Sotiriou fumagalli

BACKGROUND: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance...

BACKGROUND: Studies evaluating the presence of viral sequences in breast cancer (BC), including various strains of human papillomavirus and human herpes virus, have yielded conflicting results. Most were based on RT-PCR and in situ hybridization. METHODS: In this report we searched for expressed viral sequences in 58 BC transcriptomes using five distinct in silico methods. In addition, we complemented our RNA sequencing results with exome sequencing, PCR and immunohistochemistry (IHC) analyses...

Multifocal breast cancer (MFBC), defined as multiple synchronous unilateral lesions of invasive breast cancer, is relatively frequent and has been associated with more aggressive features than unifocal cancer. Here, we aimed to investigate the genomic heterogeneity between MFBC lesions sharing similar histopathological parameters. Characterization of different lesions from 36 patients with ductal MFBC involved the identification of non-silent coding mutations in 360 protein-coding genes (171 tumour and 36 matched normal samples)...

PURPOSE: We investigated whether mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) correlates with response to neoadjuvant human epidermal growth factor receptor 2 (HER2) -targeted therapies in patients with breast cancer. PATIENTS AND METHODS: Baseline tissue biopsies were available from patients with HER2-positive early breast cancer who were enrolled onto the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (NeoALTTO)...

BACKGROUND: Microarrays have revolutionized breast cancer (BC) research by enabling studies of gene expression on a transcriptome-wide scale. Recently, RNA-Sequencing (RNA-Seq) has emerged as an alternative for precise readouts of the transcriptome. To date, no study has compared the ability of the two technologies to quantify clinically relevant individual genes and microarray-derived gene expression signatures (GES) in a set of BC samples encompassing the known molecular BC's subtypes...

Awareness of breast cancer heterogeneity has strikingly increased in the past decade in parallel with the development of high-throughput molecular tests. Beyond the clear usefulness of antiestrogen treatment in luminal tumors and trastuzumab in HER2-positive tumors, breast cancer subtypes may have additional clinical and predictive roles that can be relevant to clinical practice. In this article, we discuss the significance of molecular subtypes in the systemic treatment of early-stage breast tumors smaller than 1 cm (T1a,bN0M0) and suggest new strategies for future treatment recommendations for these patients...

Intra-tumor heterogeneity concerns the existence of genetically different subclones within the same tumor. Single sample quantification of heterogeneity relies on precise determination of chromosomal copy numbers throughout the genome, and an assessment of whether identified mutation variant allele fractions match clonal or subclonal copy numbers. We discuss these issues using data from SNP arrays, whole exome sequencing and pathologist purity estimates on several breast cancers characterized by ERBB2 amplification...

Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme...

BACKGROUND: Molecular screening programs use next-generation sequencing (NGS) of cancer gene panels to analyze metastatic biopsies. We interrogated whether plasma could be used as an alternative to metastatic biopsies. PATIENTS AND METHODS: The Ion AmpliSeq™ Cancer Hotspot Panel v2 (Ion Torrent), covering 2800 COSMIC mutations from 50 cancer genes was used to analyze 69 tumor (primary/metastases) and 31 plasma samples from 17 metastatic breast cancer patients...

Breast cancer complexity has long been known and investigated. After a first classification of the disease based on histology features, starting from the 1980s breast cancers have been distinguished on the basis of oestrogen receptor expression and later according to HER2. By 2000 the "microarray revolution" had shown that the phenotypic differences between breast cancers were a reflection of their mRNA expression profiles, while the more recent "genomic revolution" is revealing the genomic bases of breast cancer heterogeneity...

Gene expression profiling has reshaped our understanding of breast cancer by defining and characterizing four main intrinsic molecular subtypes: human epidermal growth factor receptor 2-enriched, basal-like, luminal A, and luminal B subtypes. Luminal B breast cancer has been reported to have lower expression of hormone receptors, higher expression of proliferation markers, and higher histologic grade than luminal A. It also exhibits worse prognosis and has a distinct profile of response to hormone therapy and chemotherapy...

BACKGROUND: We have previously shown the prognostic importance of tumor-infiltrating lymphocytes (TILs) in newly diagnosed triple-negative breast cancer (TNBC) using tumor samples from a large clinical trial cohort. In this study, we aimed to validate these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease (HER2+). PATIENTS AND METHODS: A prospective-retrospective study was conducted using samples from the FinHER adjuvant, phase III trial that enrolled 1010 early-stage BC patients, 778 of whom were HER2-nonamplified...

BACKGROUND: Certain somatic alterations in breast cancer can define prognosis and response to therapy. This study investigated the frequencies, prognostic effects, and predictive effects of known cancer somatic mutations using a randomized, adjuvant, phase III clinical trial dataset. METHODS: The FinHER trial was a phase III, randomized adjuvant breast cancer trial involving 1010 women. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer were further randomized to 9 weeks of trastuzumab or no trastuzumab...

INTRODUCTION: SPARC is an important regulator of the extracellular matrix and has been suggested to improve delivery of albumin-bound cytotoxics. However, little is known regarding its role in breast cancer (BC). METHODS: We conducted a pooled analysis of publically available datasets, in which BC patients who received no systemic therapy or received neoadjuvant chemotherapy were eligible. Patients were assigned to molecular subtypes using PAM-50. We computed a SPARC module (SPARC7), composed of genes with an absolute correlation with SPARC >0...

BACKGROUND: The prognostic value of histologic grade (HG) in invasive lobular carcinoma (ILC) remains uncertain, and most ILC tumors are graded as HG2. Genomic grade (GG) is a 97-gene signature that improves the prognostic value of HG. This study evaluates whether GG may overcome the limitations of HG in ILC. METHODS: Gene expression data were generated from frozen tumor samples, and GG calculated according to the expression of 97 genes. The prognostic value of GG was assessed in a stratified Cox regression model for invasive disease-free survival (IDFS) and overall survival (OS)...

Breast cancer is a complex disease, with heterogeneous presentations and clinical courses. Standard clinico-pathological parameters, relying on single gene or protein characterization determined with sometimes poorly-reproducible technologies, have shown limitations in the classification of the disease and in the prediction of individual patient outcomes and responses to therapy. Gene-expression profiling has revealed great potential to accurately classify breast cancer and define patient prognosis and prediction to anti-cancer therapy...

The neoadjuvant setting provides a unique opportunity to study the effect of systemic treatments on breast cancer biology and to identify clinically useful prognostic and predictive biomarkers. Discrepancies and inconsistencies in the use of definitions and endpoint assessments in this setting confound the analysis and interpretation of results across clinical trials and hinder research progress. This Review represents a joint effort of the Breast International Group and the National Cancer Institute-sponsored North American Breast Cancer Group to provide clinicians and researchers with a series of standardised definitions and endpoints that could be implemented in future neoadjuvant clinical trials...

Several treatment options, including endocrine therapy, chemotherapy, and targeted therapy, have been shown to improve survival of breast cancer patients. Currently, clinical tests for predicting cancer response are not available, and individual markers have shown little predictive value. Several gene expression profiling studies have been carried out in the attempt to identify predictive signatures. The neoadjuvant setting revealed to be ideal for this purpose because it allows the direct assessment of response to treatment, and tumor is readily available for multiple time point biopsies...

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No abstract text is available yet for this article.