Development of a Machine Learning-Based Prognostic Model for Hormone Receptor-Positive Breast Cancer Using Nine-Gene Expression Signature.

Background: Determining the prognosis of hormone receptor positive (HR+) breast cancer (BC), which accounts for 80% of all BCs, is critical in improving survival outcomes. Stratifying individuals at high risk of BC-related mortality and improving prognosis has been the focus of research for over a decade. However, these tools are not universal as they are limited to clinical factors. We hypothesized that a new framework for predicting prognosis in HR+ BC patients can develop using artificial intelligence. Methods: A total of 2,338 HR+ human epidermal growth factor receptor 2 negative (HER2-) BC cases were analyzed from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) cohorts. Groups were then divided into high- and low-risk categories utilizing a recurrence prediction model (RPM). An RPM was created by extracting nine prognosis-related genes from over 18,000 genes using a logistic progression model. Results: Risk classification by RPM was significantly stratified in both the discovery cohort and validation cohort. In the time-dependent area under the curve analysis, there was some variation depending on the cohort, but accuracy was found to decline significantly after about 10 years. Cell cycle related gene sets, MYC, and PI3K-AKT-mTOR signaling were enriched in high-risk tumors by the Gene Set Enrichment Analysis. High-risk tumors were associated with high levels of immune cells from the lymphoid and myeloid lineage and immune cytolytic activity, as well as low levels of stem cells and stromal cells. High-risk tumors were also associated with poor therapeutic effects of chemotherapy and endocrine therapy. Conclusions: This model was able to stratify prognosis in multiple cohorts. This is because the model reflects major BC therapeutic target pathways and tumor immune microenvironment and, further is supported by the therapeutic effect of chemotherapy and endocrine therapy.

High miR-200c expression is associated with suppressed epithelial-mesenchymal transition, TGF-ß signaling and better survival despite enhanced cell proliferation in gastric cancer patients.

MicroRNAs are small non-coding RNAs that epigenetically regulate gene expression. MiR-200c is a known tumor suppressive microRNA found in many types of cancer, and its high expression has been associated with improved prognosis. However, the association between miR-200c expression and its clinical relevance in gastric cancer (GC) patients remains controversial. Here, we hypothesized that gastric cancer patients with high miR-200c gene expression translated to better overall survival. A total of 372 GC patients from the Cancer Genome Atlas (TCGA) were analyzed. The top three quartiles were defined as a high miR-200c expression group. High miR-200c expression was associated with decreased invasion, favorable histological type, and improved overall survival in gastric cancer patients. Unexpectedly, high miR-200c expression GC was also associated with enhanced cell proliferation, shown by MKi67 expression, proliferation score, and enrichment of Hallmark cell proliferation-related gene sets (E2F targets, G2M checkpoints, MYC targets v1 and v2) by gene set enrichment assay (GSEA). High miR-200c GC was also associated with a high mutation rate and homologous recombination deficiency. Despite the association with elevated neoantigens, high miR-200c GC was associated with significantly low infiltration of anti-cancer immune cells, decreased immune response, and with suppressed IL2, TNF-α, and IFN-γ pathways. On the other hand, GC with low miR-200c expression significantly enriched hypoxia, angiogenesis, epithelial-mesenchymal transition (EMT), and TGF-ß signaling gene sets, all of which promote cancer progression and metastasis in GSEA. In conclusion, patients with high miR-200c expression GC had better survival despite association with aggressive tumor biology, such as high mutation rates, cell proliferation, and low cancer immunity. Given that low miR-200c GC was associated with hypoxia, angiogenesis, EMT and TGF-ß signaling, we cannot help but speculate that the difference in survival by miR-200c expression may be at least partly due to the association between low miR-200c expression and aggressive biology.

GALNT1 Expression Is Associated with Angiogenesis and Is a Prognostic Biomarker for Breast Cancer in Adolescents and Young Adults (AYA).

It is well established that genetic information differs amongst the adolescent and young adult population (AYA) and older patients. Although several studies on genetic information have been conducted, no current prognostic biomarker exists to help differentiate survival outcomes amongst AYA patients. The GALNT family of genes have been associated with several cancer etiologies, such as the Tn antigen and epithelial-mesenchymal transition (EMT); however, the clinical significance of GALNT1 expression in breast cancer (BC) remains unclear. We investigated the clinical relevance of GALNT1 expression in BC using two large independent cohorts. We found that, although triple-negative BC (TNBC) had the highest GALNT1 expression compared to ER-positive/HER2-negative BC, GALNT1 levels in BC were not associated with clinical aggressiveness, including histological grade, AJCC stage and N-category, and patient survival, consistently in both the METABRIC and GSE96058 cohorts. There was also no biological difference between low- and high-GALNT1 expression BC, as analyzed by hallmark gene sets via gene set enrichment analysis (GSEA). Further, no significant difference was found in GALNT1 expression levels among AYAs and older patients. However, high GALNT1 expression was associated with significantly worse survival in AYA patients, in both cohorts. Furthermore, high GALNT1 expression was found to be an independent factor among several clinical features, including subtype, histological grade, AJCC T and N-category, in AYA patients. In both cohorts, BC with high GALNT1 expression demonstrated low levels of CD8+ T-cell infiltration, but not other anti-cancerous or pro-cancerous immune cells. Finally, high levels of GALNT1 BC demonstrated increased EMT, angiogenesis, and protein secretion in the AYA population, but not in older patients. In conclusion, our findings demonstrate that GALNT1 expression was found to be associated with angiogenesis and EMT, and may have potential as prognostic biomarker, specifically in AYA patients.

A mixed-methods study of multi-level factors influencing mammography overuse among an older ethnically diverse screening population: implications for de-implementation.

BACKGROUND: There is growing concern that routine mammography screening is overused among older women. Successful and equitable de-implementation of mammography will require a multi-level understanding of the factors contributing to mammography overuse. METHODS: This explanatory, sequential, mixed-methods study collected survey data (n= 52, 73.1% Hispanic, 73.1% Spanish-speaking) from women ≥70 years of age at the time of screening mammography, followed by semi-structured interviews with a subset of older women completing the survey (n=19, 63.2% Hispanic, 63.2% Spanish-speaking) and providers (n=5, 4 primary care, 1 obstetrics and gynecology) to better understand multi-level factors influencing mammography overuse and inform potential de-implementation strategies. We conducted a descriptive analysis of survey data and content analysis of qualitative interview data. Survey and interview data were examined separately, compared, integrated, and organized according to Norton and Chambers Continuum of Factors Influencing De-Implementation Process. RESULTS: Survey findings show that 87.2% of older women believe it is important to plan for an annual mammogram, 80.8% received a provider recommendation, and 78.9% received a reminder in the last 12 months to schedule a mammogram. Per interviews with older women, the majority were unaware of or did not perceive to have experienced overuse and intended to continue mammography screening. Findings from interviews with older women and providers suggest that there are multiple opportunities for older women to obtain a mammogram. Per provider interviews, almost all reported that reducing overuse was not viewed as a priority by the system or other providers. Providers also discussed that variation in mammography screening practices across providers, fear of malpractice, and monetary incentives may contribute to overscreening. Providers identified potential strategies to reduce overscreening including patient and provider education around harms of screening, leveraging the electronic health record to identify women who may receive less health benefit from screening, customizing system-generated reminder letters, and organizing workgroups to develop standard processes of care around mammography screening. CONCLUSIONS: Multi-level factors contributing to mammography overuse are dynamic, interconnected, and reinforced. To ensure equitable de-implementation, there is a need for more refined and empirical testing of theories, models, and frameworks for de-implementation with a strong patient-level component that considers the interplay between multilevel factors and the larger care delivery process.

Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression.

Proteins of the bromodomain and extra-terminal (BET) family are epigenetics "readers" and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. QCA570 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date.