Dones, ciència i història amb Patricia Fara

Las mujeres siempre han estado involucradas en la ciencia. ¿Pero qué hay de su presencia en la esfera pública de la ciencia: en la historia, en las instituciones ...? Hablamos de la situación de las mujeres en la ciencia, ahora y en el pasado, con Patricia Fara, historiadora de la ciencia en la Universidad de Cambridge y experta en mujeres y ciencia y en la ciencia en la Ilustración. Entre muchos otros libros, ha escrito Pandora 's breeches: women, science and power and Sex, Botany and empire: the stories of Carl Linnaeus and Joseph Banks. Invitada a la UAB por la Mención de Excelencia del Programa de Doctorado en Historia de la Ciencia del CEHIC, Fara habló de la participación de las mujeres en la ciencia desde una perspectiva histórica, en una conferencia titulada "Los fantasmas de las mujeres del pasado"("Ghosts of Women Past"), y aprovechamos la oportunidad para entrevistarla.Les dones sempre han estat involucrades en la ciència. Però què hi ha de la seva presència en l'esfera pública de la ciència: en la història, a les institucions...? Parlem de la situació de les dones en la ciència, ara i en el passat, amb Patricia Fara, historiadora de la ciència a la Universitat de Cambridge i experta en dones i ciència i en la ciència a la Il·lustració. Entre molts altres llibres, ha escrit Pandora's breeches: women, science and power and Sex, botany and empire: the stories of Carl Linnaeus and Joseph Banks. Convidada a la UAB per la Menció d'Excel·lència del Programa de Doctorat en Història de la Ciència del CEHIC, Fara va parlar de la participació de les dones en la ciència des d'una perspectiva històrica, en una conferència titulada "Els fantasmes de les dones del passat" (Ghosts of Women Past), i vam aprofitar l'oportunitat per entrevistar-la.Women have always been involved in science. But what about their presence in history, in institutions and in the public sphere of science? We talk about women's situations in science, now and in the past, with Patricia Fara, science historian at Cambridge University and expert on women in science and science in the Enlightenment. Among many other books, she has written Pandora's breeches: women, science and powerand Sex, botany and empire: the stories of Carl Linnaeus and Joseph Banks. She was invited to the UAB by the Centre for the History of Science (CEHIC) where she discussed the participation of women in science from a historical perspective in a lecture called "Ghosts of Women Past", and we took the opportunity of interviewing her

Identification of cell surface targets for CAR-T cell therapies and antibody-drug conjugates in breast cancer

Background: Two promising therapeutic strategies in oncology are chimeric antigen receptor-T cell (CAR-T) therapies and antibody-drug conjugates (ADCs). To be effective and safe, these immunotherapies require surface antigens to be sufficiently expressed in tumors and less or not expressed in normal tissues. To identify new targets for ADCs and CAR-T specifically targeting breast cancer (BC) molecular and pathology-based subtypes, we propose a novel in silico strategy based on multiple publicly available datasets and provide a comprehensive explanation of the workflow for a further implementation. Methods: We carried out differential gene expression analyses on The Cancer Genome Atlas BC RNA-sequencing data to identify BC subtype-specific upregulated genes. To fully explain the proposed target-discovering methodology, as proof of concept, we selected the 200 most upregulated genes for each subtype and undertook a comprehensive analysis of their protein expression in BC and normal tissues through several publicly available databases to identify the potentially safest and viable targets. Results: We identified 36 potentially suitable and subtype-specific tumor surface antigens (TSAs), including fibroblast growth factor receptor-4 (FGFR4), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), GDNF family receptor alpha 1 (GFRA1), integrin beta-6 (ITGB6) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We also identified 63 potential TSA pairs that might be appropriate for co-targeting strategies. Finally, we validated subtype specificity in a cohort of our patients, multiple BC cell lines and the METABRIC database. Conclusions: Overall, our in silico analysis provides a framework to identify novel and specific TSAs for the development of new CAR-T and antibody-based therapies in BC

CDK4/6-Inhibitors Versus Chemotherapy in Advanced HR+/HER2-Negative Breast Cancer: Results and Correlative Biomarker Analyses of the KENDO Randomized Phase II Trial

Background: The optimal treatment approach for hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) with aggressive characteristics remains controversial, with lack of randomized trials comparing cyclin-dependent kinase (CDK)4/6-inhibitors (CDK4/6i) + endocrine therapy (ET) with chemotherapy + ET. Materials and methods: We conducted an open-label randomized phase II trial (NCT03227328) to investigate whether chemotherapy + ET is superior to CDK4/6i + ET for HR+/HER2-negative MBC with aggressive features. PAM50 intrinsic subtypes (IS), immunological features, and gene expression were assessed on baseline samples. Results: Among 49 randomized patients (median follow-up: 35.2 months), median progression-free survival (mPFS) with chemotherapy + ET (11.2 months, 95% confidence interval [CI]: 7.7-15.4) was numerically shorter than mPFS (19.9 months, 95% CI: 9.0-30.6) with CDK4/6i + ET (hazard ratio: 1.41, 95% CI: 0.75-2.64). Basal-like tumors under CDK4/6i + ET exhibited worse PFS (mPFS: 11.4 months, 95% CI: 3.00-not reached [NR]) and overall survival (OS; mOS: 18.8 months, 95% CI: 18.8-NR) compared to other subtypes (mPFS: 20.7 months, 95% CI: 9.00-33.4; mOS: NR, 95% CI: 24.4-NR). In the chemotherapy arm, luminal A tumors showed poorer PFS (mPFS: 5.1 months, 95% CI: 2.7-NR) than other IS (mPFS: 13.2 months, 95% CI: 10.6-28.1). Genes/pathways involved in BC cell survival and proliferation were associated with worse outcomes, as opposite to most immune-related genes/signatures, especially in the CDK4/6i arm. CD24 was the only gene significantly associated with worse PFS in both arms. Tertiary lymphoid structures and higher tumor-infiltrating lymphocytes also showed favorable survival trends in the CDK4/6i arm. Conclusions: The KENDO trial, although closed prematurely, adds further evidence supporting CDK4/6i + ET use in aggressive HR+/HER2-negative MBC instead of chemotherapy. PAM50 IS, genomic, and immunological features are promising biomarkers to personalize therapeutic choices

In Silico and In Vitro Evaluation of Bevacizumab Biosimilar MB02 as an Antitumor Agent in Canine Mammary Carcinoma

Canine mammary carcinomas (CMC) are associated with major aggressive clinical behavior and high mortality. The current standard of care is based on surgical resection, without an established effective treatment scheme, highlighting the urgent need to develop novel effective therapies. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis and progression in the majority of solid cancers, including human and canine mammary carcinomas. The first therapy developed to target VEGF was bevacizumab, a recombinant humanized monoclonal antibody, which has already been approved as an anticancer agent in several human cancers. The goal of this work was to establish the therapeutic value of MB02 bevacizumab biosimilar in CMC. First, through different in silico approaches using the MUSCLE multiple-sequence alignment tool and the FoldX protein design algorithm, we were able to predict that canine VEGF is recognized by bevacizumab, after showing an extremely high sequence similarity between canine and human VEGF. Further, by using an ELISA-based in vitro binding assay, we confirmed that MB02 biosimilar was able to recognize canine VEGF. Additionally, canine VEGF-induced microvascular endothelial cell proliferation was inhibited in a concentration-dependent manner by MB02 biosimilar. These encouraging results show a high potential for MB02 as a promising therapeutic agent for the management of CMC.Fil: Cardama, Georgina Alexandra. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bucci, Paula Lorena. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lemos, Jesus. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Llavona, Candela. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Benavente, Micaela Andrea. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Hellmén, Eva. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; ArgentinaFil: Fara, María Laura. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Endocrinología; ArgentinaFil: Medrano, Eduardo. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Endocrinología; ArgentinaFil: Spitzer, Eduardo. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Endocrinología; ArgentinaFil: Demarco, Ignacio A.. No especifíca;Fil: Sabella, Patricia. No especifíca;Fil: Garona, Juan. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Cell-cycle inhibition and immune microenvironment in breast cancer treated with ribociclib and letrozole or chemotherapy

In this study, we performed genomic analyses of cell cycle and tumor microenvironment changes during and after ribociclib and letrozole or chemotherapy in the CORALLEEN trial. 106 women with untreated PAM50-defined Luminal B early breast cancers were randomly assigned to receive neoadjuvant ribociclib and letrozole or standard-of-care chemotherapy. Ki67 immunohistochemistry, tumor-infiltrating lymphocytes quantification, and RNA sequencing were obtained from tissue biopsies pre-treatment, on day 14 of treatment, and tumor specimens from surgical resection. Results showed that at surgery, Ki67 and the PAM50 proliferation scores were lower after ribociclib compared to chemotherapy. However, consistent reactivation of tumor cell proliferation from day 14 to surgery was only observed in the ribociclib arm. In tumors with complete cell cycle arrest (CCCA) at surgery, PAM50 proliferation scores were lower in the ribociclib arm compared to chemotherapy (p < 0.001), whereas the opposite was observed with tumor cellularity (p = 0.002). Gene expression signatures (GES) associated with antigen-presenting cells (APCs) and innate immune system activity showed increased expression post-chemotherapy but decreased expression post-ribociclib. Interferon-associated GES had decreased expression with CCCA and increased expression with non-CCCA. Our findings suggest that while both treatment strategies decreased proliferation, the depth and the patterns over time differed by treatment arm. Immunologically, ribociclib was associated with downregulated GES associated with APCs and the innate immune system in Luminal B tumors, contrary to existing preclinical data. Further studies are needed to understand the effect of CDK4/6 inhibition on the tumor cells and microenvironment, an effect which may vary according to tumor subtypes

Frequency and spectrum of PIK3CA somatic mutations in breast cancer

Purpose: The therascreen PIK3CA mutation assay and the alpha-specific PI3K inhibitor alpelisib are FDA-approved for identifying and treating patients with advanced PIK3CA-mutated (PIK3CAmut) breast cancer (BC). However, it is currently unknown to what extend this assay detects most PIK3CA mutations in BC. This information is critical as patients and clinicians are using this and other genomic assays to indicate alpelisib. Methods: Data from 6338 patients with BC was explored across 10 publicly available studies. The primary objective was to evaluate the proportion and distribution of PIK3CA mutations in BC. Secondary objectives were (1) to evaluate in silico the spectrum of PIK3CA mutations in BC that would be captured by the therascreen panel; (2) to evaluate the proportion and distribution of PIK3CA mutations in hormone receptor-positive/HER2-negative (HR+/HER2-), HER2+, and triple-negative BC (TNBC); and (3) to explore the identification of PIK3CA mutations in a cohort of 48 HR+/HER2- advanced BC patients by the Guardant B360 circulating tumor DNA (ctDNA) assay. Results: Patients with PIK3CAmut tumors represented 35.7% (2261/6338). Five PIK3CA mutations comprised 73% of all PIK3CA mutations: H1047R (35%), E545K (17%), E542K (11%), N345K (6%), and H1047L (4%). Therascreen gene list would capture 72% of all PIK3CA mutations and 80% of patients with a known PIK3CAmut BC. Among patients with double PIK3CAmut tumors (12% of all PIK3CAmut), the therascreen panel would capture 78% as harboring 1 single PIK3CA mutation, 17% as PIK3CAmut undetected, and 5% as PIK3CA double-mut. PIK3CA mutation rates were lower in TNBC (16%) compared to HR+/HER2 (42%) and HER2+ (31%) BC; however, the distribution of the 4 main PIK3CA mutations across subtypes was similar. Finally, 28% of PIK3CA mutations identified in ctDNA in 48 patients with advanced HR+/HER2- BC were not part of the therascreen panel. Conclusion: PIK3CA mutations in BC are heterogenous and ~ 20% of patients with a known PIK3CA mutation, and 95% with a known double PIK3CAmut tumor, would not be captured by the therascreen panel. Finally, the clinical utility of PIK3CA mutations not present in the therascreen companion diagnostic assay or identified by other sequencing-based assays needs further investigation

ERBB2mRNA expression and response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-positive breast cancer

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA.We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed para n-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally

Clinical, pathological and PAM50 gene expression features of HER2-low breast cancer

Novel antibody-drug conjugates against HER2 are showing high activity in HER2-negative breast cancer (BC) with low HER2 expression (i.e., 1+ or 2+ and lack of ERBB2 amplification). However, the clinical and molecular features of HER2-low BC are yet to be elucidated. Here, we collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative disease and made the following observations. First, the proportion of HER2-low was higher in HR-positive disease (65.4%) than triple-negative BC (TNBC, 36.6%). Second, within HR-positive disease, ERBB2 and luminal-related genes were more expressed in HER2-low than HER2 0. In contrast, no gene was found differentially expressed in TNBC according to HER2 expression. Third, within HER2-low, ERBB2 levels were higher in HR-positive disease than TNBC. Fourth, HER2-low was not associated with overall survival in HR-positive disease and TNBC. Finally, the reproducibility of HER2-low among pathologists was suboptimal. This study emphasizes the large biological heterogeneity of HER2-low BC, and the need to implement reproducible and sensitive assays to measure low HER2 expression

Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI-1805 TOT-HER3 trial and biological determinants of early response

Patritumab deruxtecan (HER3-DXd) exhibits promising efficacy in breast cancer, with its activity not directly correlated to baseline ERBB3/HER3 levels. This research investigates the genetic factors affecting HER3-DXd's response in women with early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. In the SOLTI-1805 TOT-HER3 trial, a single HER3-DXd dose was administered to 98 patients across two parts: 78 patients received 6.4 mg/kg (Part A), and 44 received a lower 5.6 mg/kg dose (Part B). The CelTIL score, measuring tumor cellularity and infiltrating lymphocytes from baseline to day 21, was used to assess drug activity. Part A demonstrated increased CelTIL score after one dose of HER3-DXd. Here we report CelTIL score and safety for Part B. In addition, the exploratory analyses of part A involve a comprehensive study of gene expression, somatic mutations, copy-number segments, and DNA-based subtypes, while Part B focuses on validating gene expression. RNA analyses show significant correlations between CelTIL responses, high proliferation genes (e.g., CCNE1, MKI67), and low expression of luminal genes (e.g., NAT1, SLC39A6). DNA findings indicate that CelTIL response is significantly associated with TP53 mutations, proliferation, non-luminal signatures, and a distinct DNA-based subtype (DNADX cluster-3). Critically, low HER2DX ERBB2 mRNA, correlates with increased HER3-DXd activity, which is validated through in vivo patient-derived xenograft models. This study proposes chemosensitivity determinants, DNA-based subtype classification, and low ERBB2 expression as potential markers for HER3-DXd activity in HER2-negative breast cancer. Patritumab deruxtecan (HER3-DXd) is a promising therapy for breast cancer, targeting HER3. Here, the authors analyse the genomic factors that affect the response to HER3-DXd in patients with early-stage HER2-negative breast cancer as part of the SOLTI-1805 TOT-HER3 clinical trial and report outcomes for Part B of the trial using lower HER3-DXd dose in patients with HER2-negative breast cancer