. [Table: see text]