Miocardiopatías restrictivas: Valoración por resonancia magnética cardiaca y tomografía multicorte / Restrictive Cardiomyopathies: Evaluation Using Cardiac MRI and Multidetector CT

Las miocardiopatías son condiciones que afectan al miocardio y generan alteración en la función cardiaca. Dentro de las miocardiopatías, el subgrupo de las restrictivas tiene como principal hallazgo la disminución en el llenado ventricular. A continuación se expone una revisión acerca de las miocardiopatías restrictivas, se analizan sus principales causas, y los hallazgos por resonancia magnética cardiaca y por tomografía computarizada. También se incluyen signos por imagen que ayudan a diferenciar las miocardiopatías restrictivas de la pericarditis constrictiva.

Cardiomyopathies are conditions that affect the myocardium and cause alteration in the cardiac function. Within the cardiomyopathies, the restrictive subgroup has as a main finding the decrease in the ventricular filling. In this manuscript we will review the restrictive cardiomyopathies and discuss their main causes, as well as their imaging findings on cardiac magnetic resonance and computed tomography. We will also include imaging signs that helps to differentiate restrictive cardiomyopathies from constrictive pericarditis.

Aneurismas, pseudoaneurismas y divertículos cardiacos / Cardiac Aneurysms, Pseudoaneurysms and Diverticula

Los aneurismas, pseudoaneurismas y divertículos cardiacos son dilataciones o evaginaciones de estructuras de la pared cardiaca: ventrículos, aurículas, septo interauricular, arterias coronarias, entre otros, de distintas causas y de morfología variable. Los avances en las diferentes modalidades diagnósticas han permitido una mayor precisión en la evaluación morfológica y funcional del corazón. Los aneurismas, pseudoaneurismas y divertículos cardiacos son manifestaciones frecuentes de diferentes condiciones, que pueden ser evaluados mediante técnicas como la resonancia magnética (RM) y la tomografía computarizada (TC) que se usan, cada vez con mayor frecuencia, para evaluar la configuración cardiaca. La resonancia magnética cardiovascular (RMC) es la técnica de elección para una mejor valoración anatómica cardiaca. El propósito de este artículo es ilustrar mediante casos clínicos el valor de estas modalidades diagnósticas no invasivas en la evaluación de los aneurismas, pseudoaneurismas y divertículos cardiacos.

Cardiac aneurysms, pseudoaneurysms, and diverticula are dilations or outpouchings of different cardiac structures: ventricles, atria, atrial septum, coronary arteries, among others, due to different causes and of variable morphology. Advances in different diagnostic modalities have allowed greater accuracy in the morphological and functional assessment of the heart. Cardiac aneurysms, pseudoaneurysms, and diverticula are common manifestations of different conditions that can be assessed by magnetic resonance imaging and computed tomography, which are increasingly used to evaluate cardiac configuration. Cardiovascular magnetic resonance (CMR) is the technique of choice for a better cardiac anatomic evaluation. This paper aims to illustrate, through clinical cases based on our experience in CediIMed, the value of these non-invasive diagnostic modalities in the evaluation of cardiac aneurysms, pseudoaneurysms, and diverticula.

Obstrucción del tracto de salida del ventrículo izquierdo / Left Ventricular Outflow Tract Obstruction

El tracto de salida del ventrículo izquierdo (TSVI) es la estructura anatómica a través de la cual sale el flujo sistólico del ventrículo izquierdo (VI) hacia la aorta. El TSVI está conformado por tres componentes: subvalvular, el cual es delimitado por el septo interventricular en sus porciones membranosas y muscular basal y la valva anterior de la válvula mitral; el componente valvular, corresponde a la válvula aórtica, y el supravalvular. En esta revisión académica se evaluarán las patologías obstructivas del tracto de salida del ventrículo izquierdo, incluyendo entidades localizadas en el sector valvular aórtico (valvulares), en la aorta ascendente (supravalvulares) y en el tracto de salida del ventrículo izquierdo proximal al plano valvular (subvalvulares).

The left ventricular outflow tract (LVOT) is the anatomic structure through which the left ventricular stroke volume passes towards the aorta. The LVOT consists of three components: subvalvular component, which is delimited by the membranous and basal muscular portions of the interventricular septum; valvular component (the aortic valve); and supravalvular component. This academic review evaluates different obstructive pathologies of the LVOT, including entities located at the aortic valve level (valvular), in the ascending aorta (supravalvular), and in the proximal portion of the LVOT (subvalvular).

Anomalías en los ductos Müllerianos: Evaluación diagnóstica por resonancia magnética / Müllerian Duct Anomalies: Diagnostic Evaluation with Magnetic Resonance Imaging

Los ductos Müllerianos son dos estructuras embrionarias que en su desarrollo pasan por tres procesos fundamentales: desarrollo, fusión ductal y reabsorción septal. Las anomalías de los ductos Müllerianos (ADM) incluyen un gran espectro de malformaciones que comprometen el útero, trompas de Falopio, cuello uterino y los dos tercios superiores de la vagina. La gravedad de las ADM y sus características morfológicas están dadas por el momento embriológico específico en el que aparece el trastorno. Las mujeres con estas anomalías consultan principalmente por amenorrea primaria, infertilidad y complicaciones obstétricas. La resonancia magnética (RM) se ha convertido en una herramienta muy útil para su adecuada evaluación por tratarse de una técnica no invasiva, que no utiliza radiación ionizante y permite una evaluación multiplanar con adecuada valoración del contorno uterino externo, lo que la constituye en una técnica necesaria para el diagnóstico preciso, así como para la planeación quirúrgica de las pacientes

The Müllerian ducts are two embryological structures that undergo three main processes during their formation: development, ductal fusion, and septal resorption. Müllerian duct anomalies (MDAs) include a large spectrum of malformations that involve the uterus, fallopian tubes, cervix, and the upper two-thirds of the vagina. The severity and morphological characteristics are given by the specific embryological moment in which the disorder occurs. Women with these anomalies present symptoms such as primary amenorrhea, infertility, and obstetric complications. Magnetic resonance imaging (MRI) has become a very useful tool for evaluation, given that it is a noninvasive technique that does not use ionizing radiation, while allowing multiplanar evaluation for a proper assessment of the external uterine contour, which makes this method a useful technique for accurate diagnosis and surgical planning

Mesotelioma pericárdico maligno: Presentación de caso / Malignant Pericardial Mesothelioma: A Case Report

Las neoplasias primarias del pericardio son raras y se clasifican como benignas y malignas. El mesotelioma pericárdico es la más frecuente en el grupo de las malignas. Las manifestaciones clínicas son variables y se presentan como consecuencia de la compresión de estructuras mediastinales, de las cuales la más grave el taponamiento cardiaco. La ecocardiografía es una técnica poco sensible para el diagnóstico de esta lesión, la cual en tomografía computarizada y en resonancia magnética se presenta como una masa de realce heterogéneo que compromete ambas capas del pericardio. El pronóstico de esta neoplasia es malo, con una sobrevida en la mayoría de los pacientes menor de 15 meses y metástasis frecuentes en ganglios linfáticos mediastinales y pulmones.

Primary pericardial neoplasms are rare. These can be classified as benign and malignant. The pericardial mesothelioma is most frequent one in the malignant group. The clinical manifestations are variable and are presented as a consequence of the compression of the mediastinal structures, of which the most serious one is cardiac tamponade. Echocardiography is not a sensitive technique for the diagnosis of pericardial neoplasms. On computed tomography and magnetic resonance, pericardial mesothelioma appears as a mass of heterogeneous enhancement that involves both layers of the pericardium. The prognosis of this tumor is poor, with a survival rate of less than 15 months in most patients and frequently metastasizes to mediastinal lymph nodes and lungs.

Volumetría del remanente gástrico poscirugía de manga gástrica / Post-Sleeve Gastric Pouch Volumetry

La cirugía bariátrica, en sus diferentes modalidades, es una técnica empleada cada vez más en el manejo de los pacientes con obesidad. La cirugía de manga gástrica es una técnica restrictiva utilizada ampliamente y que presenta buenos resultados; sin embargo, al igual que cualquier otro procedimiento, no está exento de complicaciones. En este artículo se indica una manera precisa de evaluar el volumen del remanente gástrico, ya que el incremento de este posterior a la cirugía de manga gástrica es una de las principales causas por las cuales no hay pérdida de peso luego este procedimiento.

Bariatric surgery, through its various forms, is a technique which is increasingly used in the management of patients with obesity. The gastric sleeve is a widely used restrictive technique and it has good results, however, like any other procedure is not exempt of complications. This paper discusses an accurate measurement of gastric pouch, since its increased size is a major cause of absence of weight loss after this procedure.

Divertículos y pseudodivertículos del tracto digestivo superior: Hallazgos por tomografía computarizada multidetector (TCMD): Serie de casos / Upper Gastrointestinal Tract Diverticulum and Pseudodiverticulosis: Multidetector Computed Tomography (MDCT) Findings: Case series

En diferentes estudios diagnósticos realizados en la práctica clínica encontramos de manera incidental divertículos o pseudodivertículos del tracto gastrointestinal. Este artículo presenta una revisión detallada de la patología diverticular del tracto digestivo superior y se analizan sus aspectos clínicos, epidemiológicos y los diferentes hallazgos por imagen, haciendo hincapié en su apariencia por tomografía computarizada multidetector (TCMD).

Diverticulum and pseudodiverticula of the gastrointestinal tract are incidentally found in different diagnostic studies performed in clinical practice. This article presents a detailed review of the diverticular disease of the upper gastrointestinal tract and its clinical, epidemiological aspects are discussed, as well as different imaging findings are discussed. A special emphasis is made on its appearance through Multidetector Computed Tomography (MDCT).

Elevated nuclear expression of the SMRT corepressor in breast cancer is associated with earlier tumor recurrence.

Silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), also known as nuclear corepressor 2 (NCOR2) is a transcriptional corepressor for multiple members of the nuclear receptor superfamily of transcription factors, including estrogen receptor-α (ERα). In the classical model of corepressor action, SMRT binds to antiestrogen-bound ERα at target promoters and represses ERα transcriptional activity and gene expression. Herein SMRT mRNA and protein expression was examined in a panel of 30 breast cancer cell lines. Expression of both parameters was found to vary considerably amongst lines and the correlation between protein and mRNA expression was very poor (R (2) = 0.0775). Therefore, SMRT protein levels were examined by immunohistochemical staining of a tissue microarray of 866 patients with stage I-II breast cancer. Nuclear and cytoplasmic SMRT were scored separately according to the Allred score. The majority of tumors (67 %) were negative for cytoplasmic SMRT, which when detected was found at very low levels. In contrast, nuclear SMRT was broadly detected. There was no significant difference in time to recurrence (TTR) according to SMRT expression levels in the ERα-positive tamoxifen-treated patients (P = 0.297) but the difference was significant in the untreated patients (P = 0.01). In multivariate analysis, ERα-positive tamoxifen-untreated patients with high nuclear SMRT expression (SMRT 5-8, i.e., 2nd to 4th quartile) had a shorter TTR (HR = 1.94, 95 % CI, 1.24-3.04; P = 0.004) while there was no association with SMRT expression for ERα-positive tamoxifen-treated patients. There was no association between SMRT expression and overall survival for patients, regardless of whether they received tamoxifen. Thus while SMRT protein expression was not predictive of outcome after antiestrogen therapy, it may have value in predicting tumor recurrence in patients not receiving adjuvant tamoxifen therapy.

Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies.

We studied resistance to endocrine and HER2-targeted therapies using a xenograft model of estrogen receptor positive (ER)/HER2-overexpressing breast cancer. Here, we report a novel phenotype of drug resistance in this model. MCF7/HER2-18 xenografts were treated with endocrine therapy alone or in combination with lapatinib and trastuzumab (LT) to inhibit HER2. Archival tumor tissues were stained with hematoxylin and eosin and with mucicarmine. RNA extracted from tumors at early time points and late after acquired resistance were analyzed for mucin4 (MUC4) expression by microarray and quantitative reverse transcriptase-PCR. Protein expression of the MUC4, ER, and HER2 signaling pathways was measured by immunohistochemistry and western blotting. The combination of the potent anti-HER2 regimen LT with either tamoxifen (Tam + LT) or estrogen deprivation (ED + LT) can cause complete eradication of ER-positive/HER2-overexpressing tumors in mice. Tumors developing resistance to this combination, as well as those acquiring resistance to endocrine therapy alone, exhibited a distinct histological and molecular phenotype-a striking increase in mucin-filled vacuoles and upregulation of several mucins including MUC4. At the onset of resistance, MUC4 mRNA and protein were increased. These tumors also showed upregulation and reactivation of HER2 signaling, while losing ER protein and the estrogen-regulated gene progesterone receptor. Mucins are upregulated in a preclinical model of ER-positive/HER2-overexpressing breast cancer as resistance develops to the combination of endocrine and anti-HER2 therapy. These mucin-rich tumors reactivate the HER2 pathway and shift their molecular phenotype to become more ER-negative/HER2-positive.

Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers.

PURPOSE: Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit. METHODS: We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations. RESULTS: Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007). CONCLUSION: Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.

Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features.

Some breast cancers have been shown to contain a small fraction of cells characterized by CD44(+)/CD24(-/low) cell-surface antigen profile that have high tumor-initiating potential. In addition, breast cancer cells propagated in vitro as mammospheres (MSs) have also been shown to be enriched for cells capable of self-renewal. In this study, we have defined a gene expression signature common to both CD44(+)/CD24(-/low) and MS-forming cells. To examine its clinical significance, we determined whether tumor cells surviving after conventional treatments were enriched for cells bearing this CD44(+)/CD24(-/low)-MS signature. The CD44(+)/CD24(-/low)-MS signature was found mainly in human breast tumors of the recently identified "claudin-low" molecular subtype, which is characterized by expression of many epithelial-mesenchymal-transition (EMT)-associated genes. Both CD44(+)/CD24(-/low)-MS and claudin-low signatures were more pronounced in tumor tissue remaining after either endocrine therapy (letrozole) or chemotherapy (docetaxel), consistent with the selective survival of tumor-initiating cells posttreatment. We confirmed an increased expression of mesenchymal markers, including vimentin (VIM) in cytokeratin-positive epithelial cells metalloproteinase 2 (MMP2), in two separate sets of postletrozole vs. pretreatment specimens. Taken together, these data provide supporting evidence that the residual breast tumor cell populations surviving after conventional treatment may be enriched for subpopulations of cells with both tumor-initiating and mesenchymal features. Targeting proteins involved in EMT may provide a therapeutic strategy for eliminating surviving cells to prevent recurrence and improve long-term survival in breast cancer patients.

Gene expression patterns in formalin-fixed, paraffin-embedded core biopsies predict docetaxel chemosensitivity in breast cancer patients.

Previously, we had identified gene expression patterns that predicted response to neoadjuvant docetaxel. Other studies have validated that a high Recurrence Score (RS) by the 21-gene RT-PCR assay is predictive of worse prognosis but better response to chemotherapy. We investigated whether tumor expression of these 21 genes and other candidate genes can predict response to docetaxel. Core biopsies from 97 patients were obtained before treatment with neoadjuvant docetaxel (4 cycles, 100 mg/m2 q3 weeks). Three 10-microm FFPE sections were submitted for quantitative RT-PCR assays of 192 genes that were selected from our previous work and the literature. Of the 97 patients, 81 (84%) had sufficient invasive cancer, 80 (82%) had sufficient RNA for QRTPCR assay, and 72 (74%) had clinical response data. Mean age was 48.5 years, and the median tumor size was 6 cm. Clinical complete responses (CR) were observed in 12 (17%), partial responses in 41 (57%), stable disease in 17 (24%), and progressive disease in 2 patients (3%). A significant relationship (P<0.05) between gene expression and CR was observed for 14 genes, including CYBA. CR was associated with lower expression of the ER gene group and higher expression of the proliferation gene group from the 21 gene assay. Of note, CR was more likely with a high RS (P=0.008). We have established molecular profiles of sensitivity to docetaxel. RT-PCR technology provides a potential platform for a predictive test of docetaxel chemosensitivity using small amounts of routinely processed material.

Clinical response to neoadjuvant docetaxel predicts improved outcome in patients with large locally advanced breast cancers.

PURPOSE: In the adjuvant setting, taxanes modestly improve clinical outcome and survival. The goal of the present study was to define the efficacy of neoadjuvant docetaxel in treatment-naïve large, locally advanced breast cancers and to better understand docetaxel's mechanism of action by evaluating biomarker modulation in response to treatment. PATIENTS AND METHODS: Fifty-one patients were enrolled. Patients received four cycles of docetaxel (100 mg/m2 q3weeks) followed by surgery and four cycles of doxorubicin and cyclophosphamide (60/600 mg/m2 q3weeks). Radiation and hormonal therapy were given if clinically indicated. Clinical responses were assessed at completion of neoadjuvant docetaxel. Pathological responses were considered complete (pCR) if no tumor cells were identified in the surgical specimen or near complete (npCR) if only occasional scattered tumor cells were seen. Proliferation (Ki-67) and apoptosis (cleaved caspase-3) were measured by IHC in tissue obtained at baseline and at surgery. RESULTS: The median tumor size was 9 cm (range 4-30 cm). Objective response rate was 75% with clinical complete response in 27%, partial response in 48%, and stable disease in 25% of the patients. pCR/npCR was reported in 20% of patients. With a median follow up of 28 months, 98 and 78% of the patients were alive at 12 and 24 months, respectively. Overall survival at 24 months was significantly better in patients who achieved a clinical response, 85 versus 51%, p = 0.008, but pCR/npCR was not a significant predictor of outcome. Apoptosis was induced in clinical responders (p = 0.002), while the proliferation index did not change significantly. In patients who had no clinical response to docetaxel, neither apoptosis nor proliferation changed significantly. CONCLUSION: Neoadjuvant single agent docetaxel is effective in treating patients with large locally advanced breast cancer and clinical response is associated with improved survival. Docetaxel acts therapeutically by inducing apoptosis and this can be used as a marker of response.

Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase.

PURPOSE: To evaluate growth factor receptor cross talk with the estrogen receptor (ER) in paired clinical breast cancer specimens and in a xenograft model before tamoxifen and at tumor progression as a possible mechanism for tamoxifen resistance. METHODS: Specimen pairs from 39 patients were tissue arrayed and stained for ER, progesterone receptor (PgR), Bcl-2, c-ErbB2 (HER-2), and phosphorylated (p) p38 mitogen-activated protein kinase (MAPK), p-ERK1/2 MAPK, and p-Akt. Xenograft MCF-7 tumors before and after tamoxifen resistance were assessed for levels of p-p38. RESULTS: Pretreatment, there were strong correlations between ER, PgR, and Bcl-2, and an inverse correlation between ER and HER-2. These correlations were lost in the tamoxifen- resistant tumors and replaced by strong correlations between ER and p-p38 and p-ERK. ER expression was lost in 17% of resistant tumors. Three (11%) of the 26 tumors originally negative for HER-2 became amplified and/or overexpressed at resistance. All ER-positive tumors that overexpressed HER-2 originally or at resistance expressed high levels of p-p38. In the pretreatment and tamoxifen-resistant specimens, there were strong correlations between p-p38 and p-ERK. In the tamoxifen-resistant xenograft tumors, like the clinical samples, there was a striking increase in p-p38. CONCLUSION: The molecular pathways driving tumor growth can change as the tumor progresses. Crosstalk between ER, HER-2, p38, and ERK may contribute to tamoxifen resistance and may provide molecular targets to overcome this resistance.

Neoadjuvant trastuzumab induces apoptosis in primary breast cancers.

PURPOSE: Greater understanding of the cellular response in trastuzumab-treated patients will provide insight into the clinical management of patients. PATIENTS AND METHODS: We performed a neoadjuvant trial in 35 patients with locally advanced HER-2/neu overexpressing breast cancers who received weekly trastuzumab given as a single agent for the first 3 weeks, followed by a combination of trastuzumab and docetaxel for 12 weeks before surgery. Sequential core biopsies were taken at baseline and within weeks 1 and 3 after the first dose of trastuzumab. Clinical response to trastuzumab was assessed by tumor measurements on day 22 before chemotherapy. Core biopsies were assessed by immunohistochemistry for cell cycle and proliferation (Ki67, p27, phosphorylated [p] -MAPK), apoptosis and survival (apoptotic index, p-Akt), epidermal growth factor receptor, and total and p-HER-2. RESULTS: There was early tumor regression with a median decrease of -20.0% (range. 0% to 60.4%) after only 3 weeks of trastuzumab, and eight patients (23%) had a partial response. Consistent with the clinical regressions, apoptosis was significantly induced (median increase from 3.5% to 4.7%; P = .006) within week 1, a 35% increase above baseline. No significant change in epidermal growth factor receptor score was observed in week 1, without changes in total or p-HER-2 expression. Tumors with high baseline Ki67 were less likely to respond (P = .02). CONCLUSION: In primary breast cancers, trastuzumab substantially induces apoptosis, providing a molecular explanation for both its therapeutic efficacy and its successful combination with cytotoxic chemotherapy.

Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients.

PURPOSE: Chemotherapy for operable breast cancer decreases the risk of death. Docetaxel is one of the most active agents in breast cancer, but resistance or incomplete response is frequent. PATIENTS AND METHODS: Core biopsies from 24 patients were obtained before treatment with neoadjuvant docetaxel (four cycles, 100 mg/m(2) every 3 weeks), and response was assessed after chemotherapy. After 3 months of neoadjuvant chemotherapy, surgical specimens (n = 13) were obtained, and laser capture microdissection (LCM; n = 8) was performed to enrich for tumor cells. From each core, surgical, and LCM specimen, sufficient total RNA (3 to 6 microg) was extracted for cDNA array analysis using the Affymetrix HgU95-Av2 GeneChip (Affymetrix, Santa Clara, CA). RESULTS: From the initial core biopsies, differential patterns of expression of 92 genes correlated with docetaxel response (P = .001). However, the molecular patterns of the residual cancers after 3 months of docetaxel treatment were strikingly similar, independent of initial sensitivity or resistance. This relative genetic homogeneity after treatment was observed in both LCM and non-LCM surgical specimens. The residual tumor after treatment in tumors that were initially sensitive indicates selection of a residual and resistant subpopulation of cells. The gene expression pattern was populated by genes involved in cell cycle arrest at G(2)M (eg, mitotic cyclins and cdc2) and survival pathways involving the mammalian target of rapamycin. CONCLUSION: A specific and consistent gene expression pattern was found in residual tumors after docetaxel treatment. These profiles provide therapeutic targets that could lead to improved treatment.

Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer.

BACKGROUND: Systemic chemotherapy for operable breast cancer substantially decreases the risk of death. Patients often have de novo resistance or incomplete response to docetaxel, one of the most active agents in this disease. We postulated that gene expression profiles of the primary breast cancer can predict the response to docetaxel. METHODS: We took core biopsy samples from primary breast tumours in 24 patients before treatment and then assessed tumour response to neoadjuvant docetaxel (four cycles, 100 mg/m2 daily for 3 weeks) by cDNA analysis of RNA extracted from biopsy samples using HgU95-Av2 GeneChip. FINDINGS: From the core biopsy samples, we extracted sufficient total RNA (3-6 microg) for cDNA array analysis using HgU95-Av2 GeneChip. Differential patterns of expression of 92 genes correlated with docetaxel response (p=0.001). Sensitive tumours had higher expression of genes involved in cell cycle, cytoskeleton, adhesion, protein transport, protein modification, transcription, and stress or apoptosis; whereas resistant tumours showed increased expression of some transcriptional and signal transduction genes. In leave-one-out cross-validation analysis, ten of 11 sensitive tumours (90% specificity) and 11 of 13 resistant tumours (85% sensitivity) were correctly classified, with an accuracy of 88%. This 92-gene predictor had positive and negative predictive values of 92% and 83%, respectively. Correlation between RNA expression measured by the arrays and semiquantitative RT-PCR was also ascertained, and our results were validated in an independent set of six patients. INTERPRETATION: If validated, these molecular profiles could allow development of a clinical test for docetaxel sensitivity, thus reducing unnecessary treatment for women with breast cancer.

Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results.

Trastuzumab/chemotherapy combinations have already shown superior results in metastatic breast cancer patients. The purpose of this study is to determine the clinical efficacy of neoadjuvant trastuzumab and docetaxel in women with locally advanced breast cancer, with or without metastatic disease. Treatment-naive women with HER2-overexpressing locally advanced breast cancer, with or without metastatic disease, were included. Patients received trastuzumab 4 mg/kg loading dose intravenously then 2 mg/kg weekly. On day 22, docetaxel 100 mg/m2 every 3 weeks for 4 cycles was added to weekly trastuzumab. Patients then underwent surgery and subsequent 4 cycles of AC (doxorubicin/cyclophosphamide; 60/600 mg/m2) without trastuzumab. Weekly trastuzumab was resumed 1 month after completion of AC and continued for a year. Preliminary results from the first 22 patients with median follow-up of 15.5 months (range, 2-38 months) are reported. Of these, 9 patients (40.9%) had inflammatory breast cancer, and 6 patients (27.3%) had stage IV breast cancer. Seventeen of 22 patients (77.3%) had objective clinical response, with a clinical complete response in 9 patients (40.9%). Two patients (9.1%) had decline in cardiac function and 7 patients (31.8%) experienced neutropenia, with 2 deaths (9.1%) from neutropenic sepsis. Eight patients (36.4%) have relapsed, 3 with local skin recurrence (13.6%) and 5 with distant recurrence, of whom 1 had liver metastasis (4.5%) and 4 had brain metastasis (18.2%). Combined neoadjuvant trastuzumab and docetaxel induced high clinical response rates for HER2-overexpressing breast cancer, in particular for inflammatory breast cancer. A high rate of brain metastasis was noted, particularly in patients with baseline metastatic disease.