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PURPOSE: Sixty percent of breast cancer patients develop persistent upper limb pain and dysfunction, but only limited knowledge exists about how these symptoms relate to rehabilitation access. METHODS: A postal survey was sent to patients treated at a London University Teaching Hospital (2018-2020). Data were collected on pain (Pain Detect), shoulder function (Disability of Shoulder Arm and Hand (DASH)), quality-of-life (QoL) (EQ-5D-5L), and clinical characteristics, including treatment and access to rehabilitation. The free-text section invited patients' comments on upper limb symptoms and management strategies, which were analysed thematically. Quantitative data were analysed descriptively, and the medians were examined with Mann-Whitley U-Tests or Kruskal-Wallis Test. RESULTS: Of 511 patients surveyed, 162 (32 %) questionnaires were returned and analysed. Respondents' mean age was 62 years (SD 11.3). The majority had Sentinel Node Biopsy 71 % (116/162) and mastectomy 61 % (99/162). 73 % (119/162) reported pain. Mean (SD) Pain Detect and DASH Score were respectively 11.07 (7) and 21.7 (21.5), with 51 % recording significant shoulder dysfunction, and only 28 % reporting access to rehabilitation. Individuals with neuropathic pain had significantly higher median (range) DASH score 60.8 (35.8, 75.0) p = 0.000. Median DASH score for sedentary individuals was significantly higher 22.9 (7.9, 31.8) p = 0.0009. Free-text analysis revealed persistent, progressive symptoms, mixed attitudes towards exercise and variations in access to rehabilitation and support. CONCLUSION: Two years following surgery many patients reported significant upper limb symptoms which adversely impact on QoL. However, approximately two thirds did not access potentially beneficial rehabilitation treatments. There is a need to improve pathways of care.
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BACKGROUND: Accuracy can be improved by taking multiple synchronous samples from each subject in a study to estimate the endpoint of interest if sample values are not highly correlated. If feasible, it is useful to assess the value of this cluster approach when planning studies. Multiple assessments may be the only method to increase power to an acceptable level if the number of subjects is limited. METHODS: The main aim is to estimate the difference in outcome between groups of subjects by taking one or more synchronous primary outcome samples or measurements. A summary statistic from multiple samples per subject will typically have a lower sampling error. The number of subjects can be balanced against the number of synchronous samples to minimize the sampling error, subject to design constraints. This approach can include estimating the optimum number of samples given the cost per subject and the cost per sample. RESULTS: The accuracy improvement achieved by taking multiple samples depends on the intra-class correlation (ICC). The lower the ICC, the greater the benefit that can accrue. If the ICC is high, then a second sample will provide little additional information about the subject's true value. If the ICC is very low, adding a sample can be equivalent to adding an extra subject. Benefits of multiple samples include the ability to reduce the number of subjects in a study and increase both the power and the available alpha. If, for example, the ICC is 35%, adding a second measurement can be equivalent to adding 48% more subjects to a single measurement study. CONCLUSION: A study's design can sometimes be improved by taking multiple synchronous samples. It is useful to evaluate this strategy as an extension of a single sample design. An Excel workbook is provided to allow researchers to explore the most appropriate number of samples to take in a given setting.
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Proyectos de Investigación , HumanosAsunto(s)
Anexinas/farmacocinética , Apoptosis , Glaucoma/diagnóstico por imagen , Imagen Óptica/métodos , Células Ganglionares de la Retina , Retinoscopía/métodos , Adulto , Anexinas/administración & dosificación , Anexinas/efectos adversos , Femenino , Colorantes Fluorescentes , Humanos , Masculino , Persona de Mediana Edad , Células Ganglionares de la Retina/citologíaAsunto(s)
Ensayos Clínicos como Asunto/métodos , Determinación de Punto Final , Oncología Médica/métodos , Neoplasias/terapia , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Humanos , Neoplasias/epidemiología , Neoplasias/mortalidad , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIM: To correlate residual double strand breaks (DSB) 24h after 4Gy test doses to skin in vivo and to lymphocytes in vitro with adverse effects of earlier breast radiotherapy (RT). PATIENTS AND METHODS: Patients given whole breast RT ⩾5years earlier were identified on the basis of moderate/marked or minimal/no adverse effects despite the absence ('RT-Sensitive', RT-S) or presence ('RT-Resistant', RT-R) of variables predisposing to late adverse effects. Residual DSB were quantified in skin 24h after a 4Gy test dose in 20 RT-S and 15 RT-R patients. Residual DSB were quantified in lymphocytes irradiated with 4Gy in vitro in 30/35 patients. RESULTS: Mean foci per dermal fibroblast were 3.29 (RT-S) vs 2.80 (RT-R) (p=0.137); 3.28 (RT-S) vs 2.60 (RT-R) in endothelium (p=0.158); 2.50 (RT-S) vs 2.41 (RT-R) in suprabasal keratinocytes (p=0.633); 2.70 (RT-S) vs 2.35 (RT-R) in basal epidermis (p=0.419); 12.1 (RT-S) vs 10.3 (RT-R) in lymphocytes (p=0.0052). CONCLUSIONS: Residual DSB in skin following a 4Gy dose were not significantly associated with risk of late adverse effects of breast radiotherapy, although exploratory analyses suggested an association in severely affected individuals. By contrast, a significant association was detected based on the in vitro response of lymphocytes.
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Neoplasias de la Mama/radioterapia , Mama/efectos de la radiación , Roturas del ADN de Doble Cadena , Piel/efectos de la radiación , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Linfocitos/efectos de la radiación , Persona de Mediana Edad , Dosificación Radioterapéutica , Piel/metabolismoRESUMEN
BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib. METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies. RESULTS: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib. CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).
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Antineoplásicos/uso terapéutico , Reparación del ADN , Inhibidores Enzimáticos/uso terapéutico , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Neoplasias de la Próstata/tratamiento farmacológico , Adulto , Anciano , Anemia/inducido químicamente , Proteínas de la Ataxia Telangiectasia Mutada/genética , Reparación del ADN/genética , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/efectos adversos , Fatiga/inducido químicamente , Genes BRCA2 , Genes Supresores de Tumor , Humanos , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia/tratamiento farmacológico , Ftalazinas/efectos adversos , Piperazinas/efectos adversos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: Gemcitabine and docetaxel have been shown to be active in pre-treated relapsed leiomyosarcoma. This study investigated the combination as first line treatment in patients with unresectable locally advanced/metastatic leiomyosarcoma. METHODS: Patients received gemcitabine 900 mg/m(2) days 1 and 8, and docetaxel 100 mg/m(2) day 8, administered 3-weekly for up to 8 cycles, with GCSF support on days 9-15. Patients who had received previous radiotherapy were treated at 75% dose. Patients were evaluated for response by RECIST 1.0 after cycles 2, 4, 6 and 8, and 3-monthly after completing treatment. RESULTS: Forty-four patients were evaluable for response. Eligible patients had histologically proven leiomyosarcoma of the uterus (54.5%) or other sites (45.5%). Thirty-nine patients (84.4%) had metastatic disease, and 5 (15.6%) had locally advanced disease. Six patients (13.6%) had grade 1 disease, and 23 (75%) had grade 2/3 disease. All patients had demonstrated disease progression prior to trial entry. Responses were as follows: partial response 11 (25.0%), stable disease (confirmed) 16 (36.6%), stable disease (unconfirmed) 7 (15.9%), progressive disease 10 (22.7%). Median progression-free survival and overall survival were 7.1 months (95% CI 5.7-8.3) and 17.9 months (95% CI 10.6-25.2), respectively. Progression free rates at 3 and 6 months were 70.5% (95% CI 56.7-84.2%) and 59.1% (95% CI 44.3-73.9%). CONCLUSIONS: This study demonstrates gemcitabine and docetaxel to be active in locally advanced/metastatic leiomyosarcoma in the first line setting. Further investigation comparing with current standard therapies for leiomyosarcoma is warranted.
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PURPOSE: Not all breast cancers respond to lapatinib. A change in Ki67 after short-term exposure may elucidate a biomarker profile for responsive versus nonresponsive tumors. EXPERIMENTAL DESIGN: Women with primary breast cancer were randomized (3:1) to 10 to 14 days of preoperative lapatinib or placebo in a multicenter phase II trial (ISRCTN68509377). Biopsies pre-/posttreatment were analyzed for Ki67, apoptosis, HER2, EGFR, ER, PgR, pAKT, pERK, and stathmin by IHC. Further markers were measured by RT-PCR. Primary endpoint was change in Ki67. HER2(+) was defined as 2+/3+ by IHC and FISH(+). RESULTS: One hundred twenty-one patients (lapatinib, 94; placebo, 27) were randomized; of these, 21% were HER2(+), 78% were HER2(-) nonamplified, 26% were EGFR(+). Paired samples containing tumor were obtained for 98% (118 of 121). Ki67 fell significantly with lapatinib (-31%; P < 0.001), but not with placebo (-3%). Whereas Ki67 reduction with lapatinib was greatest in HER2(+) breast cancer (-46%; P = 0.003), there was a significant Ki67 decrease in HER2(-) breast cancer (-27%; P = 0.017) with 14% of HER2(-) breast cancer demonstrating ≥50% Ki67 reduction with lapatinib. Among HER2(+) patients, the only biomarker predictive of Ki67 response was the EGFR/HER4 ligand epiregulin (EREG) (rho = -0.7; P = 0.002). Among HER2(-) tumors, only HER3 mRNA levels were significantly associated with Ki67 response on multivariate analysis (P = 0.01). In HER2(-) breast cancer, HER2 and HER3 mRNA levels were highly correlated (rho = 0.67, P < 0.001), with all Ki67 responders having elevated HER3 and HER2 expression. CONCLUSIONS: Lapatinib has antiproliferative effects in a subgroup of HER2(-) nonamplified tumors characterized by high HER3 expression. The possible role of high HER2:HER3 heterodimers in predicting response to lapatinib merits investigation in HER2(-) tumors.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Quinazolinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Proliferación Celular/efectos de los fármacos , Quimioterapia Adyuvante , Método Doble Ciego , Femenino , Humanos , Lapatinib , Persona de Mediana Edad , Periodo Preoperatorio , Quinazolinas/farmacología , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Resultado del TratamientoRESUMEN
PURPOSE: Endocrine therapies include aromatase inhibitors and the selective estrogen receptor (ER) downregulator fulvestrant. This study aimed to determine whether the reported efficacy of fulvestrant over anastrozole, and high- over low-dose fulvestrant, reflect distinct transcriptional responses. EXPERIMENTAL DESIGN: Global gene expression profiles from ERα-positive breast carcinomas before and during presurgical treatment with fulvestrant (n = 22) or anastrozole (n = 81), and corresponding in vitro models, were compared. Transcripts responding differently to fulvestrant and estrogen deprivation were identified and integrated using Gene Ontology, pathway and network analyses to evaluate their potential significance. RESULTS: The overall transcriptional response to fulvestrant and estrogen deprivation was correlated (r = 0.61 in presurgical studies, r = 0.87 in vitro), involving downregulation of estrogen-regulated and proliferation-associated genes. The transcriptional response to fulvestrant was of greater magnitude than estrogen deprivation (slope = 0.62 in presurgical studies, slope = 0.63 in vitro). Comparative analyses identified 28 genes and 40 Gene Ontology categories affected differentially by fulvestrant. Seventeen fulvestrant-specific genes, including CAV1/2, SNAI2, and NRP1, associated with ERα, androgen receptor (AR), and TP53, in a network regulating cell cycle, death, survival, and tumor morphology. Eighteen genes responding differently to fulvestrant specifically predicted antiproliferative response to fulvestrant, but not anastrozole. Transcriptional effects of low-dose fulvestrant correlated with high-dose treatment, but were of lower magnitude (ratio = 0.29). CONCLUSIONS: The transcriptional response to fulvestrant has much in common with estrogen deprivation, but is stronger with distinctions potentially attributable to arrest of estrogen-independent ERα activity and involvement of AR signaling. Genes responding differently to fulvestrant may have predictive utility. These data are consistent with the clinical efficacy of fulvestrant versus anastrozole and higher dosing regimens.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Estradiol/análogos & derivados , Estrógenos/deficiencia , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Estradiol/farmacología , Femenino , Fulvestrant , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Posmenopausia , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Gene signatures have failed to predict responses to breast cancer therapy in patients to date. In this study, we used bioinformatic methods to explore the hypothesis that the existence of multiple drug resistance mechanisms in different patients may limit the power of gene signatures to predict responses to therapy. In addition, we explored whether substratification of resistant cases could improve performance. Gene expression profiles from 1,550 breast cancers analyzed with the same microarray platform were retrieved from publicly available sources. Gene expression changes were introduced in cases defined as sensitive or resistant to a hypothetical therapy. In the resistant group, up to five different mechanisms of drug resistance causing distinct or overlapping gene expression changes were generated bioinformatically, and their impact on sensitivity, specificity, and predictive values of the signatures was investigated. We found that increasing the number of resistance mechanisms corresponding to different gene expression changes weakened the performance of the predictive signatures generated, even if the resistance-induced changes in gene expression were sufficiently strong and informative. Performance was also affected by cohort composition and the proportion of sensitive versus resistant cases or resistant cases that were mechanistically distinct. It was possible to improve response prediction by substratifying chemotherapy-resistant cases from actual datasets (non-bioinformatically perturbed datasets) and by using outliers to model multiple resistance mechanisms. Our work supports the hypothesis that the presence of multiple resistance mechanisms in a given therapy in patients limits the ability of gene signatures to make clinically useful predictions.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Modelos Genéticos , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos/genética , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Análisis por Micromatrices/métodos , Modelos EstadísticosRESUMEN
This study aimed to test whether induction of apoptosis following ex vivo X-irradiation of unstimulated blood lymphocytes correlated with clinical radiosensitivity and DNA double-strand break (DSB) repair in breast radiotherapy patients and healthy volunteers. Using small molecule inhibitors, the relationship between DSB repair and radiation-induced apoptosis was examined. Sixteen breast cancer patients with minimal (controls, n = 8) or extremely marked late radiation-induced change (cases, n = 8) and eight healthy volunteers were selected. DSBs were quantified by γH2AX/53BP1 immunofluorescence, and apoptosis was measured using a fluorogenic inhibitor of caspases assay. Mean γH2AX/53BP1 focus levels 24 h after exposure to 4 Gy were higher in cases (12.7 foci per cell) than in controls (10.3 foci per cell, p = 0.002). In contrast, the mean apoptotic fraction 48 h after 8 Gy was comparable, 37.2 % in cases and 34.7 % in controls (p = 0.442). Residual focus and apoptosis levels were not correlated within individuals (Spearman's R = -0.0059, p = 0.785). However, cells treated with DNA-PK inhibitor Nu7441 had higher focus and apoptosis levels 48 h after 1 Gy compared to mock-treated cells, suggesting that apoptosis induction following irradiation is modulated by DSB repair. This effect required functional ATM since cells treated simultaneously with Nu7441 and the ATM inhibitor Ku55933 were resistant to apoptosis despite high levels of residual foci. One clinical case displayed an impaired DNA-PK-dependent end-joining cellular phenotype. In summary, clinical radiosensitivity may be associated with impaired DSB repair in some patients. Although pharmaceutical inhibition of ATM and DNA-PK affected apoptosis induction and DSB repair, no association was observed between apoptosis and residual focus levels in patients and volunteers.
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Apoptosis/efectos de la radiación , Neoplasias de la Mama/radioterapia , Roturas del ADN de Doble Cadena/efectos de la radiación , Reparación del ADN/efectos de la radiación , Linfocitos/efectos de la radiación , Traumatismos por Radiación/genética , Traumatismos por Radiación/patología , Adulto , Anciano , Apoptosis/efectos de los fármacos , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Estudios de Casos y Controles , Cromonas/farmacología , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Proteína Quinasa Activada por ADN/metabolismo , Activación Enzimática/efectos de los fármacos , Activación Enzimática/efectos de la radiación , Femenino , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Linfocitos/citología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Persona de Mediana Edad , Morfolinas/farmacología , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Órganos en Riesgo/efectos de la radiación , Inhibidores de Proteínas Quinasas/farmacología , Pironas/farmacología , Traumatismos por Radiación/metabolismo , Tolerancia a Radiación/efectos de los fármacos , Tolerancia a Radiación/efectos de la radiación , Factores de Tiempo , Proteína 1 de Unión al Supresor Tumoral P53RESUMEN
Micropapillary carcinoma (MPC) is a rare histological special type of breast cancer, characterized by an aggressive clinical behaviour and a pattern of copy number aberrations (CNAs) distinct from that of grade- and oestrogen receptor (ER)-matched invasive carcinomas of no special type (IC-NSTs). The aims of this study were to determine whether MPCs are underpinned by a recurrent fusion gene(s) or mutations in 273 genes recurrently mutated in breast cancer. Sixteen MPCs were subjected to microarray-based comparative genomic hybridization (aCGH) analysis and Sequenom OncoCarta mutation analysis. Eight and five MPCs were subjected to targeted capture and RNA sequencing, respectively. aCGH analysis confirmed our previous observations about the repertoire of CNAs of MPCs. Sequencing analysis revealed a spectrum of mutations similar to those of luminal B IC-NSTs, and recurrent mutations affecting mitogen-activated protein kinase family genes and NBPF10. RNA-sequencing analysis identified 17 high-confidence fusion genes, eight of which were validated and two of which were in-frame. No recurrent fusions were identified in an independent series of MPCs and IC-NSTs. Forced expression of in-frame fusion genes (SLC2A1-FAF1 and BCAS4-AURKA) resulted in increased viability of breast cancer cells. In addition, genomic disruption of CDK12 caused by out-of-frame rearrangements was found in one MPC and in 13% of HER2-positive breast cancers, identified through a re-analysis of publicly available massively parallel sequencing data. In vitro analyses revealed that CDK12 gene disruption results in sensitivity to PARP inhibition, and forced expression of wild-type CDK12 in a CDK12-null cell line model resulted in relative resistance to PARP inhibition. Our findings demonstrate that MPCs are neither defined by highly recurrent mutations in the 273 genes tested, nor underpinned by a recurrent fusion gene. Although seemingly private genetic events, some of the fusion transcripts found in MPCs may play a role in maintenance of a malignant phenotype and potentially offer therapeutic opportunities.
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Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Carcinoma Papilar/genética , Regulación Neoplásica de la Expresión Génica , Fusión Génica , Mutación , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Femenino , Dosificación de Gen , Predisposición Genética a la Enfermedad , Humanos , Invasividad Neoplásica , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Análisis de Secuencia de ARN , Factores de TiempoRESUMEN
Chromosomal instability, which is a characteristic of many human cancers, contributes to intratumour heterogeneity and has been functionally implicated in resistance to taxane therapy in tumour models. However, defining the status of tumour chromosomal instability in a given tumour to test this hypothesis remains challenging. Measurements of numerical and structural chromosomal heterogeneity demonstrate that histological grade correlates with chromosomal instability in oestrogen receptor (ER)-positive breast cancer. Using data on adjuvant taxane therapy in women with breast cancer, we propose that patients with low-grade ER-positive tumours, which are thought to be chromosomally stable, might derive unexpected benefit from taxane therapy. We discuss the implications of the relationships between tumour grade, chromosomal instability and intratumour heterogeneity, the development of high-throughput methods to define tumour chromosomal instability and the potential use of chromosomal instability to tailor therapy.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Inestabilidad Cromosómica/efectos de los fármacos , Taxoides/uso terapéutico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Clasificación del TumorRESUMEN
PURPOSE: Estrogen withdrawal by treatment with aromatase inhibitors is the most effective form of endocrine therapy for postmenopausal estrogen receptor-positive (ER+) breast cancer. However, response to therapy varies markedly and understanding of the precise molecular effects of aromatase inhibitors and causes of resistance is limited. We aimed to identify in clinical breast cancer those genes and pathways most associated with resistance to aromatase inhibitors by examining the global transcriptional effects of AI treatment. EXPERIMENTAL DESIGN: Baseline and 2-week posttreatment biopsies were obtained from 112 postmenopausal women with ER+ breast cancer receiving neoadjuvant anastrozole. Gene expression data were obtained from 81 baseline and 2-week paired samples. Pathway analysis identified (i) the most prevalent changes in expression and (ii) the pretreatment genes/pathways most related to poor antiproliferative response. RESULTS: A total of 1,327 genes were differentially expressed after 2-week treatment (false discovery rate < 0.01). Proliferation-associated genes and classical estrogen-dependent genes were strongly downregulated whereas collagens and chemokines were upregulated. Pretreatment expression of an inflammatory signature correlated with antiproliferative response to anastrozole and this observation was validated in an independent study. Higher expression of immune-related genes such as SLAMF8 and TNF as well as lymphocytic infiltration were associated with poorer response (P < 0.001) and validated in an independent cohort. CONCLUSIONS: The molecular response to aromatase inhibitor treatment varies greatly between patients consistent with the variable clinical benefit from aromatase inhibitor treatment. Higher baseline expression of an inflammatory signature is associated with poor antiproliferative response and should be assessed further as a novel biomarker and potential target for aromatase inhibitor-treated patients.
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Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Anciano , Anastrozol , Biopsia , Mama/efectos de los fármacos , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/patología , Análisis por Conglomerados , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Inmunidad/genética , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Nitrilos/uso terapéutico , Posmenopausia , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Triazoles/uso terapéuticoAsunto(s)
Antineoplásicos Hormonales/farmacología , Inhibidores de la Aromatasa/farmacología , Índice de Masa Corporal , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Estrógenos/sangre , Neoplasias Hormono-Dependientes/sangre , Nitrilos/farmacología , Triazoles/farmacología , Femenino , HumanosRESUMEN
Results from the NSABP B-28 trial suggest AKT activation may predict reduced benefit from taxanes following standard anthracycline therapy. Pre-clinical data support a link between PI3 K/AKT signalling and taxane resistance. Using the UK taxotere as adjuvant chemotherapy trial (TACT), we tested the hypothesis that activation of AKT or downstream markers, p70S6K or p90RSK, identifies patients with reduced benefit from taxane chemotherapy. TACT is a multi-centre open-label phase III trial comparing four cycles of standard FEC (fluorouracil, epirubicin, cyclophosphamide) followed by four cycles of docetaxel versus eight cycles of anthracycline-based chemotherapy. Samples from 3,596 patients were available for the current study. We performed immunohistochemical analysis of activation of AKT, p70S6 K and p90RSK. Using a training set with multiple cut-offs for predictive values (10 % increments in expression), we found no evidence for a treatment by marker interaction for pAKT473, pS6 or p90RSK. pAKT473, pS6 and p90RSK expression levels were weakly correlated. A robust, preplanned statistical analysis in the TACT trial found no evidence that pAKT473, pS6 or p90RSK identifies patients deriving reduced benefit from adjuvant docetaxel. This result is consistent with the recent NASBP B28 study where the pAKT473 effect is not statistically significant for the treatment interaction test. Therefore, neither TACT nor NASBP-B28 provides statistically robust evidence of a treatment by marker interaction between pAKT473 and taxane treatment. Alternative methods for selecting patients benefitting from taxanes should be explored.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Taxoides/uso terapéutico , Adulto , Antraciclinas/uso terapéutico , Biomarcadores/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Docetaxel , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Persona de Mediana Edad , Fosforilación , Valor Predictivo de las Pruebas , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Resultado del TratamientoRESUMEN
Plasma estradiol (E2) and progesterone vary markedly through the menstrual cycle. Data on whether these differences in hormone levels affect gene expression in oestrogen receptor-positive (ER+) tumours are inconsistent. We wished to determine whether there are substantial changes in the expression of oestrogen-regulated genes (ERGs) in ER+ breast cancer through the menstrual cycle. One hundred and seventy five paraffin-embedded ER+ breast carcinomas from premenopausal patients were analysed. Timing of the ovarian cycle was confirmed using serum progesterone levels. Patients were ascribed to one of three pre-defined menstrual cycle windows: 1 (days 27-35 + 1-6), 2 (days 7-16) and 3 (days 17-26). The RNA expression of ESR1, four ERGs (PGR, GREB1, TFF1 and PDZK1), and three proliferation genes (MKI67, TOP2A and CDC20) were compared between the windows. Gene expression of the four ERGs was 53-129 % higher in window 2 than window 1 (p = 0.0013, 0.0006, 0.022 and 0.066 for PGR, GREB1, TFF1 and PDZK1, respectively) and lower (9-41 %) in window 3 compared to window 2 (p = 0.079, 0.31, 0.031 and 0.065 for PGR, GREB1, TFF1 and PDZK1, respectively). Their average expression (AvERG) was 64 % higher in window 2 than window 1 (p < 0.0001) and 21 % lower in window 3 than window 2 (p = 0.0043). There were no significant differences between the windows for ESR1 and proliferation genes. In agreement with the gene expression data, progesterone receptor protein levels measured by immunohistochemistry (IHC) were 164 and 227 % higher in windows 2 and 3, respectively, compared to window 1 (30.7 and 37.9 % cells positive vs. 11.6 %; p = 0.0003 and 0.0004, respectively), while no difference in ER IHC score was observed. In conclusion, we observed significant differences in the expression of ERGs in ER+ breast tumours across the menstrual cycle. This variability may affect the interpretation of gene expression profiles incorporating ERGs and may be exploitable as an endogenous test of endocrine responsiveness.
Asunto(s)
Neoplasias de la Mama/metabolismo , Estrógenos/metabolismo , Ciclo Menstrual/metabolismo , Receptores de Estrógenos/metabolismo , Adulto , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Estrógenos/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ciclo Menstrual/genética , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Receptores de Estrógenos/genéticaRESUMEN
AIMS: The majority of adenoid cystic carcinomas (AdCCs), regardless of anatomical site, harbour the MYB-NFIB fusion gene. The aim of this study was to characterize the repertoire of somatic genetic events affecting known cancer genes in AdCCs. METHODS AND RESULTS: DNA was extracted from 13 microdissected breast AdCCs, and subjected to a mutation survey using the Sequenom OncoCarta Panel v1.0. Genes found to be mutated in any of the breast AdCCs and genes related to the same canonical molecular pathways, as well as KIT, a proto-oncogene whose protein product is expressed in AdCCs, were sequenced in an additional 68 AdCCs from various anatomical sites by Sanger sequencing. Using the Sequenom MassARRAY platform and Sanger sequencing, mutations in BRAF and HRAS were identified in three and one cases, respectively (breast, and head and neck). KIT, which has previously been reported to be mutated in AdCCs, was also investigated, but no mutations were identified. CONCLUSIONS: Our results demonstrate that mutations in genes pertaining to the canonical RAS pathway are found in a minority of AdCCs, and that activating KIT mutations are either absent or remarkably rare in these cancers, and unlikely to constitute a driver and therapeutic target for patients with AdCC.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Adenoide Quístico/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias Pulmonares/genética , Mutación/genética , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Adenoide Quístico/metabolismo , Carcinoma Adenoide Quístico/patología , Análisis Mutacional de ADN/métodos , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismoRESUMEN
Breast density is a significant predictor in the risk of developing breast cancer. Several methods are available for assessing breast density, but most are subject to intra-observer variability and are unable to assess the breast as a three-dimensional structure. Using Quantra(™) to quantify breast density, we have correlated this with risk factors to determine what impact these variables have on breast density. Women attending for full field digital mammography at the South West London Breast Screening Unit between December 2008 and March 2009 were invited to participate in the study by questionnaire. Consenting women returned the questionnaire allowing further data collection including demographics, menopausal status and hormone replacement therapy (HRT) use. Data were correlated against breast density measurements to determine the degree of association. Mammograms were assessed on a Hologic(™) workstation and breast density calculated using Quantra(™). Quantra(™) is an automated algorithm for volumetric assessment of breast tissue composition from digital mammograms. Six-hundred and eighty-three women were invited to participate. Those with implants or mastectomy were excluded. Three-hundred and twenty questionnaires were fully completed and able to be assessed. The mean age of participants was 59 years (range 49-81). Mean density was 19.7% (range 8.5-48.5%). There was a decrease in density with age (Pearson product-moment correlation coefficient -0.17). Correlation between density and HRT use showed a significant positive result (correlation coefficient 0.07). Quantra(™) has shown to be an accurate, reproducible tool for quantifying breast density, demonstrated by its correlation with lifestyle and demographic data. Given its ease of acquisition this may be the future of breast density quantification in the digital age.