In Situ Malignant Transformation and Progenitor-Mediated Cell Budding: Two Different Pathways for Breast Ductal and Lobular Tumor Invasion

The human breast lobular and ductal structures and the derived tumors from these structures differ substantial in their morphology, microenvironment, biological presentation, functions, and clinical prognosis. Based on these differences, we have proposed that pre-invasive lobular tumors may progress to invasive lesions through “in situ malignant transformation”, in which the entire myoepithelial cell layer within a given lobule or lobular clusters undergoes extensive degeneration and disruptions, which allows the entire epithelial cell population associated with these myoepithelial cell layers directly invade the stroma or vascular structures. In contrast, pre-invasive ductal tumors may invade the stroma or vascular structures through “progenitor-mediated cell budding”, in which focal myoepithelial cell degeneration-induced aberrant leukocyte infiltration causes focal disruptions in the tumor capsules, which selectively favor monoclonal proliferation of the overlying tumor stem cells or a biologically more aggressive cell clone. Our current study attempted to provide more direct morphological and immunohistochemical data that are consistent with our hypotheses

Perspectives of patients with advanced or metastatic non-small cell lung cancer on symptoms, impacts on daily activities, and thresholds for meaningful change: a qualitative research study

IntroductionAdvanced or metastatic non-small cell lung cancer (NSCLC) is associated with significant symptom burden. It is important to understand the impact of these disease-and treatment-related symptoms on patients’ daily lives and explore from a patient perspective what constitutes a meaningful change in NSCLC symptoms.MethodsPatient experience of advanced or metastatic NSCLC was explored in this prospective, non-interventional qualitative research study recruiting patients from the United States (US). Interviews were conducted to explore the most important symptoms, daily life impacts, and patients’ perspectives of what constitutes meaningful change when considering their current symptoms versus 6–12 months prior, based on the Patient Global Impression of Severity (PGI-S) and Patient Global Impression of Change (PGI-C) items.ResultsBetween February and April 2022, 19 US-based patients with Stage IV NSCLC were recruited; 95% were female, 63% were White, 79% had been diagnosed >1 year prior, and 63% were receiving targeted therapy. Over half the patients indicated their most important symptoms were fatigue, shortness of breath, and cough. Patient differentiation between whether symptoms were disease- or treatment-related lacked concordance, and often patients were unable to distinguish the two. The most frequently mentioned impacts of these symptoms on patients’ daily lives were difficulty walking, sleep disturbance, anxiety/depression, impact on relationships, and difficulty doing daily tasks. Most patients considered a one-point change on the PGI-S or PGI-C to be meaningful based on rating their symptom severity at the time of the interview compared with 6–12 months before the interview.ConclusionBased on their own symptom experience, patients with advanced or metastatic NSCLC indicated a one-point threshold for meaningful change, whether improvement or worsening. This suggests a one-point change on the PGI-S or PGI-C may be a potential anchor for patient-reported outcome (PRO) endpoints used in clinical trials. It is important to use PRO instruments that capture the symptoms and impacts identified as most important to patients. These findings highlight the importance of using qualitative methods to assess disease-related symptoms, treatment-related side effects, and the impacts on daily life for patients with advanced or metastatic NSCLC, underscoring how qualitative assessments can complement quantitative PRO instruments for evaluating clinical trials

Consensus Recommendations for Advancing Breast Cancer: Risk Identification and Screening in Ethnically Diverse Younger Women

A need exists for a breast cancer risk identification paradigm that utilizes relevant demographic, clinical, and other readily obtainable patient-specific data in order to provide individualized cancer risk assessment, direct screening efforts, and detect breast cancer at an early disease stage in historically underserved populations, such as younger women (under age 40) and minority populations, who represent a disproportionate number of military beneficiaries. Recognizing this unique need for military beneficiaries, a consensus panel was convened by the USA TATRC to review available evidence for individualized breast cancer risk assessment and screening in young (< 40), ethnically diverse women with an overall goal of improving care for military beneficiaries. In the process of review and discussion, it was determined to publish our findings as the panel believes that our recommendations have the potential to reduce health disparities in risk assessment, health promotion, disease prevention, and early cancer detection within and in other underserved populations outside of the military. This paper aims to provide clinicians with an overview of the clinical factors, evidence and recommendations that are being used to advance risk assessment and screening for breast cancer in the military

Role of deregulated microRNAs in breast cancer progression Using FFPE tissue

MicroRNAs (miRNAs) contribute to cancer initiation and progression by silencing the expression of their target genes, causing either mRNA molecule degradation or translational inhibition. Intraductal epithelial proliferations of the breast are histologically and clinically classified into normal, atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). To better understand the progression of ductal breast cancer development, we attempt to identify deregulated miRNAs in this process using Formalin-Fixed, Paraffin-Embedded (FFPE) tissues from breast cancer patients. Following tissue microdissection, we obtained 8 normal, 4 ADH, 6 DCIS and 7 IDC samples, which were subject to RNA isolation and miRNA expression profiling analysis. We found that miR-21, miR-200b/c, miR-141, and miR-183 were consistently up-regulated in ADH, DCIS and IDC compared to normal, while miR-557 was uniquely down-regulated in DCIS. Interestingly, the most significant miRNA deregulations occurred during the transition from normal to ADH. However, the data did not reveal a step-wise miRNA alteration among discrete steps along tumor progression, which is in accordance with previous reports of mRNA profiling of different stages of breast cancer. Furthermore, the expression of MSH2 and SMAD7, two important molecules involving TGF-β pathway, was restored following miR-21 knockdown in both MCF-7 and Hs578T breast cancer cells. In this study, we have not only identified a number of potential candidate miRNAs for breast cancer, but also found that deregulation of miRNA expression during breast tumorigenesis might be an early event since it occurred significantly during normal to ADH transition. Consequently, we have demonstrated the feasibility of miRNA expression profiling analysis using archived FFPE tissues, typically with rich clinical information, as a means of miRNA biomarker discovery