LINC00662 Promotes Aggressive Traits by Modulating OCT4 Expression through miR-335-5p in Gallbladder Cancer Cells.

Long non-coding RNAs (lncRNAs) are nucleotide sequences that participate in different biological processes and are associated with different pathologies, including cancer. Long intergenic non-protein-coding RNA 662 (LINC00662) has been reported to be involved in different cancers, including colorectal, prostate, and breast cancer. However, its role in gallbladder cancer has not yet been described.

Giredestrant for Estrogen Receptor-Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study.

Purpose: To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor-positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455).

Methods: Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone-releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity.

CDK4/6i-treated HR+/HER2- breast cancer tumors show higher ESR1 mutation prevalence and more altered genomic landscape.

As CDK4/6 inhibitor (CDK4/6i) approval changed treatment strategies for patients with hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer (BC), understanding how exposure to CDK4/6i affects the tumor genomic landscape is critical for precision oncology. Using real-world data (RWD) with tumor genomic profiling from 5910 patients with metastatic HR+/HER2- BC, we investigated the evolution of alteration prevalence in commonly mutated genes across patient journeys. We found that ESR1 is more often altered in tumors exposed to at least 1 year of adjuvant endocrine therapy, contrasting with TP53 alterations.

UGT1A4 Polymorphism is not Associated with a Clinically Relevant Change in Giredestrant Exposure.

Purpose: Giredestrant is a potent, orally bioavailable, small-molecule selective estrogen receptor antagonist and degrader (SERD) that is being developed for the treatment of patients with estrogen receptor (ER)-positive breast cancer. In vitro, giredestrant was primarily metabolized by UGT1A4. The goal of this study was to investigate if UGT1A4 polymorphism had a clinically relevant impact on giredestrant exposure.

Advances towards the use of gastrointestinal tumor patient-derived organoids as a therapeutic decision-making tool.

In December 2022 the US Food and Drug Administration (FDA) removed the requirement that drugs in development must undergo animal testing before clinical evaluation, a declaration that now demands the establishment and verification of ex vivo preclinical models that closely represent tumor complexity and that can predict therapeutic response. Fortunately, the emergence of patient-derived organoid (PDOs) culture has enabled the ex vivo mimicking of the pathophysiology of human tumors with the reassembly of tissue-specific features. These features include histopathological variability, molecular expression profiles, genetic and cellular heterogeneity of parental tissue, and furthermore growing evidence suggests the ability to predict patient therapeutic response.

Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer.

Purpose: We describe the clinical pharmacology characterization of giredestrant in a first-in-human study.

Experimental Design: This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor-positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily.

The Role of MicroRNAs in Breast Cancer and the Challenges of Their Clinical Application.

MicroRNAs (miRNAs) constitute a subclass of non-coding RNAs that exert substantial influence on gene-expression regulation. Their tightly controlled expression plays a pivotal role in various cellular processes, while their dysregulation has been implicated in numerous pathological conditions, including cancer. Among cancers affecting women, breast cancer (BC) is the most prevalent malignant tumor.

Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study.

Background: The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer.

Methods: In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%.

Long Non-Coding RNAs (lncRNAs) as Regulators of the PI3K/AKT/mTOR Pathway in Gastric Carcinoma.

Gastric cancer (GC) represents ~10% of the global cancer-related deaths, increasingly affecting the younger population in active stages of life. The high mortality of GC is due to late diagnosis, the presence of metastasis and drug resistance development. Additionally, current clinical markers do not guide the patient management adequately, thereby new and more reliable biomarkers and therapeutic targets are still needed for this disease.

Concentration QTc analysis of giredestrant: Overcoming QT/heart rate confounding in the presence of drug-induced heart rate changes.

Concentration-QTc (C-QTc) analysis has become a common approach for evaluating proarrhythmic risk and delayed cardiac repolarization of oncology drug candidates. Significant heart rate (HR) change has been associated with certain classes of oncology drugs and can result in over- or underestimation of the true QT prolongation risk. Because oncology early clinical trials typically lack a placebo control arm or time-matched, treatment-free baseline electrocardiogram collection, significant HR change brings additional challenges to C-QTc analysis in the oncology setting.

A Single Variant in Pri-miRNA-155 Associated with Susceptibility to Hereditary Breast Cancer Promotes Aggressiveness in Breast Cancer Cells.

Variants in genes encoding for microRNAs have been associated with their deregulation in breast cancer (BC). Sequencing of microRNAs deregulated in BC was performed using DNA from Chilean patients with a strong family history and negative for mutations in BRCA1/BRCA2. Seventeen variants were identified, three of which were selected for a case-control association study: rs376491654 (miR-335), rs755634302 (miR-497), and rs190708267 (miR-155).

Environmental and Lifestyle Risk Factors in the Carcinogenesis of Gallbladder Cancer.

Gallbladder cancer (GBC) is an aggressive neoplasm that in an early stage is generally asymptomatic and, in most cases, is diagnosed in advanced stages with a very low life expectancy because there is no curative treatment. Therefore, understanding the early carcinogenic mechanisms of this pathology is crucial to proposing preventive strategies for this cancer. The main risk factor is the presence of gallstones, which are associated with some environmental factors such as a sedentary lifestyle and a high-fat diet.

The Emerging Role of PIWI-Interacting RNAs (piRNAs) in Gastrointestinal Cancers: An Updated Perspective.

Gastrointestinal (GI) cancers produce ~3.4 million related deaths worldwide, comprising 35% of all cancer-related deaths. The high mortality among GI cancers is due to late diagnosis, the presence of metastasis and drug resistance development.

Role of lncRNAs in the Development of an Aggressive Phenotype in Gallbladder Cancer.

Long non-coding RNAs are sequences longer than 200 nucleotides that are involved in different normal and abnormal biological processes exerting their effect on proliferation and differentiation, among other cell features. Functionally, lncRNAs can regulate gene expression within the cells by acting at transcriptional, post-transcriptional, translational, or post-translational levels. However, in pathological conditions such as cancer, the expression of these molecules is deregulated, becoming elements that can help in the acquisition of tumoral characteristics in the cells that trigger carcinogenesis and cancer progression.

Primary results from TAIL: a global single-arm safety study of atezolizumab monotherapy in a diverse population of patients with previously treated advanced non-small cell lung cancer.

Background: Atezolizumab treatment improves survival, with manageable safety, in patients with previously treated advanced/metastatic non-small cell lung cancer. The global phase III/IV study TAIL (NCT03285763) was conducted to evaluate the safety and efficacy of atezolizumab monotherapy in a clinically diverse population of patients with previously treated non-small cell lung cancer, including those not eligible for pivotal trials.

Methods: Patients with stage IIIB/IV non-small cell lung cancer whose disease progressed after 1-2 lines of chemotherapy were eligible for this open-label, single-arm, multicenter study, including those with severe renal impairment, an Eastern Cooperative Oncology Group performance status of 2, prior anti-programmed death 1 (PD-1) therapy, and autoimmune disease.

Phosphorylation of Endothelin-Converting Enzyme-1c at Serines 18 and 20 by CK2 Promotes Aggressiveness Traits in Colorectal Cancer Cells.

Endothelin-converting enzyme-1 (ECE1) activates the endothelin-1 peptide, which upregulates pathways that are related to diverse hallmarks of cancer. ECE1 is expressed as four isoforms differing in their N-terminal domains. Protein kinase CK2 phosphorylates the N-terminus of isoform ECE1c, enhancing its stability and promoting invasiveness of colorectal cancer cells.

Endothelin-converting enzyme-1c promotes stem cell traits and aggressiveness in colorectal cancer cells.

Endothelin-1 is a mitogenic peptide that activates several proliferation, survival, and invasiveness pathways. The effects of endothelin-1 rely on its activation by endothelin-converting enzyme-1 (ECE1), which is expressed as four isoforms with different cytoplasmic N termini. Recently, isoform ECE1c has been suggested to have a role in cancer aggressiveness.

A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS).

Objectives: Active smokers with non-small-cell lung cancer (NSCLC) have increased erlotinib metabolism versus non-smoking patients, which reduces exposure. Therefore, an increased erlotinib dose may be beneficial. The CurrentS study (NCT01183858) assessed efficacy and safety of 300mg erlotinib (E300) as second-line therapy in current smokers with locally advanced or metastatic NSCLC versus the standard 150mg dose (E150).

Tumor marker analyses from the phase III, placebo-controlled, FASTACT-2 study of intercalated erlotinib with gemcitabine/platinum in the first-line treatment of advanced non-small-cell lung cancer.

Objectives: The FASTACT-2 study of intercalated erlotinib with chemotherapy in Asian patients found that EGFR mutations were the main driver behind the significant progression-free survival (PFS) benefit noted in the overall population. Further exploratory biomarker analyses were conducted to provide additional insight.

Materials And Methods: This multicenter, randomized, placebo-controlled, double-blind, phase III study investigated intercalated first-line erlotinib or placebo with gemcitabine/platinum, followed by maintenance erlotinib or placebo, for patients with stage IIIB/IV non-small cell lung cancer (NSCLC).

Bevacizumab Prevents Brain Metastases Formation in Lung Adenocarcinoma.

Patients with nonsquamous non-small cell lung cancer (nsNSCLC; largely lung adenocarcinoma) are at high risk of developing brain metastases. Preclinical data suggested that anti-VEGF-A therapy may prevent the formation of nsNSCLC brain metastases. Whether non-brain metastases are also prevented, and whether bevacizumab shows a brain metastases-preventive activity in cancer patients is unknown.

First-Line Erlotinib Therapy Until and Beyond Response Evaluation Criteria in Solid Tumors Progression in Asian Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer: The ASPIRATION Study.

Importance: Continuing molecularly targeted treatment beyond disease progression in non-small-cell lung cancer (NSCLC) has appeared promising in retrospective analyses, highlighting the challenge to identify whether progression is the optimal time to switch treatment.

Objective: To study the efficacy of first-line erlotinib therapy in patients with NSCLC with activating EGFR mutations and postprogression erlotinib therapy.

Design, Setting, And Participants: ASPIRATION (Asian Pacific trial of Tarceva as first-line in EGFR mutation) was a phase 2, open-label, single-arm study conducted from 2011 to 2012 in 23 centers in Hong Kong, Korea, Taiwan, and Thailand of adults with stage IV, EGFR mutation-positive NSCLC, with ECOG performance status 0 to 2.

Erlotinib-associated rash in patients with EGFR mutation-positive non-small-cell lung cancer treated in the EURTAC trial.

Aim: This analysis investigates incidence and time course of rash in the EURTAC study.

Materials & Methods: Patients with EGFR mutation-positive non-small-cell lung cancer were randomized 1:1 to receive once daily erlotinib or 3-weekly cycles of chemotherapy.

Results: Of the 86 erlotinib-treated patients, 71 reported rash.

Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089).

Purpose: Maintenance therapy is associated with improved survival in patients with non-small-cell lung cancer (NSCLC), but few studies have compared active agents in this setting. AVAPERL evaluated the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment.

Patients And Methods: Patients with advanced nonsquamous NSCLC received first-line bevacizumab 7.

Squamous cell carcinoma of the lung: molecular subtypes and therapeutic opportunities.

Lung cancer is the leading cause of cancer-related deaths worldwide. Next to adenocarcinoma, squamous cell carcinoma (SCC) of the lung is the most frequent histologic subtype in non-small cell lung cancer. Encouraging new treatments (i.