Association between plasma metabolites and gene expression profiles in five porcine endocrine tissues

Background: Endocrine tissues play a fundamental role in maintaining homeostasis of plasma metabolites such as non-esterified fatty acids and glucose, the levels of which reflect the energy balance or the health status of animals. However, the relationship between the transcriptome of endocrine tissues and plasma metabolites has been poorly studied. Methods: We determined the blood levels of 12 plasma metabolites in 27 pigs belonging to five breeds, each breed consisting of both females and males. The transcriptome of five endocrine tissues i.e. hypothalamus, adenohypophysis, thyroid gland, gonads and backfat tissues from 16 out of the 27 pigs was also determined. Sex and breed effects on the 12 plasma metabolites were investigated and associations between genes expressed in the five endocrine tissues and the 12 plasma metabolites measured were analyzed. A probeset was defined as a quantitative trait transcript (QTT) when its association with a particular metabolic trait achieved a nominal P value < 0.01. Results: A larger than expected number of QTT was found for non-esterified fatty acids and alanine aminotransferase in at least two tissues. The associations were highly tissue-specific. The QTT within the tissues were divided into co-expression network modules enriched for genes in Kyoto Encyclopedia of Genes and Genomes or gene ontology categories that are related to the physiological functions of the corresponding tissues. We also explored a multi-tissue co-expression network using QTT for non-esterified fatty acids from the five tissues and found that a module, enriched in hypothalamus QTT, was positioned at the centre of the entire multi-tissue network. Conclusions: These results emphasize the relationships between endocrine tissues and plasma metabolites in terms of gene expression. Highly tissue-specific association patterns suggest that candidate genes or gene pathways should be investigated in the context of specific tissues

Inhibition of Rac controls NPM–ALK-dependent lymphoma development and dissemination

Nucleophosmin-anaplastic lymphoma kinase (NPM–ALK) is a tyrosine kinase oncogene responsible for the pathogenesis of the majority of human ALK-positive lymphomas. We recently reported that it activated the Rac1 GTPase in anaplastic large-cell lymphoma (ALCL), leading to Rac-dependent formation of active invadopodia required for invasiveness. Herein, we went further into the study of this pathway and used the inhibitor of Rac, NSC23766, to validate its potential as a molecular target in ALCL in vitro and in vivo in a xenograft model and in a conditional model of NPM–ALK transgenic mice. Our data demonstrate that Rac regulates important effectors of NPM–ALK-induced transformation such as Erk1/2, p38 and Akt. Moreover, inhibition of Rac signaling abrogates NPM–ALK-elicited disease progression and metastasis in mice, highlighting the potential of small GTPases and their regulators as additional therapic targets in lymphomas

Circulating tumor DNA for predicting recurrence in patients with operable breast cancer: a systematic review and meta-analysis

The incorporation of circulating tumor DNA (ctDNA) into the management of operable breast cancer (BC) has been hampered by the heterogeneous results from different studies. We aimed to assess the prognostic value of ctDNA in patients with operable (non metastatic) BC.This work was supported by Lombardy Region Italy [grant agreement number RR33] as part of the project ‘I controlli periodici (follow-up) dopo la diagnosi e le terapie in pazienti liberi da malattia e asintomatici: verso una person- alizzazione delle strategie di follow-up’.Medicin

Extended follow-up of palbociclib with fulvestrant or letrozole for endocrine-sensitive, hormone receptor-positive/HER2-negative advanced breast cancer in the PARSIFAL trial

Background: Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are the mainstay for hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). While the approved CDK4/6i have demonstrated significant improvements in progression-free survival (PFS), inconsistencies exist for overall survival (OS) benefits. Here, we report updated efficacy results from PARSIFAL, a randomized phase II study, that evaluated first-line palbociclib with either letrozole or fulvestrant in postmenopausal patients with endocrine-sensitive, HR-positive/HER2-negative ABC. Patients and methods: PARSIFAL-LONG was an international, multicenter, observational study that extended follow-up for patients included in PARSIFAL. The primary objective evaluated updated OS of palbociclib combined with endocrine therapy (fulvestrant or letrozole). Secondary objectives included updated investigator-assessed PFS and subsequent antineoplastic therapies. Exploratory endpoints included identification of new clinical prognostic markers for OS, specifically PFS duration. Results: A total of 419 of 486 (86.2%) patients from PARSIFAL were included. Median follow-up was 7.3 years (interquartile range 6.7-7.7 years). At data cut-off (8 January 2024), no differences in efficacy were observed between fulvestrant and letrozole for OS (hazard ratio 1.01, 95% confidence interval [CI], 0.80-1.28, P = 0.927) or PFS (hazard ratio 1.06,95% CI, 0.85-1.31, P = 0.612). Median OS for the overall PARSIFAL-LONG population was 61.8 months (95% CI 56.5-68.4 months), representing the highest OS reported to date for palbociclib and aligning with outcomes observed for other CDK4/6i in this setting. Median PFS was 32.6 months (95% CI 27.5-38.1 months). A total of 85 (20.3%) patients were defined as early progressors (PFS ≤ 12 months). These patients had a shorter median post-progression OS than patients who remained progression free at 12 months (18.7 versus 27.4 months; hazard ratio 0.65, P = 0.004). Conclusions: Extended analysis from PARSIFAL confirmed no difference between fulvestrant and letrozole when combined with palbociclib for patients with endocrine-sensitive, HR-positive/HER2-negative ABC. Efficacy results were consistent with those reported in the pivotal first-line trials involving CDK4/6i. Progression within the first year on CDK4/6i may indicate a poorer prognosis

Profiling the gut and oral microbiota of hormone receptor-positive, HER2-negative metastatic breast cancer patients receiving pembrolizumab and eribulin

Aim: Changes in host-associated microbial communities (i.e., the microbiota) may modulate responses to checkpoint blockade immunotherapy. In the KELLY phase II study (NCT03222856), we previously demonstrated that pembrolizumab [anti-programmed cell death protein 1 (PD-1)] combined with eribulin (plus microtubule-targeting chemotherapy) showed encouraging antitumor activity in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC) who had received prior treatments.Methods: A total of 58 fecal and 67 saliva samples were prospectively collected from a subset of 28 patients at baseline (BL), after three treatment cycles, and end of treatment. Shotgun metagenomics, 16S rRNA gene amplicon sequencing, and bioinformatics and statistical approaches were used to characterize fecal and oral microbiota profiles.Results: Treatment caused no substantial perturbations in gut or oral microbiota, suggesting minimal drug-related microbial toxicity. Bacteroides and Faecalibacterium were the dominant gut microbiota genera, while Prevotella and Streptococcus were present in both oral and gut samples, highlighting potential gut-oral microbial interactions. Additionally, clinical benefit (CB) appeared to be associated with gut-associated Bacteroides fragilis (B. fragilis) and a BL oral abundance of Streptococcus ≥ 30%. Notably, B. fragilis NCTC 9343 supernatant induced dose-dependent lactate dehydrogenase (LDH) release from the MCF-7 (HR-positive/HER2-negative) BC cell line.Conclusion: These findings suggest that specific gut and oral microbiota may modulate the effectiveness of combinatory anti-BC therapies, potentially through the action of microbial metabolites

Prognostic value of residual disease (RD) biology and gene expression changes during the neoadjuvant treatment in patients with HER2-positive early breast cancer (EBC)

Background: In human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), we investigated tumor and immune changes during neoadjuvant treatment and their impact on residual disease (RD) biology and prognostic implications across four neoadjuvant studies of trastuzumab with or without lapatinib, and with or without chemotherapy: CALGB 40601, PAMELA, NeoALTTO, and NSABP B-41. Patients and methods: We compared tumor and immune gene expression changes during neoadjuvant treatment and their association with event-free survival (EFS) by uni- and multivariable Cox regression models in different cohorts and timepoints: 452 RD samples at baseline including 169 with a paired RD, and biomarker changes during neoadjuvant therapy, evaluating model performance via the c-index. Results: Analysis of 169 paired tumor samples revealed a shift in intrinsic subtype proportions from HER2-enriched at baseline (50.3%) to normal-like (49.1%) followed by luminal A (18.9%) in RD. This luminal phenotypic change was supported by decreased correlation to the HER2-enriched centroid, ERBB2, and HER2 amplicon genes and increased correlation to the luminal A centroid (Wilcoxon test P &lt; 0.001). Additionally, RD showed relative immune activation marked by significant increases in B-cell, CD8 T-cell, and natural killer cell signatures (Wilcoxon test P &lt; 0.05). In multivariable Cox models, intrinsic subtypes at baseline provided more prognostic information, while immune gene expression signatures provided more prognostic information in RD. Notably, the best multivariable EFS model (c-index = 0.77) integrated the immunoglobulin G signature from RD samples (adjusted hazard ratio 0.45, 95% confidence interval 0.30-0.67, adjusted P = 0.002). Conclusions: In patients with HER2-positive EBC and RD, tumor biomarkers provide more prognostic information at baseline. In contrast, immune biomarkers perform better for EFS prognosis in RD

Inhibition of Anaplastic Lymphoma Kinase (ALK) Activity Provides a Therapeutic Approach for CLTC-ALK-Positive Human Diffuse Large B Cell Lymphomas

ALK positive diffuse large B-cell lymphomas (DLBCL) are a distinct lymphoma subtype associated with a poor outcome. Most of them feature a t(2;17) encoding a clathrin (CLTC)-ALK fusion protein. The contribution of deregulated ALK-activity in the pathogenesis and maintenance of these DLBCLs is not yet known. We established and characterized the first CLTC-ALK positive DLBCL cell line (LM1). LM1 formed tumors in NOD-SCID mice. The selective ALK inhibitor NVP-TAE684 inhibited growth of LM1 cells in vitro at nanomolar concentrations. NVP-TAE684 repressed ALK-activated signalling pathways and induced apoptosis of LM1 DLBCL cells. Inhibition of ALK-activity resulted in sustained tumor regression in the xenotransplant tumor model. These data indicate a role of CLTC-ALK in the maintenance of the malignant phenotype thereby providing a rationale therapeutic target for these otherwise refractory tumors

A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation

Background: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer. Methods: We derived a combined prognostic model using retrospective clinical–pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1–105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data. Findings: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1–2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3–99·9), 88·9% (83·2–95·0), and 73·9% (66·0–82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0–0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4–5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1–0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0–98·3%) and in the high-risk group was 81·1% (71·5–92·1). Interpretation: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting. Funding: Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research

Novel therapies in breast cancer: what is new from ASCO 2008

<p>Abstract</p> <p>Introduction</p> <p>Breast cancer is the most common female cancer and the second most common cause of female cancer-related deaths in the United States. World-wide, more than one million women will be diagnosed with breast cancer annually. In 2007, more than 175,000 women were diagnosed with breast cancer in the United States. However, deaths due to breast cancer have decreased in the recent years in part because of improved screening techniques, surgical interventions, understanding of the pathogenesis of the disease, and utilization of traditional chemotherapies in a more efficacious manner. One of the more exciting areas of improvement in the treatment of breast cancer is the entrance of novel therapies now available to oncologists. In the field of cancer therapeutics, the area of targeted and biologic therapies has been progressing at a rapid rate, particularly in the treatment of breast cancer.</p> <p>Since the advent of imatinib for the successful treatment of chronic myelogenous leukemia in the 2001, clinicians have been searching for comparable therapies that could be as efficacious and as tolerable. In order for targeted therapies to be effective, the agent must be able to inhibit critical regulatory pathways which promote tumor cell growth and proliferation. The targets must be identifiable, quantifiable and capable of being interrupted.</p> <p>In the field of breast cancer, two advances in targeted therapy have led to great strides in the understanding and treatment of breast cancer, namely hormonal therapy for estrogen positive receptor breast cancer and antibodies directed towards the inhibition of human epidermal growth factor receptor (HER)2. These advances have revolutionized the understanding and the treatment strategies for breast cancer. Building upon these successes, a host of novel agents are currently being investigated and used in clinical trials that will hopefully prove to be as fruitful. This review will focus on novel therapies in the field of breast cancer with a focus on metastatic breast cancer (MBC) and updates from the recent annual ASCO meeting and contains a summary of the results.</p

LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT2A receptor

Compounds that activate the 5-HT2A receptor, such as lysergic acid diethylamide (LSD), act as hallucinogens in humans. One notable exception is the LSD congener lisuride, which does not have hallucinogenic effects in humans even though it is a potent 5-HT2A agonist. LSD and other hallucinogens have been shown to disrupt prepulse inhibition (PPI), an operational measure of sensorimotor gating, by activating 5-HT2A receptors in rats. We tested whether lisuride disrupts PPI in male Sprague–Dawley rats. Experiments were also conducted to identify the mechanism(s) responsible for the effect of lisuride on PPI and to compare the effects of lisuride to those of LSD. Confirming a previous report, LSD (0.05, 0.1, and 0.2 mg/kg, s.c.) reduced PPI, and the effect of LSD was blocked by pretreatment with the selective 5-HT2A antagonist MDL 11,939. Administration of lisuride (0.0375, 0.075, and 0.15 mg/kg, s.c.) also reduced PPI. However, the PPI disruption induced by lisuride (0.075 mg/kg) was not blocked by pretreatment with MDL 11,939 or the selective 5-HT1A antagonist WAY-100635 but was prevented by pretreatment with the selective dopamine D2/D3 receptor antagonist raclopride (0.1 mg/kg, s.c). The effect of LSD on PPI is mediated by the 5-HT2A receptor, whereas activation of the 5-HT2A receptor does not appear to contribute to the effect of lisuride on PPI. These findings demonstrate that lisuride and LSD disrupt PPI via distinct receptor mechanisms and provide additional support for the classification of lisuride as a non-hallucinogenic 5-HT2A agonist