Predictive gene expression profile for adjuvant taxane benefit in breast cancer in the MATADOR trial.

The primary objective of the prospective, randomized, multicenter, phase 3 biomarker Microarray Analysis in breast cancer to Taylor Adjuvant Drugs Or Regimens trial (MATADOR: ISRCTN61893718) is to generate a gene expression profile that can predict benefit from either docetaxel, doxorubicin, and cyclophosphamide (TAC) or dose-dense scheduled doxorubicin and cyclophosphamide (ddAC). Patients with a pT1-3, pN0-3 tumor were randomized 1:1 between ddAC and TAC. The primary endpoint was a gene profile-treatment interaction for recurrence-free survival (RFS).

Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence.

Unlabelled: In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial.

Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer.

Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5-10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases.

Comprehensive characterization of pre- and post-treatment samples of breast cancer reveal potential mechanisms of chemotherapy resistance.

When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome, and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identify biomarkers of response and resistance mechanisms.

Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments.

Purpose: Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types.

Reduced NCOR2 expression accelerates androgen deprivation therapy failure in prostate cancer.

This study addresses the roles of nuclear receptor corepressor 2 (NCOR2) in prostate cancer (PC) progression in response to androgen deprivation therapy (ADT). Reduced NCOR2 expression significantly associates with shorter disease-free survival in patients with PC receiving adjuvant ADT. Utilizing the CWR22 xenograft model, we demonstrate that stably reduced NCOR2 expression accelerates disease recurrence following ADT, associates with gene expression patterns that include neuroendocrine features, and induces DNA hypermethylation.

An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer.

Cancers adapt to increasingly potent targeted therapies by reprogramming their phenotype. Here we investigated such a phenomenon in prostate cancer, in which tumours can escape epithelial lineage confinement and transition to a high-plasticity state as an adaptive response to potent androgen receptor (AR) antagonism. We found that AR activity can be maintained as tumours adopt alternative lineage identities, with changes in chromatin architecture guiding AR transcriptional rerouting.

Functional mapping of androgen receptor enhancer activity.

Background: Androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10-100× more binding sites than differentially expressed genes.

A case-control study to identify molecular risk factors for local recurrence in young breast cancer patients.

Purpose: To investigate risk factors for local recurrence (LR) after breast conserving therapy in young breast cancer patients randomized in the "Young Boost Trial".

Material & Methods: In the "Young Boost Trial" 2421 patients ≤50 years old were randomized between a 16 Gy and 26 Gy boost after breast conserving surgery and whole breast radiation (50 Gy). We performed a case-control study comparing patients who developed a LR (cases) and for each of them three control patients free of recurrence (controls).

Response to Preoperative Radiation Therapy in Relation to Gene Expression Patterns in Breast Cancer Patients.

Purpose: We aimed to study radiation-induced gene expression changes and to identify differences in gene expression between patients with and without response to radiation therapy (RT) for invasive breast cancer with the purpose of exploring whether a predictive signature could be developed. Such a signature could assist in optimizing individualized locoregional treatment.

Methods And Materials: RNA-seq using next-generation sequencing was performed on fresh frozen samples from pretreatment biopsies and post-RT surgery specimens from patients with low-risk breast cancer treated within the multicenter preoperative accelerated partial breast irradiation trial.

The molecular genetic make-up of male breast cancer.

Male breast cancer (MBC) is extremely rare and accounts for less than 1% of all breast malignancies. Therefore, clinical management of MBC is currently guided by research on the disease in females. In this study, DNA obtained from 45 formalin-fixed paraffin-embedded (FFPE) MBCs with and 90 MBCs (52 FFPE and 38 fresh-frozen) without matched normal tissues was subjected to massively parallel sequencing targeting all exons of 1943 cancer-related genes.

GPCR-SAS: A web application for statistical analyses on G protein-coupled receptors sequences.

G protein-coupled receptors (GPCRs) are one of the largest protein families in mammals. They mediate signal transduction across cell membranes and are important targets for the pharmaceutical industry. The G Protein-Coupled Receptors-Sequence Analysis and Statistics (GPCR-SAS) web application provides a set of tools to perform comparative analysis of sequence positions between receptors, based on a curated structural-informed multiple sequence alignment.

Enrichment of high-grade tumors in breast cancer gene expression studies.

Purpose: Gene expression (GE) profiling for breast cancer classification and prognostication has become increasingly used in clinical diagnostics. GE profiling requires a reasonable tumor cell percentage and high-quality RNA. As a consequence, a certain amount of samples drop out.

Long-term prognosis of young breast cancer patients (≤40 years) who did not receive adjuvant systemic treatment: protocol for the PARADIGM initiative cohort study.

Introduction: Currently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient's prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated.

Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1β in tumor-associated macrophages.

Patients with primary solid malignancies frequently exhibit signs of systemic inflammation. Notably, elevated levels of neutrophils and their associated soluble mediators are regularly observed in cancer patients, and correlate with reduced survival and increased metastasis formation. Recently, we demonstrated a mechanistic link between mammary tumor-induced IL17-producing γδ T cells, systemic expansion of immunosuppressive neutrophils and metastasis formation in a genetically engineered mouse model for invasive breast cancer.

Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study.

Background: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type.

Methods: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted.

TP53 mutated glioblastoma stem-like cell cultures are sensitive to dual mTORC1/2 inhibition while resistance in TP53 wild type cultures can be overcome by combined inhibition of mTORC1/2 and Bcl-2.

Background: Glioblastoma is the most malignant tumor of the central nervous system and still lacks effective treatment. This study explores mutational biomarkers of 11 drugs targeting either the RTK/Ras/PI3K, the p53 or the Rb pathway using 25 patient-derived glioblastoma stem-like cell cultures (GSCs).

Results: We found that TP53 mutated GSCs were approximately 3.

RUBIC identifies driver genes by detecting recurrent DNA copy number breaks.

The frequent recurrence of copy number aberrations across tumour samples is a reliable hallmark of certain cancer driver genes. However, state-of-the-art algorithms for detecting recurrent aberrations fail to detect several known drivers. In this study, we propose RUBIC, an approach that detects recurrent copy number breaks, rather than recurrently amplified or deleted regions.

Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases.

Tumor organoids are 3D cultures of cancer cells. They can be derived from the tumor of each individual patient, thereby providing an attractive ex vivo assay to tailor treatment. Using patient-derived tumor organoids for this purpose requires that organoids derived from biopsies maintain the genetic diversity of the in vivo tumor.

Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response.

Introduction: In triple negative breast cancers (TNBC) the initial response to chemotherapy is often favorable, but relapse and chemotherapy resistance frequently occur in advanced disease. Hence there is an urgent need for targeted treatments in this breast cancer subtype. In the current study we deep sequenced DNA of tumors prior to chemotherapy to search for predictors of response or resistance.

Genome-Wide Identification and Characterization of Novel Factors Conferring Resistance to Topoisomerase II Poisons in Cancer.

The topoisomerase II poisons doxorubicin and etoposide constitute longstanding cornerstones of chemotherapy. Despite their extensive clinical use, many patients do not respond to these drugs. Using a genome-wide gene knockout approach, we identified Keap1, the SWI/SNF complex, and C9orf82 (CAAP1) as independent factors capable of driving drug resistance through diverse molecular mechanisms, all converging on the DNA double-strand break (DSB) and repair pathway.

Effective Therapeutic Intervention and Comprehensive Genetic Analysis of mTOR Signaling in PEComa: A Case Report.

Background/aim: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms. The exact genetic alterations underlying the pathophysiology of PEComas are largely unknown, although it has been shown that activation of the Mammalian target of rapamycin (mTOR) signaling pathway plays a pivotal role. Herein we describe the successful treatment of a patient with metastatic PEComa with the mTOR inhibitor everolimus and a comprehensive analysis to identify mechanisms for response.

CopywriteR: DNA copy number detection from off-target sequence data.

Current methods for detection of copy number variants (CNV) and aberrations (CNA) from targeted sequencing data are based on the depth of coverage of captured exons. Accurate CNA determination is complicated by uneven genomic distribution and non-uniform capture efficiency of targeted exons. Here we present CopywriteR, which eludes these problems by exploiting 'off-target' sequence reads.