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1.
Breast Cancer Res Treat ; 153(1): 145-52, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26210520

RESUMO

The Neoadjuvant response index (NRI) has been proposed as a simple measure of downstaging by neoadjuvant treatment in breast cancer. It was previously found to predict recurrence-free survival (RFS) in triple-negative (TN) breast cancer. It was at least as accurate as the standard binary system, the absence or presence of a pathological complete remission (pCR), which is the commonly employed outcome measure. The NRI was evaluated in an independent consecutive series of patients to validate the previous findings. Univariable and multivariable analyses were done to assess the predictive value of clinical parameters and of the NRI for RFS. We combined the original and validation series of patients to build a multivariable predictive model for RFS after neoadjuvant chemotherapy in TN breast cancer. The validation set (N = 108) confirmed that patients with a higher-than-median NRI (>0.7) had excellent RFS (P = 0.002), similar to that of patients who had achieved a pCR. Multivariable analysis in 191 patients showed that the NRI was a strong independent predictor of RFS (P = 0.0002), with N-stage (P = 0.001) and T-stage (P = 0.014) ranking second and third, respectively. Importantly, among patients who did not achieve a pCR (NRI values below 1), higher NRI values were still associated with better RFS. The NRI is a simple method and a practical tool to predict RFS in TN breast cancer patients treated with neoadjuvant chemotherapy. It adds prognostic information to the presence or absence of pCR and could be useful to compare the efficacies of different chemotherapy regimens.


Assuntos
Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/patologia , Adulto Jovem
2.
Br J Cancer ; 108(10): 2172-7, 2013 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-23558900

RESUMO

BACKGROUND: BRCAness is defined as shared tumour characteristics between sporadic and BRCA-mutated cancers. However, how to exactly measure BRCAness and its frequency in breast cancer is not known. Assays to establish BRCAness would be extremely valuable for the clinical management of these tumours. We assessed BRCAness characteristics frequencies in a large cohort of triple-negative breast cancers (TNBCs). METHODS: As a measure of BRCAness, we determined a specific BRCA1-like pattern by array Comparative Genomic Hybridisation (aCGH), and BRCA1 promoter methylation in 377 TNBCs, obtained from 3 different patient cohorts. Clinicopathological data were available for all tumours, BRCA1-germline mutation status and chemotherapy response data were available for a subset. RESULTS: Of the tumours, 66-69% had a BRCA1-like aCGH profile and 27-37% showed BRCA1 promoter methylation. BRCA1-germline mutations and BRCA1 promoter methylation were mutually exclusive events (P=1 × 10(-5)). BRCAness was associated with younger age and grade 3 tumours. Chemotherapy response was significantly higher in BRCA1-mutated tumours, but not in tumours with BRCAness (63% (12 out of 19) vs 35% (18 out of 52) pathological complete remission rate, respectively). CONCLUSION: The majority of the TNBCs show BRCAness, and those tumours share clinicopathological characteristics with BRCA1-mutated tumours. A better characterisation of TNBC and the presence of BRCAness could have consequences for both hereditary breast cancer screening and the treatment of these tumours.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Genes BRCA1 , Heterozigoto , Adolescente , Adulto , Idoso , Neoplasias da Mama/metabolismo , Análise Mutacional de DNA , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Adulto Jovem
3.
Br J Cancer ; 109(12): 2965-72, 2013 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-24149178

RESUMO

BACKGROUND: Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a series of patients with 'luminal'-type breast cancer in whom the second half of neoadjuvant chemotherapy was selected based on the response to the first half. METHODS: Patients with oestrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer received three courses of neoadjuvant dose-dense doxorubicin and cyclophosphamide (ddAC). Three further courses of ddAC were administered in case of a 'favourable response' on the interim magnetic resonance imaging (MRI) and a switch to docetaxel and capecitabine (DC) was made in case of an 'unfavourable response', using previously published response criteria. The efficacy of this approach was evaluated by tumour size reductions on serial contrast-enhanced MRI, pathologic response and relapse-free survival. RESULTS: Two hundred and forty-six patients received three courses of ddAC. One hundred and sixty-four patients (67%) had a favourable response at the interim MRI, with a mean tumour size reduction of 31% after the first three courses and 34% after the second three courses. Patients with unfavourable responsive tumours had a mean tumour size reduction of 12% after three courses and received three courses of DC rather than ddAC. This led to a mean shrinkage of 27%. CONCLUSION: The tumour size reduction of initially less responsive tumours after treatment adaptation adds further evidence that a response-adapted strategy may enhance the efficacy of neoadjuvant chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/biossíntese , Adolescente , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Capecitabina , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Docetaxel , Doxorrubicina/administração & dosagem , Feminino , Filgrastim , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptores de Estrogênio/biossíntese , Proteínas Recombinantes/administração & dosagem , Análise de Sobrevida , Taxoides/administração & dosagem , Adulto Jovem
4.
Ann Oncol ; 24(2): 537-542, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23117071

RESUMO

BACKGROUND: The growth modulation index (GMI) is the ratio of time to progression with the nth line (TTP(n)) of therapy to the TTP(n)(-1) with the n-1th line. GMI >1.33 is considered as a sign of activity in phase II trials. PATIENTS AND METHODS: This retrospective analysis evaluated the concordance between the GMI and the efficacy outcomes in 279 patients with advanced soft tissue sarcoma (ASTS) treated with trabectedin 1.5 mg/m² (24-h infusion every 3 weeks) in four phase II trials. RESULTS: One hundred and forty-two (51%) patients received one prior line and 137 ≥ 2 lines. The median TTP(n) was 2.8 months (range 0.2-26.8), whereas the median TTP(n)(-1) was 4.0 months (0.3-79.5). The median GMI was 0.6 (0.0-14.4). Overall, 177 patients (63%) had a GMI <1; 21 (8%) a GMI equal to 1-1.33 and 81 (29%) a GMI >1.33, which correlated with the median overall survival in those patients (9.1, 13.9 and 23.8 months, respectively, P = 0.0005). A high concordance rate between the GMI and response rate (P < 0.0001) and progression-free survival (PFS, P < 0.0001) was observed. Good performance status (PS) was the only factor associated with GMI >1.33 (PS = 0; P < 0.04). CONCLUSIONS: A high GMI was associated with favorable efficacy outcomes in patients treated with trabectedin. Further research is needed to assess GMI as an indicator in this setting.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Dioxóis/uso terapêutico , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Terapia de Salvação , Sarcoma/metabolismo , Sarcoma/mortalidade , Sarcoma/patologia , Trabectedina , Resultado do Tratamento , Adulto Jovem
5.
Breast Cancer Res Treat ; 140(1): 63-71, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23828499

RESUMO

Intrinsic subtypes are widely accepted for the classification of breast cancer. Lacking gene expression data, surrogate classifications based on immunohistochemistry (IHC) have been proposed. A recent St. Gallen consensus meeting recommends to use this "surrogate intrinsic subtypes" for predicting adjuvant chemotherapy resistance, implying that "Surrogate Luminal A" breast cancers should only receive endocrine therapy. In this study we assessed both gene expression based intrinsic subtypes as well as surrogate intrinsic subtypes regarding their power to predict neoadjuvant chemotherapy benefit. Single institution data of 560 breast cancer patients were reviewed. Gene expression data was available for 247 patients. Subtypes were determined on the basis of IHC, Ki67, histological grade, endocrine responsiveness, and gene expression, and were correlated with chemotherapy response and recurrence-free survival. In ER+/HER2- tumors, a high histological grade was the best predictor for chemotherapy benefit, both in terms of pCR (p = 0.004) and recurrence-free survival (p = 0.002). The gene expression based and surrogate intrinsic subtype based on Ki67 had no predictive or prognostic value in ER+/HER2- tumors. Histological grade, ER, PR, and HER2 were the best predictive factors for chemotherapy response in breast cancer. We propose to continue the conventional use of these markers.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Quimioterapia Adjuvante , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Valor Preditivo dos Testes , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Análise de Sobrevida , Resultado do Tratamento
6.
Ann Oncol ; 23(9): 2301-2305, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22357256

RESUMO

BACKGROUND: We have previously reported an array comparative genomic hybridization profile that identifies triple-negative breast cancers (TNBC), with BRCA1 dysfunction and a high sensitivity to intensified dose bifunctional alkylating agents. To determine the effect of conventional-dose chemotherapy in patients with this so-called BRCA1-like profile, clinical characteristics and survival were studied in a large group of TNBC patients. PATIENTS AND METHODS: DNA was isolated and BRCA1-like status was assessed in 101 patients with early-stage TNBC receiving adjuvant cyclophosphamide-based chemotherapy. Clinical characteristics and survival were compared between BRCA1-like and non-BRCA1-like groups. Results Sixty-six tumors (65%) had a BRCA1-like profile. Patients with BRCA1-like tumors tended to be younger and had more often node-negative disease (P = 0.06 and P = 0.03, respectively). Five-year recurrence-free survival was 80% for the BRCA1-like group and 75% for the non-BRCA1-like group (P = 0.35). T stage was the only variable significantly associated with survival. CONCLUSIONS: BRCA1-like tumors share clinical features, like young age at diagnosis and similar nodal status, with breast cancers in BRCA1 mutation carriers. Their prognosis is similar to that of non-BRCA1-like tumors when conventional-dose chemotherapy is administered. TNBCs that are classified as BRCA1-like may contain a defect in homologous recombination and could, in theory, benefit from the addition of poly ADP ribose polymerase inhibitors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Neoplasias da Mama/metabolismo , Recidiva Local de Neoplasia/prevenção & controle , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Docetaxel , Epirubicina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxoides/administração & dosagem , Resultado do Tratamento , Adulto Jovem
7.
Breast Cancer Res Treat ; 131(3): 827-36, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21472434

RESUMO

A pathological complete remission (pCR) is rarely achieved by neoadjuvant chemotherapy in estrogen receptor-positive (ER+) HER2-negative (HER2-) tumors. Therefore, its use might be questionable in specific groups of this tumor type. To select which patients benefit and which could be spared neoadjuvant chemotherapy, we tested standard pathology and molecular markers in ER+ HER2- breast tumors. Pretreatment biopsies were available from 211 ER+ HER2- tumors, who had been treated with neoadjuvant chemotherapy (adriamycin/cyclophosphamide). mRNA expression data were available for 132 tumors. We determined progesterone receptor expression (PR), endocrine sensitivity, HER2 expression, histology, proliferation, and molecular subtypes. We correlated these data to chemotherapy response using pCR rates and the previously published neoadjuvant response index (NRI). PR-negative tumors (n = 65, 30.8%) and luminal B type tumors (n = 43, 20.4%) responded significantly better to chemotherapy than other tumors. These associations remained significant in multivariate analysis. However, even in the subgroup of patients with the lowest response rate, comprising tumors that had both a positive-PR expression and the luminal A subtype (n = 58, 44%), the majority of the patients had downstaging because of chemotherapy. For histology (lobular vs. ductal), endocrine sensitivity, and proliferation, no associations with chemotherapy response were observed. Gene expression array analysis resulted in 28 significant genes (FDR < 0.1). PR expression and luminal B status are associated with a better response to neoadjuvant chemotherapy. However, both markers had only weak response predictive power, and it was not possible to identify a subgroup with no or only minimal chemotherapy benefit. Therefore, the decision to refrain from neoadjuvant chemotherapy to ER+ HER2- breast tumors should not be based on predictive markers, but exclusively on estimates of prognosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Resultado do Tratamento
8.
Eur J Nucl Med Mol Imaging ; 39(12): 1830-8, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22895862

RESUMO

PURPOSE: The aim of this study was to evaluate the association of primary tumour (18)F-fluorodeoxyglucose (FDG) uptake with clinical, histopathological and molecular characteristics of breast cancer patients scheduled for neoadjuvant chemotherapy. Second, we wished to establish for which patients pretreatment positron emission tomography (PET)/CT could safely be omitted because of low FDG uptake. METHODS: PET/CT was performed in 214 primary stage II or III breast cancer patients in the prone position with hanging breasts. Tumour FDG uptake was qualitatively evaluated to determine the possibility of response monitoring with PET/CT and was quantitatively assessed using maximum standardized uptake values (SUV(max)). FDG uptake was compared with age, TNM stage, histology, hormone and human epidermal growth factor receptor 2 status, grade, Ki-67 and molecular subtype in univariable and multivariable analyses. RESULTS: In 203 tumours (95 %) FDG uptake was considered sufficient for response monitoring. No subgroup of patients with consistently low tumour FDG uptake could be identified. In a univariable analysis, SUV(max) was significantly higher in patients with distant metastases at staging examination, non-lobular carcinomas, tumours with negative hormone receptors, triple negative tumours, grade 3 tumours, and in tumours with a high proliferation index (Ki-67 expression). After multiple linear regression analysis, triple negative and grade 3 tumours were significantly associated with a higher SUV(max). CONCLUSION: Primary tumour FDG uptake in breast cancer patients scheduled for neoadjuvant chemotherapy is significantly higher in tumours with prognostically unfavourable characteristics. Based on tumour characteristics associated with low tumour FDG uptake, this study was unable to identify a subgroup of patients unlikely to benefit from pretreatment PET/CT.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Carcinoma/diagnóstico por imagem , Fluordesoxiglucose F18 , Compostos Radiofarmacêuticos , Adulto , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Carcinoma/diagnóstico , Carcinoma/tratamento farmacológico , Quimioterapia Adjuvante , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Pessoa de Meia-Idade , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Prognóstico , Compostos Radiofarmacêuticos/farmacocinética , Tomografia Computadorizada por Raios X
9.
Ann Oncol ; 22(4): 870-876, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20937646

RESUMO

BACKGROUND: Tumors with homologous recombination deficiency (HRD), such as BRCA1-associated breast cancers, are not able to reliably repair DNA double-strand breaks (DSBs) and are therefore highly sensitive to both DSB-inducing chemotherapy and poly (ADP-ribose) polymerase inhibitors. We have studied markers that may indicate the presence of HRD in HER2-negative breast cancers and related them to neoadjuvant chemotherapy response. PATIENTS AND METHODS: Array comparative genomic hybridization (aCGH), BRCA1 promoter methylation, BRCA1 messenger RNA (mRNA) expression and EMSY amplification were assessed in 163 HER2-negative pretreatment biopsies from patients scheduled for neoadjuvant chemotherapy. RESULTS: Features of BRCA1 dysfunction were frequent in triple-negative (TN) tumors: a BRCA1-like aCGH pattern, promoter methylation and reduced mRNA expression were observed in, respectively, 57%, 25% and 36% of the TN tumors. In ER+ tumors, a BRCA2-like aCGH pattern and the amplification of the BRCA2 inhibiting gene EMSY were frequently observed (43% and 13%, respectively) and this BRCA2-like profile was associated with a better response to neoadjuvant chemotherapy. CONCLUSIONS: Abnormalities associated with BRCA1 inactivation are present in about half of the TN breast cancers but were not predictive of chemotherapy response. In ER+/HER2- tumors, a BRCA2-like aCGH pattern was predictive of chemotherapy response. These findings should be confirmed in independent series.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Terapia Neoadjuvante , Recombinação Genética , Adulto , Idoso , Neoplasias da Mama/patologia , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Mensageiro/genética , Receptor ErbB-2/deficiência , Receptores de Estrogênio/deficiência , Receptores de Prostaglandina/deficiência , Resultado do Tratamento
10.
Ann Oncol ; 22(7): 1561-1570, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21135055

RESUMO

BACKGROUND: Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-like(CGH) classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents. PATIENTS AND METHODS: We evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss through mutation or promoter methylation and immunohistochemical basal-like status in the triple-negative subgroup (TN subgroup). RESULTS: We observed greater benefit from HD-PB chemotherapy versus conventional chemotherapy among patients with BRCA1-like(CGH) tumours [41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04-0.43] compared with patients with non-BRCA1-like(CGH) tumours (189/230 = 82%, HR = 0.78, 95% CI 0.50-1.20), with a significant difference (test for interaction P = 0.006). Similar results were obtained for overall survival (P interaction = 0.04) and when analyses were restricted to the TN subgroup. Sixty-three percent (20/32) of assessable BRCA1-like(CGH) tumours harboured either a BRCA1 mutation (n = 8) or BRCA1 methylation (n = 12). CONCLUSION: BRCA1 loss as assessed by CGH analysis can identify patients with substantially improved outcome after adjuvant DSB-inducing chemotherapy when compared with standard anthracycline-based chemotherapy in our series.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Neoplasias da Mama/tratamento farmacológico , Carcinoma Basocelular/tratamento farmacológico , Hibridização Genômica Comparativa , Mutação/genética , Receptor ErbB-2/metabolismo , Adulto , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Carboplatina/administração & dosagem , Carcinoma Basocelular/classificação , Carcinoma Basocelular/genética , Ciclofosfamida/administração & dosagem , Metilação de DNA , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Regiões Promotoras Genéticas , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Tiotepa/administração & dosagem , Resultado do Tratamento
11.
Ann Oncol ; 21(3): 481-487, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19717533

RESUMO

BACKGROUND: The response of primary breast cancer to chemotherapy is usually expressed either as a pathological complete remission (pCR) or as 'no pCR'. A more quantitative measure is called for. PATIENTS AND METHODS: The 'neoadjuvant response index' (NRI) was calculated by adding a breast response score (a number from a five-point scale) to an axillary response score (a number from a three-point scale) and dividing this by the score that would have been obtained in case of a pCR in both breast and axilla. Consequently, the NRI is a number between 0 (representing no response) and 1 (a pCR of both breast and axilla). RESULTS: The NRI was calculated in 267 patients who had received neoadjuvant chemotherapy. The average NRI was 0.48 (median 0.40). Forty-one patients (15%) had an NRI of 0; 55 patients (21%) had an NRI of 1 (pCR). 'Highly endocrine responsive' tumors responded substantially less than 'incompletely endocrine responsive' ones. In triple negatives, an NRI of >0.70 was associated with a better recurrence-free survival than a lower NRI. CONCLUSIONS: The NRI proposed here may be useful to better reflect the efficacy of neoadjuvant systemic regimens than the binary pCR-'no pCR' system.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Estadiamento de Neoplasias , Indução de Remissão , Taxa de Sobrevida , Resultado do Tratamento
12.
Ann Surg Oncol ; 17(9): 2411-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20373039

RESUMO

BACKGROUND: Breast cancer is increasingly considered a heterogeneous disease. The aim of this study was to assess the differences between histological and receptor-based subtypes in breast-conserving surgery and pathological complete response (pCR) after neoadjuvant chemotherapy. METHOD: A consecutive series of 254 patients with operable breast cancer treated with neoadjuvant chemotherapy was analyzed. Tumors were classified according to their receptor status in estrogen receptor (ER)-positive tumors (HER2-negative), triple-negative tumors, and HER2-positive tumors. The type of surgery feasible prior to neoadjuvant chemotherapy was compared with the actual surgery performed. RESULTS: The overall increase in breast-conserving surgery was 37% (73 of 198). In patients with ductal and lobular carcinomas this increase was 41% (63 of 152, 95% confidence interval [95% CI] 0.34-0.49) and 20% (7 of 35, 95% CI 0.10-0.36), respectively (P = 0.02). Half of the patients with lobular carcinoma had to undergo a secondary mastectomy because of incomplete resection margins. In ER-positive, triple-negative and HER2-positive tumors, the increase in breast-conserving surgery was 39% (42 of 109, 95% CI 0.30-0.48), 24% (11 of 45, 95% CI 0.14-0.38), and 45% (20 of 44, 95% CI 0.32-0.60) (P = 0.11). The pCR rate in ductal and lobular carcinomas was 12% (23 of 195) and 2% (1 of 42), respectively (P = 0.09). In ER-positive, triple-negative and HER2-positive tumors the pCR rates were 2% (3 of 138), 28% (16 of 57), and 18% (10 of 56), respectively. Multivariate analysis showed that the receptor-based subtype was the only significant predictor of pCR (P = 0.004). CONCLUSION: In lobular tumors the benefit with regard to breast-conserving surgery of neoadjuvant chemotherapy is questionable. Although in ER-positive tumors the pCR rate is low, the increase in breast-conserving surgery was remarkable in ductal ER-positive tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/cirurgia , Ciclofosfamida/administração & dosagem , Docetaxel , Doxorrubicina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Hormônio-Dependentes/metabolismo , Estudos Retrospectivos , Taxoides/administração & dosagem , Resultado do Tratamento , Adulto Jovem
13.
Bone Marrow Transplant ; 42(7): 475-81, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18622420

RESUMO

Neutropenia following high-dose chemotherapy leads to a high incidence of infectious complications, of which central venous catheter-related infections predominate. Catheter-related infections and associated risk factors in 392 patients participating in a randomized adjuvant breast cancer trial and assigned to receive high-dose chemotherapy and peripheral stem-cell reinfusion were evaluated. Median catheter dwell time was 25 days (range 1-141). Catheter-related infections were seen in 28.3% of patients (11 infections per 1000 catheter-days). Coagulase-negative staphylococci were found in 104 of 186 positive blood cultures (56%). No systemic fungal infections occurred. Cox regression analysis showed that duration of neutropenia >10 days (P=0.04), using the catheter for both stem-cell apheresis and high-dose chemotherapy (P= <0.01), and use of total parenteral nutrition (TPN, P=0.04) were predictive for catheter-related infections. In conclusion, a high incidence of catheter-related infections after high-dose chemotherapy was seen related to duration of neutropenia, use of the catheter for both stem-cell apheresis and high-dose chemotherapy, and use of TPN. Selective use and choice of catheters could lead to a substantial reduction of catheter-related infectious complications.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cateterismo/efeitos adversos , Cateteres de Demora/efeitos adversos , Terapia Combinada/efeitos adversos , Infecções/etiologia , Nutrição Parenteral Total/efeitos adversos , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Antineoplásicos/administração & dosagem , Neoplasias da Mama/complicações , Neoplasias da Mama/cirurgia , Feminino , Humanos , Infecções/epidemiologia , Países Baixos , Neutropenia/etiologia , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo
14.
Ned Tijdschr Geneeskd ; 152(46): 2519-25, 2008 Nov 15.
Artigo em Holandês | MEDLINE | ID: mdl-19055260

RESUMO

OBJECTIVE: To analyse the extent to which primary systemic therapy (PST) achieves the main goals in patients with operable primary breast cancer, these goals being breast-conserving therapy and pathological complete remission (pCR), and to evaluate the response. DESIGN: Retrospective. METHOD: In a retrospective analysis of 254 patients treated with PST in 2000-2007 in the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, patients with inoperable disease (T4 and/or N3) were excluded. The response was mostly evaluated using contrast-enhanced MRI, whereby the chemotherapy regimen was switched if the reduction in the largest diameter of contrast washout was less than 25%. pCR was defined as no evidence of invasive cancer in the breast and axilla in the resection specimen. RESULTS: In patients with ductal carcinoma and lobular carcinoma an increase in breast-conserving therapy was seen in 32% and 17% of patients respectively. The pCR rate was 12% and 2% respectively. Secondary mastectomy because of irradical resection was required in 3% and 50% respectively. Multivariate analysis indicated that molecular type, defined on the basis of the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2), i.e. luminal (oestrogen receptor-positive), basal (hormone receptor-negative and HER2-negative) and HER2-positive tumours treated with trastuzumab was the only independent predictor of pCR; 2%, 28% and 35% respectively (p=0.004). In 43 patients the chemotherapy regimen was adjusted because the tumour did not respond sufficiently. A favourable clinical response was observed in 72% (31/43) of these patients. CONCLUSION: The observed increase in the number of breast-conserving therapies after PST was clinically relevant. PST may be more effective when contrast-enhanced MRI is used for interim evaluation, based on which the treatment may be switched. There was a clear difference in histological and molecular types of tumour and therefore the choice of treatment may be adjusted accordingly.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/terapia , Quimioterapia Adjuvante/métodos , Terapia Neoadjuvante/métodos , Cuidados Pré-Operatórios/métodos , Adulto , Idoso , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Ductal de Mama/terapia , Feminino , Humanos , Metástase Linfática , Mastectomia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
15.
J Clin Invest ; 93(2): 516-20, 1994 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-7906694

RESUMO

We evaluated the prognostic significance of p185c-erbB-2 expression and ras gene mutations in all patients diagnosed with a pulmonary adenocarcinoma between 1982 and 1985 at the University of Iowa. p185c-erbB-2 expression was detected in 15 cases (34%). A ras gene mutation was found in 16 cases (36%) and all were in codon-12 of K-ras. No N-ras mutations were identified. Both p185c-erbB-2 expression and a K-ras mutation were found only in codon-12 and present in six cases (14%). By univariate analysis p185c-erbB-2 expression was associated with shortened survival (P = 0.02) while the presence of a K-ras mutation was not (P = 0.16). Multivariate analysis by the Cox proportional hazards model, controlling for patient age and tumor stage, also continued to identify p185c-erbB-2 expression as an independent unfavorable prognostic factor (P = 0.01). In this model a K-ras mutation also approached significance as a poor prognostic indicator (P = 0.06). The impact of both p185c-erbB-2 expression and a K-ras mutation on survival was additive and highly significant (P = 0.004). This additive nature suggests that together these two markers identify a high-risk population of lung adenocarcinoma patients that may benefit from aggressive therapy.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/análise , Receptores ErbB/biossíntese , Genes ras , Neoplasias Pulmonares/genética , Mutação Puntual , Proteínas Proto-Oncogênicas/biossíntese , Proto-Oncogenes , Análise Atuarial , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Fatores Etários , Sequência de Bases , Primers do DNA , DNA de Neoplasias/isolamento & purificação , DNA de Neoplasias/metabolismo , Receptores ErbB/análise , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Dados de Sequência Molecular , Análise Multivariada , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas/análise , Receptor ErbB-2 , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo
16.
Eur J Surg Oncol ; 43(4): 625-635, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27847287

RESUMO

INTRODUCTION: 18F-FDG PET/CT has high positive predictive value for the detection of avid lymph node metastases in breast cancer patients. We analysed the effect of upstaging lymph nodes by PET/CT on short-term outcome in stage II/III breast cancer patients. PATIENTS AND METHODS: A total of 278 stage II/III primary breast cancer patients (mean age 48.9 years, range 19-75 years) were re-staged with 18F-FDG PET/CT before start of pre-operative systemic treatment (PST). Patients were divided in three groups based on risk for local recurrence: a low - (T2N0), intermediate - (T0-2N1 and T3N0) and a high-risk group (T0-3N2-3, T3N1 and T4). Within these groups we looked at local recurrence-free survival (LRFS), recurrence-free survival (RFS) and overall survival (OS) within the first 3 years of follow-up. RESULTS: With a median follow-up (FU) of 50 months the RFS, LRFS and OS were 87%, 88% and 92% respectively for the whole group. PET/CT upstaged 43 patients from the low- and intermediate risk group to the high-risk group, based on detection of ≥4 avid axillary nodes or occult N2/3-disease. Patients upstaged with PET/CT had more events for all three analyses compared to the original risk groups, which resulted in a significantly worse RFS (69.8%; p = 0.03) a nearly significantly worse LRFS (p = 0.052) and no effect in OS (p = 0.433). DISCUSSION: Additional PET/CT staging allows breast cancer patients to be treated according to the true stage, still stage II/III breast cancer patients upstaged to N2/3 by PET/CT have worse short-term outcome, despite adjustment of treatment, than patients staged high-risk with conventional imaging.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Adulto , Idoso , Axila , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Carboplatina/administração & dosagem , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/diagnóstico por imagem , Carcinoma Lobular/patologia , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Fluordesoxiglucose F18 , Humanos , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Compostos Radiofarmacêuticos , Trastuzumab/administração & dosagem , Adulto Jovem
17.
J Clin Oncol ; 23(3): 576-84, 2005 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-15659504

RESUMO

PURPOSE: This nonrandomized multicenter phase II study was performed to evaluate the activity and safety of Ecteinascidin (ET-743) administered at a dose of 1.5 mg/m(2) as a 24-hour continuous infusion every 3 weeks in patients with pretreated advanced soft tissue sarcoma. PATIENTS AND METHODS: Patients with documented progressive advanced soft tissue sarcoma received ET-743 as second- or third-line chemotherapy. Antitumor activity was evaluated every 6 weeks until progression, excessive toxicity, or patient refusal. RESULTS: One hundred four patients from eight European institutions were included in the study (March 1999 to November 2000). A total of 410 cycles were administered in 99 assessable patients. Toxicity mainly involved reversible grade 3 to 4 asymptomatic elevation of transaminases in 40% of patients, and grade 3 to 4 neutropenia was observed in 52% of patients. There were eight partial responses (PR; objective regression rate, 8%), 45 no change (NC; > 6 months in 26% of patients), and 39 progressive disease. A progression arrest rate (PR + NC) of 56% was observed in leiomyosarcoma and 61% in synovialosarcoma. The median duration of the time to progression was 105 days, and the 6-month progression-free survival was 29%. The median duration of survival was 9.2 months. CONCLUSION: ET-743 seems to be a promising active agent in advanced soft tissue sarcoma, with no cumulative toxicities. The 6-months progression-free survival observed in advanced soft tissue sarcoma compares favorably with those obtained with other active drugs tested in second-line chemotherapy in previous European Organisation for the Research and Treatment of Cancer trials. The median overall survival was unusually long in these heavily pretreated patients mainly due to the high number of patients who benefit from the drug in terms of tumor control.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Isoquinolinas/uso terapêutico , Sarcoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacologia , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Dioxóis/farmacologia , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacologia , Masculino , Pessoa de Meia-Idade , Tetra-Hidroisoquinolinas , Trabectedina , Resultado do Tratamento
18.
J Natl Cancer Inst ; 83(14): 1024-7, 1991 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-2072410

RESUMO

To investigate a possible relationship between the exposure to tobacco smoke and the presence of ras point mutations, we examined lung adenocarcinoma samples from 27 smokers and from 27 nonsmokers. Activating point mutations in K-ras (also known as KRAS2) and N-ras (also known as NRAS) were determined by using the polymerase chain reaction and oligonucleotide hybridization to detect the mutated sequences. Mutations were more often found in adenocarcinomas obtained from smokers (eight of 27) than in adenocarcinomas obtained from nonsmokers (two of 27) (P = .044, Fisher's exact test). All mutations were present in K-ras codon 12. None of the other parameters examined differed significantly between the ras-positive and ras-negative groups. We conclude that exposure to carcinogenic agents in tobacco smoke is an important factor in the induction of point mutations in K-ras in human lung adenocarcinomas, but that K-ras mutations may also infrequently occur in tumors of non-smokers.


Assuntos
Adenocarcinoma/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes ras/genética , Neoplasias Pulmonares/genética , Fumar/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Códon/genética , DNA de Neoplasias/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Reação em Cadeia da Polimerase
19.
J Natl Cancer Inst ; 82(17): 1416-20, 1990 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-2388293

RESUMO

Pentostatin was used to treat 26 patients with advanced B-cell chronic lymphocytic leukemia resistant to conventional treatment. Twenty patients had progressive disease on previous regimens and six had had partial remission and then relapsed 3-34 months after previous chemotherapy. Eleven patients had previously been treated with three different regimens. 10 had been treated with two regimens, and five had been treated with one regimen. Pentostatin was administered at a dosage of 4 mg/m2 weekly for 3 weeks, then 4 mg/m2 every other week for 6 weeks and once a month for 6 months. Seven of 26 assessable patients (27%) achieved partial remission and five (19%) achieved clinical improvement. The median duration of partial remission until relapse or death was 210 days. Myelosuppression was minor and transient in responsive patients, indicating some degree of selective effect on lymphocytes. Except for one patient who died of cerebral hemorrhage during the first 6 weeks of treatment, no drug-related deaths were registered. Major toxic effects included nausea in 17 patients (mainly grade 1), infections in 15, and liver enzyme elevations in five. Thus, pentostatin is active, even in patients with advanced B-cell chronic lymphocytic leukemia that is refractory to multiple chemotherapy regimens. Response can be achieved with mild myelosuppression.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pentostatina/uso terapêutico , Adulto , Idoso , Avaliação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pentostatina/efeitos adversos
20.
J Natl Cancer Inst ; 90(3): 210-8, 1998 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-9462678

RESUMO

BACKGROUND: Although high-dose chemotherapy is rapidly gaining acceptance as a treatment option for a number of cancers, the long-term toxic effects of such therapy are a concern. Cognitive deficits (e.g., problems with memory and concentration) are not uncommon after chemotherapy, but they have not been documented systematically. In this study, we assessed the prevalence of cognitive deficits in a group of patients with high-risk breast cancer who were randomly assigned to receive either high-dose or standard-dose adjuvant chemotherapy plus tamoxifen, and we investigated whether high-dose chemotherapy impaired cognitive functioning more than standard-dose chemotherapy. METHODS: Cognitive functioning was evaluated by use of a battery of neuropsychologic tests. In addition, patients were interviewed with regard to cognitive problems, health-related quality of life, anxiety, and depression. Results from patients who received adjuvant systemic therapy were compared with results from patients who had early stage breast cancer not treated with such therapy (control patients). RESULTS: The study population consisted of 34 patients treated with high-dose chemotherapy plus tamoxifen, 36 patients treated with standard-dose chemotherapy plus tamoxifen, and 34 control patients. For all patients, the average time since the completion of last nonhormonal therapy was 2 years. Cognitive impairment was found in 32% of the patients treated with high-dose chemotherapy, in 17% of the patients treated with standard-dose chemotherapy, and in 9% of the control patients. In comparison with the control patients, patients treated with high-dose chemotherapy appeared to have an 8.2-times higher risk of cognitive impairment (odds ratio; 95% confidence interval [CI] = 1.8-37.7); in comparison with the patients who received standard-dose chemotherapy, this risk of impairment was 3.5-times higher (95% CI = 1.0-12.8). CONCLUSION: High-dose chemotherapy appears to impair cognitive functioning more than standard-dose chemotherapy. Central nervous system toxicity may be a dose-limiting factor in high-dose chemotherapy regimens.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Transtornos Cognitivos/induzido quimicamente , Adulto , Ansiedade , Neoplasias da Mama/psicologia , Transtornos Cognitivos/psicologia , Depressão , Feminino , Humanos , Pessoa de Meia-Idade , Testes Neuropsicológicos , Razão de Chances , Prevalência , Qualidade de Vida , Risco
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