A prognostic miRNA based signature in early-stage HER2-positive breast cancer patients.

e12600 Background: In early-stage HER2+ breast cancer (BC), escalation or de-escalation of systemic treatment is an unmet need. Integration of promising biomarkers into risk scoring will further help progressing in the field. We aim to develop a prognostic signature that integrates two miRNAs (A and B) and quantitative and qualitative clinical variables in patients diagnosed with HER2+ BC. Methods: This study was conducted in a retrospective cohort of 45 HER2+ BC patients. Patients received standard treatment for localized disease. We calculated a prognostic signature for disease-free survival (DFS) using principal components analysis for mixed data combining clinicopathological data (Ki67…

A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients

Background Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40% approximately. To provide further insight into the prediction of pCR, we evaluated the role of an epigenetic methylation-based signature. Methods Epigenetic assessment of DNA extracted from biopsy archived samples previous to NAC from TNBC patients was performed. Patients included were categorized according to previous response to NAC in responder (pCR or residual cancer burden, RCB = 0) or non-responder (non-pCR or RCB > 0) patients. A methyloma study was performed in a discovery cohort by the Infinium HumanMethylation450 BeadChip (450K arra…

Primary results of the first nationwide molecular screening program in Spain for patients with advanced breast cancer (AGATA SOLTI-1301 study)

Circulating miR-30b-5p levels in plasma as a novel potential biomarker for early detection of breast cancer

Background Recently, microRNAs have been demonstrated to be potential non-invasive biomarkers for diagnosis, prognosis assessment or prediction of response to treatment in cancer. In this study, we evaluate the potential of miR-30b-5p as a biomarker for early diagnosis of breast cancer (BC) in tissue and plasma. Methods Expression of miR-30b-5p was determined in a series of 112 BC and 40 normal breast tissues. Circulating miR-30b-5p levels in plasma samples were determined in a discovery cohort of 38 BC patients and 40 healthy donors and in a validation cohort of 83 BC patients and 83 healthy volunteers. miR-30b-5p expression was measured by quantitative real-time PCR and receiver operating…

Non-canonical NF-κB pathway activation predicts outcome in borderline oestrogen receptor positive breast carcinoma

Background: NF-κB signalling appears deregulated in breast tumours. The purpose of this study was to determine whether the non-canonical NF-κB pathway, is activated in oestrogen receptor positive (ER+) breast cancer, to identify any correlation between its activity and the clinico-pathological phenotype and to explore whether NF-κB2 and RelB subunits and/or any of their target genes might be used as a predictive marker. Methods: Two independent cohorts of ER+ early breast cancer patients treated with adjuvant endocrine therapy were included in the study. Activation of RelB and NF-κB2 subunits was determined in a training set of 121 patients by measuring DNA-binding activities in nuclear ext…

An evaluation of the impact of technical bias on the concordance rate between primary and recurrent tumors in breast cancer.

Abstract Purpose Whether or not to biopsy the metastasis in recurrent breast cancer has become mired in controversy. Several studies have shown an important discordance of the immunohistochemical (IHC) determinations for ER, PR and HER2 between primary (PT) and recurrent tumors (RT). Yet it remains unknown within this what impact technical issues have. The aim of our study was to assess whether technical variability might have an impact on the concordance between PT and RT. Methods IHC determinations in paired biopsies from PT and RT were compared under routine vs study conditions. In the former, pathological analysis reproduced the conditions used in the routine of a University Pathology D…

PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer.

Abstract The purpose of this work was to determine whether there are differences in PIK3CA mutation status and PTEN protein expression between primary and matched metastatic breast tumors as this could influence patient management. Paraffin sections of 50 μm were used for DNA extraction and slides of 3 μm for immunohistochemistry (IHC) and FISH. Estrogen receptor, progesterone receptor, and HER2 IHC were repeated in a central laboratory for both primary tumors and metastases. PTEN levels were assessed by IHC and phosphoinositide 3-kinase (PI3K) pathway mutations were detected by a mass spectroscopy–based approach. Median age was 48 years (range: 30–83 years). Tumor subtype included 72% horm…

Concordance of Genomic Alterations between Primary and Recurrent Breast Cancer

Abstract There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered “actionable.” Alterations…

Cutaneous sclerosing Pacinian-like perineurioma

Cutaneous sclerosing Pacinian-like perineurioma Aims: The term perineurioma has been used to designate a variety of clinically and histologically different proliferations of perineurial cells based on immunohistochemical and/or ultrastructural characterization. There are two different groups of neoplasms derived from perineurial cells: extraneural or soft tissue perineuriomas, and intraneural perineuriomas. Recently, a sclerosing variant of cutaneous perineurioma has been described. Methods and results: We report a case of a cutaneous form of perineurioma, combining features of the intraneural and sclerosing varieties, as well as showing a Pacinian pattern of growth. In order to assess the …

Incidence of oncogenes in PI3K/AKT and MAPK signaling pathways in breast cancer

Abstract PD3-6: ConvertHER: Evolution of genomic alterations from primary to metastatic breast cancer

Abstract Background: Changes in breast cancer receptor status over disease progression and treatment have been described to a point that could alter response to therapy. There is growing interest in delivering biomarker/genomically-based targeted therapies. We aimed to determine the concordance of genomic alterations between primary (P) and metastatic (M) breast cancer in a prospective collection study. Methods: Targeted capture and next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 202 cancer relevant genes in 61 pairs (primary and corresponding recurrence/metastasis). Tumors were classified at baseline as [hormone receptor (HR)+/HER2-, H…

The role of AXL as mechanism of resistance to trastuzumab and a prognostic factor in breast cancer HER2 positive: A translational approach

Abstract Background Breast cancer (BC) is a heterogeneous disease. HER2+ BC represents between 15-30% of cases. Trastuzumab (T), a monoclonal antibody, has been successfully improved clinical benefits in both adjuvant and in metastatic settings. Despite this evidence, many patients experience resistance to therapy. The objective of this study is to assess AXL as a potential mechanism of resistance and its implication as a prognostic factor. Methods We used three cell lines with acquired resistance to T. Resistant models were generated by treating parental cells (AU565, SKR3, BT474) with constant dose of T (15mg/mL) for 6 months. Cell viability was estimated by MTT assay. Proteins were asses…

No effect of length time bias on the genomic risk in ER+ HER2-stage I-IIA breast cancer (BC) patients according to diagnosis in a screening programme: An exploratory analysis

MamaPred: A new and innovative approach to determine recurrence risk in HR+/HER2- early-stage breast cancer using HTG EdgeSeq technology.

558 Background: Genomic platforms, such as Mammaprint (Agendia) (MP) and OncoType (Genomic Health) (OT), have been validated to determine the risk of relapse in therapeutic decision-making in early-stage hormone receptor positive (HR+), epidermal growth factor receptor 2 (HER2) negative breast cancer (BC). Discordances in risk allocation between these platforms affect up to 30% of patients. This study aims to develop the MamaPred test to improve the diagnostic performance of recurrence risk in HR+/HER2- early-stage BC. Methods: A total of 606 HR+/HER2- early-stage BC previously tested with OT [n = 287; Low Risk (LR) = 165, Intermediate Risk (IR) = 103 and High Risk (HR) = 19] and MP (n = 3…

Removal of primary tumor improves survival in metastatic breast cancer. Does timing of surgery influence outcomes?

Resection of intact primary tumor is controversial in metastatic breast cancer patients. The aim of this study is to review the impact of surgical resection of primary tumor on overall survival and to assess the role of timing of surgery on survival rates.208 patients with metastatic breast cancer diagnosed between 1982 and 2005 in the Hospital Clinico of Valencia (Spain) were analysed. Exclusion criteria were age80, PS 3-4, Charlson score 3 or follow-up90 days. 123 of these underwent surgery and 85 did not. In order to assess the role of timing, the "surgery" cohort was divided into two sub-groups: "before" (n = 78) or "after" (n = 45) diagnosis of disseminated disease.In the surgery group…

miR-503-5p induces doxorubicin resistance in triple-negative breast cancer.

1083 Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer (BC) subtype comprising approximately 15% of BC. Conventional cytotoxic chemotherapies continue to be the mainstay for treatment of this BC, which lacks targetable markers. In this context, microRNAs have been described to have an important role. The aim of this work was to elucidate the function of miR-503-5p in doxorubicin resistance in TNBC. Methods: miR-503-5p expression was evaluated in the TNBC cell line with acquired resistance to doxorubicin (MDA-MB-231R) and its parental cell line (MDA-MB-231), by qRT-PCR. Studies of gain/loss of function of miR-503-5p were carried out in MDA-MB-231 and MDA-MB-231…

Global transcriptome deregulation of breast cancer in very young women samples

The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver

AbstractAs the catalogue of oncogenic driver mutations is expanding, it is becoming clear that alterations in a given gene should not be lumped into one single class, since they might have different functions. The transcription factorGATA3is a paradigm of this. Here, we address the functions of the most commonGATA3mutation (X308_Splice) which generates a neoprotein that we designate as neoGATA3, associated with good patient prognosis. Based on extensive analyses of molecular and clinical data from approximately 3000 breast cancer patients, supported by mechanistic studiesin vitro, we show that neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone rece…

Thirteen miRNAs involved in the response of breast cancer cells to doxorubicin.

e12019 Background: Mature microRNAs (miRNAs) are a class of naturally occurring, small non-coding RNA molecules, about 21–25 nucleotides. Growing evidence shows that miRNAs exhibit a variety of regulatory functions related to cell growth, development, and differentiation, and are associated with a wide variety of human diseases. Several miRNAs have been linked to cancer; since expression analysis studies have revealed perturbed miRNA expression in tumors compared to normal tissues. As a consequence, human miRNAs are likely to be highly useful as biomarkers, especially for future cancer diagnostics, and are emerging as targets for disease intervention. Since doxorubicin (DOX) has been used …

Overexpression of the truncated form of high mobility group a proteins (HMGA2) in human myometrial cells induces leiomyoma-like tissue formation

The pathogenesis of uterine leiomyomas, the most common benign tumor in women, is still unknown. This lack of basic knowledge limits the development of novel non-invasive therapies. Our group has previously demonstrated that leiomyoma side population (SP) cells are present in tumor lesions and act like putative tumor-initiating stemcells in human leiomyoma. Moreover, accumulated evidence demonstrates that these benign tumors of mesenchymal origin are characterized by rearrangements of the High Mobility Group A proteins (HMGA). In this work, we tested the hypothesis that leiomyoma development may be due to overexpression of HMGA2 (encoding high mobility group AT-hook2) in myometrial stem cel…

Biphasic dermatofibrosarcoma protuberans with a labyrinthine plexiform high‐grade fibrosarcomatous transformation

Several variants of dermatofibrosarcoma protuberans, a low-grade superficial sarcoma, are well recognized. The most prognostically important is the fibrosarcomatous variant. We report a case of biphasic dermatofibrosarcoma protuberans in which the high-grade component exhibited a previously undescribed plexiform pattern. A clinicopathological study complemented with immunohistochemical, ultrastructural, reverse transcription polymerase chain reaction and fluorescence in situ hybridization analyses of this unique case. Histopathologically, a conventional low-grade dermatofibrosarcoma protuberans was admixed with intratumoral high-grade areas showing a striking labyrinthine plexiform pattern …

Patología de los tumores neuroblásticos: evaluación pronóstica. Experiencia del centro español de referencia de la SEOP para estudios biopatológicos del neuroblastoma (1992-2005)

Resumen Antecedentes Los tumores neuroblasticos son los tumores solidos extracraneales mas frecuentes en la infancia y se caracterizan por una evolucion clinica heterogenea que va desde una progresion rapida a una regresion tumoral espontanea. Existen factores pronosticos conocidos que determinan dicha evolucion como son la edad, estadiaje, histopatologia, estatus de MYCN, ploidia y diversas ganancias y perdidas cromosomicas. El objetivo del trabajo es describir nuestra experiencia como laboratorio de referencia espanol para la determinacion de estos parametros pronosticos. Metodos Material tumoral de pacientes con neuroblastoma, remitido a nuestro laboratorio desde 1992 hasta 2005, ha sido…

Clinical application of mutational analysis in breast cancer patients: The relevance of PIK3CA analysis for precision medicine

Abstract Background The identification of biomarkers to drive treatment is one of the most important objectives of precision medicine. During last years, the role of PIK3CA mutations have been related to clinical benefit deriving from treatment with PI3K, and mTOR inhibitors. In breast cancer (BC), PIK3CA mutations are widely present and the use, in clinical trials, of selective inhibitors improved clinical outcomes. The aim of this study is to assess the value of a monocentric genomic screening program to select patients for trials with experimental targeted agents. Methods We examined PIK3CA mutation in a cohort of 312 metastatic BC patients diagnosed at Hospital Clinico Valencia-INCLIVA …