Biomarkers of response and resistance to immune checkpoint inhibitors in breast cancer.

Immune checkpoint inhibitors (ICIs) have recently been approved in subsets of patients with breast cancer (BC). Currently, programmed death ligand 1 (PD-L1) immunohistochemistry is used as a biomarker of response for metastatic triple negative breast cancer (TNBC). Other tumor-agnostic indications in metastatic BC include high tumor mutational burden and mismatch repair deficiency.

Stromal tumor infiltrating lymphocytes and TNBC-DX provide complementary prognostic information in triple-negative breast cancer.

Patients with triple-negative breast cancer (TNBC) who achieve pathologic complete response (pCR) to neoadjuvant systemic therapy have favorable survival, while those with residual disease have high recurrence risk. Stromal tumor infiltrating lymphocytes (sTILs) and TNBC-DX both predict pCR in TNBC. Whether these two biomarkers provide complementary information has not been tested.

Practical implementation of AI in a non-academic, non-commercial Pathology laboratory: Real world experience and lessons learned.

Aims: As pathology departments transition towards digital workflows, the integration of artificial intelligence (AI) is anticipated to become increasingly common. This study aimed to describe the real-world implementation and impact of AI integration in routine pathological diagnostics, specifically focusing on prostate biopsy evaluations at the Department of Pathology, ZAS Hospitals, Antwerp.

Methods And Results: An AI tool for analysing prostate biopsies was integrated into the department's daily workflow by embedding it into existing laboratory information and reporting systems.

Aboriginal and Torres Strait Islander Females and Survival from Breast Cancer.

Background: Despite access to universal health care, Aboriginal and Torres Strait Islander females (hereafter respectfully referred to as Aboriginal) in Australia have higher breast cancer incidence and mortality rates. We investigated the factors contributing to these survival disparities.

Methods: Aboriginal females (n = 395; 0.

Quantitative proteomics analysis of triple-negative breast cancers.

Triple-negative breast cancer (TNBC) accounts for approximately 15% of all Breast Cancer (BC) cases with poorer prognosis and clinical outcomes compared to other BC subtypes due to greater tumor heterogeneity and few therapeutically targetable oncogenic drivers. To reveal actionable pathways for anti-cancer treatment, we use a proteomic approach to quantitatively compare the abundances of 6306 proteins across 55 formalin-fixed and paraffin-embedded (FFPE) TNBC tumors. We identified four major TNBC clusters by unsupervised clustering analysis of protein abundances.

AI-driven biomarkers for antibody-drug conjugates.

Currently, no biomarker reliably predicts the efficacy of antibody-drug conjugates (ADCs). In this issue of Cancer Cell, Ma et al. present a predictive model for HER2-targeting ADC efficacy, incorporating immune-system components, hormone receptor status, clinical staging, and HER2+ cell proportion.

Neoadjuvant nivolumab and chemotherapy in early estrogen receptor-positive breast cancer: a randomized phase 3 trial.

Patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer (BC) have low pathological complete response (pCR) rates with neoadjuvant chemotherapy. A subset of ER+/HER2- BC contains dense lymphocytic infiltration. We hypothesized that addition of an anti-programmed death 1 agent may increase pCR rates in this BC subtype.

Preliminary characterisation of the spatial immune and vascular environment in triple negative basal breast carcinomas using multiplex fluorescent immunohistochemistry.

Triple negative breast cancers often contain higher numbers of tumour-infiltrating lymphocytes compared with other breast cancer subtypes, with their number correlating with prolonged survival. Since little is known about tumour-infiltrating lymphocyte trafficking in triple negative breast cancers, we investigated the relationship between tumour-infiltrating lymphocytes and the vascular compartment to better understand the immune tumour microenvironment in this aggressive cancer type. We aimed to identify mechanisms and signaling pathways responsible for immune cell trafficking in triple negative breast cancers, specifically of basal type, that could potentially be manipulated to change such tumours from immune "cold" to "hot" thereby increasing the likelihood of successful immunotherapy in this challenging patient population.

Prioritizing cases from a multi-institutional cohort for a dataset of pathologist annotations.

Objective: With the increasing energy surrounding the development of artificial intelligence and machine learning (AI/ML) models, the use of the same external validation dataset by various developers allows for a direct comparison of model performance. Through our High Throughput Truthing project, we are creating a validation dataset for AI/ML models trained in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple negative breast cancer (TNBC).

Materials And Methods: We obtained clinical metadata for hematoxylin and eosin-stained glass slides and corresponding scanned whole slide images (WSIs) of TNBC core biopsies from two US academic medical centers.

Identification of HER2-positive breast cancer molecular subtypes with potential clinical implications in the ALTTO clinical trial.

In HER2-positive breast cancer, clinical outcome and sensitivity to HER2-targeted therapies are influenced by both tumor and microenvironment features. However, we are currently unable to depict the molecular heterogeneity of this disease with sufficient granularity. Here, by performing gene expression profiling in HER2-positive breast cancers from patients receiving adjuvant trastuzumab in the ALTTO clinical trial (NCT00490139), we identify and characterize five molecular subtypes associated with the risk of distant recurrence: immune-enriched, proliferative/metabolic-enriched, mesenchymal/stroma-enriched, luminal, and ERBB2-dependent.

Origins and impact of extrachromosomal DNA.

Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer. Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.

Sustained lymphocyte decreases after treatment for early breast cancer.

The role of adaptive immunity in long-term outcomes in early breast cancer is increasingly recognised. Standard (neo)adjuvant chemotherapy can have adverse effects on immune cells. We conducted a retrospective longitudinal study of full blood counts (FBC) of 200 patients receiving (neo)adjuvant chemotherapy for early breast cancer at a single institution.

MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution.

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue.

Empowering effective biomarker-driven precision oncology: A call to action.

Precision oncology has a significant role to play in delivering optimal patient care. Biomarkers are critical enablers for precision oncology across the continuum of cancer diagnosis, in defining patient prognosis, and in predicting the response to treatments and their potential toxicities, as well as delineating the risk of hereditary cancer syndromes. Biomarkers also potentiate cancer drug development, accelerating patient access to safe and effective therapies.

Development of a deep-learning model tailored for HER2 detection in breast cancer to aid pathologists in interpreting HER2-low cases.

Aims: Over 50% of breast cancer cases are "Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC)", characterized by HER2 immunohistochemistry (IHC) scores of 1+ or 2+ alongside no amplification on fluorescence in situ hybridization (FISH) testing. The development of new anti-HER2 antibody-drug conjugates (ADCs) for treating HER2-low breast cancers illustrates the importance of accurately assessing HER2 status, particularly HER2-low breast cancer. In this study we evaluated the performance of a deep-learning (DL) model for the assessment of HER2, including an assessment of the causes of discordances of HER2-Null between a pathologist and the DL model.

Towards targeting the breast cancer immune microenvironment.

The tumour immune microenvironment is shaped by the crosstalk between cancer cells, immune cells, fibroblasts, endothelial cells and other stromal components. Although the immune tumour microenvironment (TME) serves as a source of therapeutic targets, it is also considered a friend or foe to tumour-directed therapies. This is readily illustrated by the importance of T cells in triple-negative breast cancer (TNBC), culminating in the advent of immune checkpoint therapy in combination with cytotoxic chemotherapy as standard of care for both early and advanced-stage TNBC, as well as recent promising signs of efficacy in a subset of hormone receptor-positive disease.

A panoptic segmentation dataset and deep-learning approach for explainable scoring of tumor-infiltrating lymphocytes.

Tumor-Infiltrating Lymphocytes (TILs) have strong prognostic and predictive value in breast cancer, but their visual assessment is subjective. To improve reproducibility, the International Immuno-oncology Working Group recently released recommendations for the computational assessment of TILs that build on visual scoring guidelines. However, existing resources do not adequately address these recommendations due to the lack of annotation datasets that enable joint, panoptic segmentation of tissue regions and cells.

Tumor-Infiltrating Lymphocytes in Patients With Stage I Triple-Negative Breast Cancer Untreated With Chemotherapy.

Importance: The absolute benefit of chemotherapy for all patients with stage I triple-negative breast cancer (TNBC) is unclear, and biomarkers are not currently available for selecting patients with an excellent outcome for whom neoadjuvant or adjuvant chemotherapy may have negligible benefit. High levels of stromal tumor-infiltrating lymphocytes (sTILs) are associated with favorable survival in TNBC, but data solely in stage I TNBC are lacking.

Objective: To examine the outcomes of patients of all ages with stage I TNBC solely and who received neither neoadjuvant nor adjuvant chemotherapy, according to centrally reviewed sTIL levels at prespecified cutoffs.

Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer.

Unlabelled: Understanding the role of the tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs in treatment-naïve early-stage lung cancer using imaging mass cytometry in the TRACERx study (n = 81 patients/198 samples/2.3 million cells).