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PURPOSE: Stromal tumor-infiltrating lymphocytes (sTIL) are associated with pathologic complete response (pCR) and long-term outcomes for triple-negative breast cancer (TNBC) in the setting of anthracycline-based chemotherapy. The impact of sTILs on refining outcomes beyond prognostic information provided by pCR in anthracycline-free neoadjuvant chemotherapy (NAC) is not known. EXPERIMENTAL DESIGN: This is a pooled analysis of two studies where patients with stage I (T>1 cm)-III TNBC received carboplatin (AUC 6) plus docetaxel (75 mg/m2; CbD) NAC. sTILs were evaluated centrally on pre-treatment hematoxylin and eosin slides using standard criteria. Cox regression analysis was used to examine the effect of variables on event-free survival (EFS) and overall survival (OS). RESULTS: Among 474 patients, 44% had node-positive disease. Median sTILs were 5% (range, 1%-95%), and 32% of patients had ≥30% sTILs. pCR rate was 51%. On multivariable analysis, T stage (OR, 2.08; P = 0.007), nodal status (OR, 1.64; P = 0.035), and sTILs (OR, 1.10; P = 0.011) were associated with pCR. On multivariate analysis, nodal status (HR, 0.46; P = 0.008), pCR (HR, 0.20; P < 0.001), and sTILs (HR, 0.95; P = 0.049) were associated with OS. At 30% cut-point, sTILs stratified outcomes in stage III disease, with 5-year OS 86% versus 57% in ≥30% versus <30% sTILs (HR, 0.29; P = 0.014), and numeric trend in stage II, with 5-year OS 93% versus 89% in ≥30% versus <30% sTILs (HR, 0.55; P = 0.179). Among stage II-III patients with pCR, EFS was better in those with ≥30% sTILs (HR, 0.16; P, 0.047). CONCLUSIONS: sTILs density was an independent predictor of OS beyond clinicopathologic features and pathologic response in patients with TNBC treated with anthracycline-free CbD chemotherapy. Notably, sTILs density stratified outcomes beyond tumor-node-metastasis (TNM) stage and pathologic response. These findings highlight the role of sTILs in patient selection and stratification for neo/adjuvant escalation and de-escalation strategies.
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Protocolos de Quimioterapia Combinada Antineoplásica , Linfocitos Infiltrantes de Tumor , Terapia Neoadyuvante , Neoplasias de la Mama Triple Negativas , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Femenino , Terapia Neoadyuvante/métodos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/mortalidad , Neoplasias de la Mama Triple Negativas/patología , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Anciano , Antraciclinas/administración & dosificación , Antraciclinas/uso terapéutico , Pronóstico , Estadificación de Neoplasias , Resultado del Tratamiento , Docetaxel/administración & dosificación , Docetaxel/uso terapéutico , Carboplatino/administración & dosificaciónRESUMEN
BACKGROUND: RAS testing is used to select patients with anti-epidermal growth factor receptor (EGFR) therapies sensitivity in metastatic colorectal cancer (mCRC). However, other biomarkers such as BRAF, PIK3CA/PTEN, and p-IGF-1R+/MMP7+ (double positive [DP] phenotype) have not been prospectively assessed to predict anti-EGFR resistance. MATERIALS AND METHODS: We designed a multicenter prospective trial (NCT01276379) to evaluate whether the biomarkers BRAF mutation, PIK3CA mutation/PTEN loss, and DP phenotype can improve the prediction for 12-months progression-free survival (PFS) over the use of clinical variables exclusively in patients with RAS wild-type (WT) mCRC treated with standard chemotherapy plus biweekly cetuximab as first-line therapy. The planned sample size was 170 RAS WT patients to detect a 20% difference in 12-month PFS based on the analysis of clinical and selected biomarkers (α = .05, ß = .2). The discriminatory capacity of the biomarkers was evaluated using receiver operating characteristic curves. RESULTS: We included 181 RAS WT patients. The biomarker distribution was as follows: BRAF mutant, 20 patients (11%); PIK3CA mutated/PTEN loss, 98 patients (58%); DP, 23 patients (12.7%). The clinical variables in the clinical score were progression status >0, left-sided tumor, and resectable liver metastasis as the only metastatic site. The area under the curve (AUC) of the score containing the clinical variables was 0.67 (95% confidence interval [CI], 0.60-0.75). The AUC of the score with clinical variables and BRAF mutational status was 0.68 (0.61-0.75, p = .37). The AUC of the score with clinical variables and PI3KCA mutation/PTEN status was 0.69 (0.61-0.76, p = .32). The AUC of the score with clinical variables and DP phenotype was 0.66 (0.58-0.73, p = .09). CONCLUSION: The addition of BRAF, PIK3CA/PTEN, and DP to a clinical score does not improve the discrimination of 12-month PFS. IMPLICATIONS FOR PRACTICE: This prospective biomarker design study has important clinical implications because many prospective clinical trials are designed with the hypothesis that BRAF mutation per se and MEK and PIK3CA downstream pathways are critical for colorectal tumor survival. The results lead to the question of whether these pathways should be considered as passengers instead of drivers.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Proteínas ras/genética , Anciano , Antineoplásicos Inmunológicos/uso terapéutico , Cetuximab/uso terapéutico , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Supervivencia sin Progresión , Estudios ProspectivosRESUMEN
Response to polyadenosine diphosphate ribose polymerase (PARP) inhibitors in platinum-resistant ovarian cancer and in the absence of BRCA mutations is very low. Combining PARP inhibitors with other agents might overcome this lack of activity. Here we describe the rationale and design of GEICO1601-ROLANDO (resistant ovarian cancer treated with olaparib and pegylated liposomal doxorubin; NCT03161132). ROLANDO is a Phase II single-arm multicenter trial in which patients are treated with a combination of olaparib and pegylated liposomal doxorubicin (PLD) in platinum-resistant epithelial ovarian, primary peritoneal, or Fallopian tube cancer regardless of the BRCA mutation status. The primary end point is progression-free survival at 6 months. Other secondary end points are response rate, disease control rate, quality of life and overall survival.
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Purpose: Triple-negative breast cancer (TNBC) requires the iden- tification of reliable predictors of response to neoadjuvant chemotherapy (NACT). For this purpose, we aimed to evaluate the performance of the TNBCtype-4 classifier in a cohort of patients with TNBC treated with neoadjuvant carboplatin and docetaxel (TCb).Methods: Patients with TNBC were accrued in a nonrandomized trial of neoadjuvant carboplatin AUC 6 and docetaxel 75 mg/m2 for six cycles. Response was evaluated in terms of pathologic complete response (pCR, ypT0/is ypN0) and residual cancer burden by Symmans and colleagues. Lehmann's subtyping was performed using the TNBCtype online tool from RNAseq data, and germline sequencing of a panel of seven DNA damage repair genes was conducted.Results: Ninety-four out of the 121 patients enrolled in the trial had RNAseq available. The overall pCR rate was 44.7%. Lehmann subtype distribution was 34.0% BL1, 20.2% BL2, 23.4% M, 14.9% LAR, and 7.4% were classified as ER+. Response to NACT with TCb was significantly associated with Lehmann subtype (P = 0.027), even in multivariate analysis including tumor size and nodal involvement, with BL1 patients achieving the highest pCR rate (65.6%), followed by BL2 (47.4%), M (36.4%), and LAR (21.4%). BL1 was associated with a significant younger age at diagnosis and higher ki67 values. Among our 10 germline mutation carriers, 30% were BL1, 40% were BL2, and 30% were M.Conclusions: TNBCtype-4 is associated with significantly different pCR rates for the different subtypes, with BL1 and LAR displaying the best and worse responses to NACT, respectively. Clin Cancer Res; 24(8); 1845-52. ©2018 AACR.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Carboplatino/administración & dosificación , Docetaxel/administración & dosificación , Femenino , Perfilación de la Expresión Génica , Genes BRCA1 , Genes BRCA2 , Heterocigoto , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Clasificación del Tumor , Estadificación de Neoplasias , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/mortalidad , Carga TumoralRESUMEN
BACKGROUND: Axitinib, an antiangiogenic multikinase inhibitor (MKI), was evaluated in the compassionate use programme (CUP) in Spain (October 2012-November 2014). SUBJECTS AND METHODS: 47 patients with advanced radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC, n = 34) or medullary thyroid cancer (MTC, n = 13) with documented disease progression were treated with axitinib 5 mg b.i.d. The primary efficacy endpoint was objective response rate (ORR) by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Progression-free survival (PFS) and adverse events (AEs) were secondary objectives. Regulatory authorities validated the CUP, and all patients signed informed consent form. RESULTS: Axitinib was administered as first-line therapy in 17 patients (36.2%), as second-line in 18 patients (38.3%) and as third/fourth-line in 12 patients (25.5%). With a median follow-up of 11.5 months (0-24.3), ORR was 27.7% (DTC: 29.4% and MTC: 23.1%) and median PFS was 8.1 months (95% CI: 4.1-12.2) (DTC: 7.4 months (95% CI: 3.1-11.8) and MTC: 9.4 months (95% CI: 4.8-13.9)). Better outcomes were reported with first-line axitinib, with an ORR of 53% and a median PFS of 13.6 months compared with 16.7% and 10.6 months as second-line treatment. Twelve (25.5%) patients required dose reduction to 3 mg b.i.d. All-grade AEs included asthenia (53.2%), diarrhoea (36.2%), hypertension (31.9%) and mucositis (29.8%); grade 3/4 AEs included anorexia (6.4%), diarrhoea (4.3%) and cardiac toxicity (4.3%). CONCLUSION: Axitinib had a tolerable safety profile and clinically meaningful activity in refractory and progressive thyroid cancer regardless of histology as first-line therapy. To our knowledge, this is the first time that cross-resistance between MKIs is suggested in thyroid cancer, highlighting the importance of prospective sequential clinical studies.
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Imidazoles/uso terapéutico , Indazoles/uso terapéutico , Radioisótopos de Yodo , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Axitinib , Carcinoma Neuroendocrino/diagnóstico por imagen , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/epidemiología , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos , España/epidemiología , Neoplasias de la Tiroides/epidemiología , Resultado del TratamientoRESUMEN
PURPOSE: To describe estradiol (E2), estrone (E1), and estrone sulfate (E1S) levels during the first year of monthly triptorelin plus exemestane or tamoxifen and to assess possible suboptimal suppression while receiving exemestane plus triptorelin. PATIENTS AND METHODS: Premenopausal patients with early breast cancer on the Suppression of Ovarian Function Trial who selected triptorelin as the ovarian suppression method and were randomly assigned to exemestane plus triptorelin or tamoxifen plus triptorelin were enrolled until the target population of 120 patients was reached. Blood sampling time points were 0, 3, 6, 12, 18, 24, 36, and 48 months. Serum estrogens were measured with a highly sensitive and specific assay. This preplanned 12-month analysis evaluated E2, E1, E1S, follicle-stimulating hormone, and luteinizing hormone levels in all patients and the proportion of patients with E2 levels greater than 2.72 pg/mL at any time point during treatment with exemestane plus triptorelin. RESULTS: One hundred sixteen patients (exemestane, n = 86; tamoxifen, n = 30; median age, 44 years; median E2, 51 pg/mL; 55% prior chemotherapy) started triptorelin and had one or more samples drawn. With exemestane plus triptorelin, median reductions from baseline E2, E1, and E1S levels were consistently ≥ 95%, resulting in significantly lower levels than with tamoxifen plus triptorelin at all time points. Among patients on exemestane plus triptorelin, 25%, 24%, and 17% had an E2 level greater than 2.72 pg/mL at 3, 6, and 12 months, respectively. Baseline factors related to on-treatment E2 level greater than 2.72 pg/mL were no prior chemotherapy (P = .06), higher body mass index (P = .05), and lower follicle-stimulating hormone and luteinizing hormone (each P < .01). CONCLUSION: During the first year, most patients on exemestane plus triptorelin had E2 levels below the defined threshold of 2.72 pg/mL, consistent with levels reported in postmenopausal patients on aromatase inhibitors, but at each time point, at least 17% of patients had levels greater than the threshold.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Estrógenos/sangre , Ovario/efectos de los fármacos , Adulto , Androstadienos/administración & dosificación , Antineoplásicos Hormonales , Neoplasias de la Mama/fisiopatología , Quimioterapia Adyuvante , Estradiol/sangre , Estrona/análogos & derivados , Estrona/sangre , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Hormona Luteinizante/sangre , Ovario/fisiopatología , Tamoxifeno/administración & dosificación , Pamoato de Triptorelina/administración & dosificaciónRESUMEN
BACKGROUND: Studies suggest a relationship between hypertension and outcome in bevacizumab-treated patients with metastatic colorectal cancer (mCRC). We performed a retrospective analysis of two phase II studies (BECA and BECOX) to determine if hypertension and proteinuria predict outcome in elderly patients with mCRC treated with bevacizumab. PATIENTS AND METHODS: Patients ≥ 70 years of age received either capecitabine 1250 mg/m(2) bid days 1-14 + bevacizumab 7.5 mg/kg day 1 every 21 days (BECA study) or capecitabine 1000 mg/m(2) bid days 1-14 with bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m(2) day 1 (BECOX study). The primary objective was to correlate hypertension and proteinuria with overall response rate (ORR), time to progression (TTP) and overall survival (OS). Secondary objectives included identification of risk factors associated with the development of hypertension and proteinuria and determining whether development of hypertension or proteinuria in the first 2 cycles was related to ORR, disease-control rate (DCR), TTP or OS. RESULTS: In total, 127 patients (median age 75.5 years) were included in the study. Hypertension correlated with DCR and OS; proteinuria correlated with ORR and DCR. Proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors for hypertension were female gender (odds ratio [OR] 0.241; P = 0.011) and more bevacizumab cycles (OR 1.112; P = 0.002); risk factors for proteinuria were diabetes (OR 3.869; P = 0.006) and more bevacizumab cycles (OR 1.181; P<0.0001). Multivariate analysis identified as having prognostic value: baseline lactate dehydrogenase, haemoglobin, number of metastatic lesions and DCR. CONCLUSION: This analysis of two phase II studies suggests that hypertension is significantly correlated with OS but not with ORR and TTP, whereas proteinuria is correlated with ORR but not with OS and TTP. Both hypertension and proteinuria are associated with the duration of bevacizumab treatment and do not represent an independent prognostic factor.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/tratamiento farmacológico , Hipertensión/complicaciones , Proteinuria/complicaciones , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Capecitabina , Ensayos Clínicos Fase II como Asunto , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , Humanos , Masculino , Análisis Multivariante , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: We sought to evaluate toxicity and efficacy of an alternating week schedule of paclitaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Patients (n=27, mean age 56 years, range 27-73 years) received paclitaxel (100 mg/m(2) i.v. infusion over 1 h) on days 1 and 15 alternating with gemcitabine (1000 mg/m(2)) on days 8 and 22 of a 36-day cycle. Responses were evaluated after three cycles, and after the proposed six cycles. RESULTS: In total, 116 cycles were administered (mean 4.25 cycles per patient). Haematological toxicity was slight: febrile neutropenia (n=1) and neutropenia grade III-IV (n=5). Non-haematological toxicities included arthromyalgia grade II (n=6) and neurotoxicity grade III (n=1). Objective response was 29%, stable disease 25% and disease progression 46%. Median duration of response was 8 months (95% CI 5-11 months), median progression-free survival was 7 months (95% CI 4-11 months), median overall survival was 13 months (95% CI 7-17 months) and survival at 1 year was 52%. CONCLUSIONS: A regimen of alternating weekly paclitaxel and gemcitabine is feasible in patients with advanced NSCLC, showing a lower toxicity profile compared with other platinum-based combinations, which makes this novel scheme attractive for these patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/administración & dosificación , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Desoxicitidina/efectos adversos , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Paclitaxel/efectos adversos , Tasa de Supervivencia , GemcitabinaRESUMEN
Our study attempts to determine the prognostic value of the quantitative measurement of the oncoprotein p185(Her-2/neu) in a group of patients with breast cancer and positive node involvement. In a series of 217 patients with breast cancer and positive nodes in whom the oncoprotein p185 was quantitatively determined by ELISA, we analyzed the clinico-pathological variables including age, menopausal status, tumor size, number of affected nodes, type and histology grade and the molecular variables such as the oestrogen and progesterone receptors (ER and PR, respectively), pS2 and Cathepsin D (CD). Using 260 fmol/mg protein as a cut-off point, 18% of the tumors presented as overexpressing p185. The p185 showed no relationship with any of the clinico-pathological variables studied except that its concentration was elevated in ductal and lobular histology types and in the moderate and poorly differentiated histology grades. With a median follow-up of 50 months (range 1-90), the univariate analysis of disease-free survival (DFS) and overall survival (OS) showed that the histology grade, tumor size, the number of infiltrated nodes, the p185 and the ER were the variables associated with the clinical course of the disease in the patients. In the multivariate analysis, however, only the tumor size, number of affected ganglia, the p185 and the ER remained associated with the clinical progression of the disease. The patients with p185 overexpression had a risk, not only of relapse but also death from the disease, of more than twice that of the patients who had normal p185 concentrations. When the p185 was divided into 3 categories based on +/-1 x SD above or below the mean, the patients with high and low p185 showed, in the univariate analysis, a similar relationship with DFS but not with OS. In the multivariate analysis, both with the DFS as with the OS, only a high p185 concentration retained its association with the clinical course of the disease in the patients. Our results suggest that by quantitatively determining (using ELISA) the p185 oncoprotein, groups of cancer patients of high risk could be better identified for more effective clinical management.