Response- and Progression-Based End Points in Trial and Observational Cohorts of Patients With NSCLC.

Importance: Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to assess therapeutic response in clinical trials but not in routine care; thus, RECIST-based end points are difficult to include in observational studies. Clinician-anchored approaches for measuring clinical response have been validated but not widely compared with clinical trial data, limiting their use as evidence for clinical decision-making.

Objective: To compare response- and progression-based end points in clinical trial and observational cohorts of patients with non-small cell lung cancer (NSCLC).

Tumor sequencing of African ancestry reveals differences in clinically relevant alterations across common cancers.

Cancer genomes from patients with African (AFR) ancestry have been poorly studied in clinical research. We leverage two large genomic cohorts to investigate the relationship between genomic alterations and AFR ancestry in six common cancers. Cross-cancer type associations, such as an enrichment of MYC amplification with AFR ancestry in lung, breast, and prostate cancers, and depletion of BRAF alterations are observed in colorectal and pancreatic cancers.

A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer.

Purpose: To report the safety and efficacy of ipatasertib (AKT inhibitor) combined with rucaparib (PARP inhibitor) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with second-generation androgen receptor inhibitors.

Patients And Methods: In this two-part phase Ib trial (NCT03840200), patients with advanced prostate, breast, or ovarian cancer received ipatasertib (300 or 400 mg daily) plus rucaparib (400 or 600 mg twice daily) to assess safety and identify a recommended phase II dose (RP2D). A part 1 dose-escalation phase was followed by a part 2 dose-expansion phase in which only patients with mCRPC received the RP2D.

Comparison of Mutation Prevalence in Breast Cancer Across Predicted Ancestry Populations.

Purpose: Understanding the differences in biomarker prevalence that may exist among diverse populations is invaluable to accurately forecast biomarker-driven clinical trial enrollment metrics and to advance inclusive research and health equity. This study evaluated the frequency and types of mutations (mut) detected in predicted genetic ancestry subgroups across breast cancer (BC) subtypes.

Methods: Analyses were conducted using real-world genomic data from adult patients with BC treated in an academic or community setting in the United States and whose tumor tissue was submitted for comprehensive genomic profiling.

Real-world survival outcomes in patients with locally advanced or metastatic NTRK fusion-positive solid tumors receiving standard-of-care therapies other than targeted TRK inhibitors.

The clinical profiles and outcomes of patients with neurotrophic tropomyosin receptor kinase fusion-positive (NTRK+) solid tumors receiving standard of care other than tropomyosin receptor kinase inhibitor (TRKi) targeted therapy have not been well documented. Here, we describe the clinical characteristics of patients with NTRK+ tumors treated in clinical practice using information from a United States electronic health record-derived clinicogenomic database. We also compared survival outcomes in NTRK+ patients and matched NTRK fusion-negative (NTRK-) patients and investigated the clinical prognostic value of NTRK fusions.

NTRK gene fusions are detected in both secretory and non-secretory breast cancers.

NTRK fusions represent a new biomarker-defined population that can be treated with TRK inhibitors. Although rare, NTRK fusions are detected across a wide range of solid tumors. Previous reports suggest that NTRK fusions are limited to the secretory subtype of breast cancer.

Prediction and characterization of diffuse large B-cell lymphoma cell-of-origin subtypes using targeted sequencing.

The aim of the present study was to determine cell of origin (COO) from a platform using a DNA-based method, COO DNA classifier (COODC). A targeted exome-sequencing platform that applies the mutational profile of a sample was used to classify COO subtype. Two major mutational signatures associated with COO were identified: Catalogue of Somatic Mutations in Cancer (COSMIC) signature 23 enriched in activated B cell (ABC) and COSMIC signature 3, which suggested increased frequency in germinal center B cell (GCB).

A Novel Next-Generation Sequencing Approach to Detecting Microsatellite Instability and Pan-Tumor Characterization of 1000 Microsatellite Instability-High Cases in 67,000 Patient Samples.

Microsatellite instability (MSI) is an important biomarker for predicting response to immune checkpoint inhibitor therapy, as emphasized by the recent checkpoint inhibitor approval for MSI-high (MSI-H) solid tumors. Herein, we describe and validate a novel method for determining MSI status from a next-generation sequencing comprehensive genomic profiling assay using formalin-fixed, paraffin-embedded samples. This method is 97% (65/67) concordant with current standards, PCR and immunohistochemistry.

Bioorthogonal Labeling of Human Prostate Cancer Tissue Slice Cultures for Glycoproteomics.

Sialylated glycans are found at elevated levels in many types of cancer and have been implicated in disease progression. However, the specific glycoproteins that contribute to the cancer cell-surface sialylation are not well characterized, specifically in bona fide human disease tissue. Metabolic and bioorthogonal labeling methods have previously enabled the enrichment and identification of sialoglycoproteins from cultured cells and model organisms.

Optimization and comprehensive characterization of a faithful tissue culture model of the benign and malignant human prostate.

Few preclinical models accurately depict normal human prostate tissue or primary prostate cancer (PCa). In vitro systems typically lack complex cellular interactions among structured prostatic epithelia and a stromal microenvironment, and genetic and molecular fidelity are concerns in both in vitro and in vivo models. 'Tissue slice cultures' (TSCs) provide realistic preclinical models of diverse tissues and organs, but have not been fully developed or widely utilized for prostate studies.

Imaging the glycosylation state of cell surface glycoproteins by two-photon fluorescence lifetime imaging microscopy.

Metabolic labeling of azido sugars combined with two-photon fluorescence lifetime imaging microscopy enables the visualization of specific glycoforms of endogenous proteins. This method can be utilized to detect glycosylated proteins in both cell culture and intact human tissue slices.

A role for interleukin-1 alpha in the 1,25 dihydroxyvitamin D3 response in mammary epithelial cells.

Breast cancer is the most common non-cutaneous malignancy in American women, and better preventative strategies are needed. Epidemiological and laboratory studies point to vitamin D3 as a promising chemopreventative agent for breast cancer. Vitamin D3 metabolites induce anti-proliferative effects in breast cancer cells in vitro and in vivo, but few studies have investigated their effects in normal mammary epithelial cells.

Interleukin-1α mediates the antiproliferative effects of 1,25-dihydroxyvitamin D3 in prostate progenitor/stem cells.

Vitamin D(3) is a promising preventative and therapeutic agent for prostate cancer, but its implementation is hampered by a lack of understanding about its mechanism of action. Upon treatment with 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3), vitamin D(3)], the metabolically active form of vitamin D(3), adult prostate progenitor/stem cells (PrP/SC) undergo cell-cycle arrest, senescence, and differentiation to an androgen receptor-positive luminal epithelial cell fate. Microarray analyses of control- and vitamin D(3)-treated PrP/SCs revealed global gene expression signatures consistent with induction of differentiation.

The tissue-specific stem cell as a target for chemoprevention.

While cancer treatment modalities are gradually improving due to increased knowledge about tumor heterogeneity and the cancer stem cell hypothesis, there remains a disconnect between tumor detection and mortality rates. The increasing knowledge of stem cell biology and its contribution to cancer progression illuminates the potential for chemopreventative regimens that effectively target the tissue-specific stem cell. Several signaling pathways have emerged that are critical for regulating stem cell self-renewal and multilineage differentiation over a range of tissue types, including Wnt, Hedgehog, and Notch signaling.

Characterization of adult prostatic progenitor/stem cells exhibiting self-renewal and multilineage differentiation.

Demonstration of the hallmarks of stem cells, self-renewal and multilineage differentiation, is a challenge that has not been met for numerous tissues postulated to possess adult stem cells, including prostate tissue. Using a defined medium, we reproducibly isolated and maintained adult mouse prostatic cells with characteristics of progenitor/stem cells. Clonal populations of cells demonstrated tissue-specific multilineage differentiation by their ability to generate organized prostatic ductal structures in vivo, with luminal and basal cell layers, when grafted under the renal capsules of mice in the presence of fetal rat urogenital mesenchyme.