RESUMEN
BACKGROUND: The impact of the first coronavirus disease 2019 (COVID-19) wave on cancer patient management was measured within the nationwide network of the Unicancer comprehensive cancer centers in France. PATIENTS AND METHODS: The number of patients diagnosed and treated within 17 of the 18 Unicancer centers was collected in 2020 and compared with that during the same periods between 2016 and 2019. Unicancer centers treat close to 20% of cancer patients in France yearly. The reduction in the number of patients attending the Unicancer centers was analyzed per regions and cancer types. The impact of delayed care on cancer-related deaths was calculated based on different hypotheses. RESULTS: A 6.8% decrease in patients managed within Unicancer in the first 7 months of 2020 versus 2019 was observed. This reduction reached 21% during April and May, and was not compensated in June and July, nor later until November 2020. This reduction was observed only for newly diagnosed patients, while the clinical activity for previously diagnosed patients increased by 4% similar to previous years. The reduction was more pronounced in women, in breast and prostate cancers, and for patients without metastasis. Using an estimated hazard ratio of 1.06 per month of delay in diagnosis and treatment of new patients, we calculated that the delays observed in the 5-month period from March to July 2020 may result in an excess mortality due to cancer of 1000-6000 patients in coming years. CONCLUSIONS: In this study, the delays in cancer patient management were observed only for newly diagnosed patients, more frequently in women, for breast cancer, prostate cancer, and nonmetastatic cancers. These delays may result is an excess risk of cancer-related deaths in the coming years.
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COVID-19 , Neoplasias/complicaciones , COVID-19/complicaciones , Femenino , Francia , Humanos , Masculino , SARS-CoV-2RESUMEN
HER2 status is essential for breast cancer subtyping and for systemic treatment decisions as patients with HER2-positive tumours can benefit from anti-HER2 targeted therapies. However, few data are available on the current HER2-positive breast cancers rate and its evolution across years. Using data from the Côte d'Or breast cancer registry, we identified, between 1998 and 2011, 3220 women with invasive breast cancer diagnosed in the same laboratory which carries out regular internal quality controls and participates in multiannual international quality control programmes. Throughout the studied period of time, despite an increase of annual breast cancer cases, HER2 positivity rate remained stable (13.1%; P = 0.495), as did the proportion of tumours with positive hormone receptor status (P = 0.467) and the proportion of SBR grade II/III tumours (P = 0.747). Other characteristics, less strongly associated with HER2-positive status, showed either no annual variation (nodal and metastatic status, tumour size) or an annual positive trend (mean age, lobular carcinomas) or an annual negative trend (ductal carcinomas). These data reveal that in a population with stable clinical and pathological characteristics, and with the use of standardised assays, HER2 positivity rate remains stable over time. These results also emphasise that current HER2 positivity rate is lower than initially reported.
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Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Receptor ErbB-2/metabolismo , Sistema de Registros , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/patología , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Crecimiento Demográfico , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
PURPOSE: The aim of this study was to assess the Institut Gustave Roussy/M.D. Anderson Cancer Center (IGR/MDACC) nomogram in predicting pathologic complete response (pCR) to preoperative chemotherapy in a cohort of human epidermal growth factor receptor 2 (HER2)-positive tumors treated with preoperative chemotherapy with trastuzumab. We then combine clinical and pathological variables associated with pCR into a new nomogram specific to HER2-positive tumors treated by preoperative chemotherapy with trastuzumab. PATIENTS AND METHODS: Data from 270 patients with HER2-positive tumors treated with preoperative chemotherapy with trastuzumab at the Institut Curie and at the Georges François Leclerc Cancer Center were used to assess the IGR/MDACC nomogram and to subsequently develop a new nomogram for pCR based on multivariate logistic regression. Model performance was quantified in terms of calibration and discrimination. We studied the utility of the new nomogram using decision curve analysis. RESULTS: The IGR/MDACC nomogram was not accurate for the prediction of pCR in HER2-positive tumors treated by preoperative chemotherapy with trastuzumab, with poor discrimination (AUC = 0.54, 95% CI 0.51-0.58) and poor calibration (p = 0.01). After uni- and multivariate analysis, a new pCR nomogram was built based on T stage (TNM), hormone receptor status, and Ki67 (%). The model had good discrimination with an area under the curve (AUC) at 0.74 (95% CI 0.70-0.79) and adequate calibration (p = 0.93). By decision curve analysis, the model was shown to be relevant between thresholds of 0.3 and 0.7. CONCLUSION: To the best of our knowledge, ours is the first nomogram to predict pCR in HER2-positive tumors treated by preoperative chemotherapy with trastuzumab. To ensure generalizability, this model needs to be externally validated.
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Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Cuidados Preoperatorios , Trastuzumab/uso terapéutico , Adulto , Antineoplásicos Inmunológicos/administración & dosificación , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Toma de Decisiones Clínicas , Terapia Combinada , Técnicas de Apoyo para la Decisión , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Pronóstico , Curva ROC , Receptor ErbB-2/metabolismo , Reproducibilidad de los Resultados , Estudios Retrospectivos , Trastuzumab/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Trastuzumab emtansine (T-DM1) exhibited enhanced antitumor activity when combined with docetaxel or pertuzumab in preclinical studies. This phase Ib/IIa study assessed the feasibility of T-DM1 + docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and T-DM1 + docetaxel ± pertuzumab in patients with HER2-positive locally advanced breast cancer (LABC). PATIENTS AND METHODS: Phase Ib (part 1) explored dose escalation, with T-DM1 + docetaxel administered for greater than or equal to six cycles in patients with MBC. Phase Ib (part 2) began with the maximum tolerated dose (MTD) identified in part 1. Patients with LABC were administered less than or equal to six cycles of T-DM1 + docetaxel or T-DM1 + docetaxel + pertuzumab. Phase IIa explored the MTDs identified in phase Ib. RESULTS: Administered with T-DM1 (3.6 mg/kg), the docetaxel MTD was 60 mg/m(2) in MBC. In LABC, the MTD was 100 mg/m(2) docetaxel in combination with T-DM1 (3.6 mg/kg), given with granulocyte colony-stimulating factor (G-CSF). Administered with T-DM1 (3.6 mg/kg) + pertuzumab (840 mg, cycle 1; 420 mg, subsequent cycles), the docetaxel MTD in LABC was 75 mg/m(2) with G-CSF support. Neutropenia was the most common grade 3-4 adverse event (AE; MBC, 72% and LABC, 29%). In total, 48% (12/25) of MBC patients and 47% (34/73) of LABC patients experienced AEs requiring dose modification. In MBC (median prior systemic agents = 5), the objective response rate was 80.0% (20/25; 95% confidence interval [CI] 59.3-93.2) and the median progression-free survival was 13.8 months (range, 1.6-33.5). The pathologic complete response (ypT0/is, ypN0) rate in LABC was 60.3% (44/73; 95% CI 48.1-71.5). Pharmacokinetic analyses indicated a low risk of drug-drug interaction between T-DM1 and docetaxel. CONCLUSIONS: T-DM1 combined with docetaxel ± pertuzumab appeared efficacious in MBC or LABC; however, nearly half of patients experienced AEs requiring dose reductions with these T-DM1 combinations. CLINICALTRIALSGOV IDENTIFIER: NCT00934856.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Maitansina/análogos & derivados , Receptor ErbB-2/genética , Taxoides/administración & dosificación , Trastuzumab/administración & dosificación , Ado-Trastuzumab Emtansina , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Docetaxel , Femenino , Factor Estimulante de Colonias de Granulocitos/genética , Humanos , Maitansina/administración & dosificación , Maitansina/efectos adversos , Maitansina/farmacocinética , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Taxoides/efectos adversos , Taxoides/farmacocinética , Trastuzumab/efectos adversos , Trastuzumab/farmacocinéticaRESUMEN
BACKGROUND: Objective was to determine maximum tolerated dose (MTD), recommended dose (RD) and schedule, safety, pharmacokinetic (PK) profile, pharmacodynamic (PD) effects, and antitumor activity of Debio0932, a new second-generation oral heat shock protein (HSP) inhibitor. PATIENTS AND METHODS: This was a multicenter, uncontrolled, open-label, nonrandomized, dose-escalation study in adults with treatment-resistant advanced cancer. Groups of three patients received oral Debio0932 either daily or every other day. The starting dose of 50 mg was escalated until the MTD was reached, i.e. dose-limiting toxicity (DLT) occurred in ≥2 patients. Further 9 patients and an extension cohort of 30 patients were treated at the next lower dose (=RD). Adverse events (AEs), tumor response, PK, and HSP70 levels in peripheral blood mononuclear cells were recorded over 30 days. RESULTS: Fifty patients were treated with doses up to 1600 mg, at which level three DLT occurred (febrile neutropenia, diarrhea, asthenia). In total, 39 patients were then treated at the RD of 1000 mg daily. Most common drug-related AEs were asthenia and gastrointestinal events. No ocular toxicities were observed. Debio0932 was rapidly absorbed and metabolized. Plasma steady state was reached within 9 days. Volume of distribution was high and elimination half-life was 9-11 h. Food had no effect on PK. PD showed large interpatient variability, but no dose-effect relationship. Partial tumor response was observed in 2 patients (NSCLC and breast cancer), stable disease (SD) in 12 patients (5 of 8 NSCLC patients). In the extension cohort, 9 patients had SD, and 1 patient a partial metabolic tumor response. CONCLUSION: Debio0932 has limited clinical activity, together with manageable toxicity. Further development as adjunct treatment of NSCLC at daily doses of 1000 mg is warranted. CLINICAL TRIAL: NCT01168752.
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Antineoplásicos/administración & dosificación , Benzodioxoles/administración & dosificación , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Imidazoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Benzodioxoles/efectos adversos , Benzodioxoles/farmacocinética , Biotransformación , Cálculo de Dosificación de Drogas , Femenino , Proteínas HSP90 de Choque Térmico/metabolismo , Semivida , Humanos , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Absorción Intestinal , Masculino , Dosis Máxima Tolerada , Tasa de Depuración Metabólica , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasias/metabolismo , Neoplasias/patología , Ensayos Clínicos Controlados no Aleatorios como Asunto , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: Safety assessment beyond the dose-limiting toxicity evaluation period provides relevant information to define the recommended phase II dose (RP2D) of a new treatment. We retrospectively analyzed three phase I trials to illustrate two indicators: per-cycle probability of graded toxicity and cumulative probability of severe toxicity over the treatment period. PATIENTS AND METHODS: Data were collected from two continual reassessment method (CRM) trials (T1: aviscumine in solid tumors with short time on treatment; T2: erlotinib + radiotherapy in brainstem gliomas with longer time on treatment) and one 3 + 3 design (T3: liposomal doxorubicin + cyclophosphamide combination in ovarian carcinoma). The probability of severe and moderate or severe toxicity per cycle was estimated at each dose level with mixed proportional odds model. The cumulative probability of severe toxicity was also estimated with the time-to-event CRM. RESULTS: Eighty-three patients were included in the three trials; 94, 96 and 72 treatment cycles were administered, in T1, T2 and T3, respectively. Moderate toxicities were at least twice as frequent as severe toxicities. An increased probability of toxicity over time was detected in T3 [P = 0.04; per-cycle probability of severe toxicity: 27% (cycle 1) to 59% (cycle 6) at the RP2D]. At the RP2D, 37% of patients experienced at least one severe toxicity over the first six cycles in T2, and 78% in T3. CONCLUSIONS: Dedicated methods can be used to analyze toxicities from all cycles of treatment. They do not delay accrual and should be integrated in the analysis and reporting of phase I dose-finding trials.
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Antineoplásicos/efectos adversos , Ensayos Clínicos Fase I como Asunto/normas , Dosis Máxima Tolerada , Modelos Estadísticos , Neoplasias/tratamiento farmacológico , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: At 42.5 months of median follow-up, PHARE failed to show that 6 was non-inferior to 12 months of adjuvant trastuzumab. From the results of PHARE, questions remain regarding whether the magnitude of benefit derived from 1 year is sufficient to justify its systematic use for different patient subgroups. METHODS: Treatment effects were evaluated according to various tumour characteristics, and the multivariate Cox proportional hazards regression models were carried out on metastases-free survival (MFS) in the 12 months control arm. A prognostic score was defined providing the identification of patient categories with similar risks. The 6-month arm was used as a validation set in order to test for heterogeneity. This study is registered at clinicaltrials.gov, number NCT00381901. RESULTS: A total of 261 metastatic events were observed and four prognostic groups were defined: very low, low, intermediate and high risk in the 12-month arm. The corresponding 3-year MFS rates were 98.3%, 95.8%, 90.4% and 78.4% in the four prognostic groups, respectively. In the 6-month arm, the 3-year MFS rates were 98.3%, 94.2%, 85.7% and 74.8% in the four prognostic groups, respectively. CONCLUSION: In the very low-risk group, the potential absolute benefit of standard duration of trastuzumab was small enough to indicate that optimal standard treatment might be clinically questionable. On the other hand, the 3-year metastasis occurrence rates strongly support the need for a search of a more efficient treatment in the low-, intermediate- and high-risk groups.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Femenino , Francia/epidemiología , Humanos , Metástasis Linfática , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptor ErbB-2/metabolismo , Análisis de Supervivencia , Trastuzumab , Carga TumoralRESUMEN
BACKGROUND: Pathological complete response (pCR) following chemotherapy is strongly associated with both breast cancer subtype and long-term survival. Within a phase III neoadjuvant chemotherapy trial, we sought to determine whether the prognostic implications of pCR, TP53 status and treatment arm (taxane versus non-taxane) differed between intrinsic subtypes. PATIENTS AND METHODS: Patients were randomized to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET). pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in primary tumour and lymph nodes. We used a simplified intrinsic subtypes classification, as suggested by the 2011 St Gallen consensus. Interactions between pCR, TP53 status, treatment arm and intrinsic subtype on event-free survival (EFS), distant metastasis-free survival (DMFS) and overall survival (OS) were studied using a landmark and a two-step approach multivariate analyses. RESULTS: Sufficient data for pCR analyses were available in 1212 (65%) of 1856 patients randomized. pCR occurred in 222 of 1212 (18%) patients: 37 of 496 (7.5%) luminal A, 22 of 147 (15%) luminal B/HER2 negative, 51 of 230 (22%) luminal B/HER2 positive, 43 of 118 (36%) HER2 positive/non-luminal, 69 of 221(31%) triple negative (TN). The prognostic effect of pCR on EFS did not differ between subtypes and was an independent predictor for better EFS [hazard ratio (HR) = 0.40, P < 0.001 in favour of pCR], DMFS (HR = 0.32, P < 0.001) and OS (HR = 0.32, P < 0.001). Chemotherapy arm was an independent predictor only for EFS (HR = 0.73, P = 0.004 in favour of T-ET). The interaction between TP53, intrinsic subtypes and survival outcomes only approached statistical significance for EFS (P = 0.1). CONCLUSIONS: pCR is an independent predictor of favourable clinical outcomes in all molecular subtypes in a two-step multivariate analysis. CLINICALTRIALSGOV: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/mortalidad , Terapia Neoadyuvante , Adulto , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Quimioterapia Adyuvante/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
This population-based study aimed to describe the effects of neoadjuvant chemotherapy (NC) on survival in breast cancer (BC) patients in daily practice. BC patients treated with NC followed by surgery and radiotherapy, were retrospectively selected from 1982 to 2005 using the Côte d'Or BC registry. These patients were matched for the baseline AJCC (American Joint Committee on Cancer) stage, age at diagnosis, date of diagnosis and oestrogens receptors status to those who had undergone surgery followed by adjuvant chemotherapy and radiotherapy. The prognostic effect of NC on survival in BC patients was assessed with relative survival (RS) analyses. From 1982 to 2005, 210 patients with BC diagnosed in Côte d'Or were treated with NC followed by surgery and radiotherapy. For these patients, mean age at diagnosis was 50 (SD = 11). The main tumour characteristics were clinical AJCC stage 3 (46%) and an advanced Scarff Bloom and Richardson (SBR) stage (80%). Breast conserving surgery was performed in 84 patients (40%), 151 patients (72%) were treated with anthracyclines as the NC and the 5-year RS rate was 71%. Among these patients, 92 (37%) were matched. In this population, multivariate analyses showed that the use of NC did not independently influence RS: relative excess risk = 0.93 (0.50, 1.71).
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Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama Masculina/tratamiento farmacológico , Neoplasias de la Mama Masculina/mortalidad , Estudios de Casos y Controles , Quimioterapia Adyuvante/mortalidad , Femenino , Francia/epidemiología , Humanos , Masculino , Mastectomía Segmentaria/mortalidad , Mastectomía Segmentaria/estadística & datos numéricos , Persona de Mediana Edad , Terapia Neoadyuvante/mortalidad , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Vinflunine is a novel tubulin-targeted agent that is currently indicated as a monotherapy in bladder cancer patients. The recommended dose of 320 mg/m(2) is given as an intravenous infusion once every 3 weeks. Vinflunine is metabolized through CYP3A4 and mainly eliminated via the feces. A phase I trial was designed to explore the tolerability and pharmacokinetics of vinflunine in cancer patients with ranging degrees of liver dysfunction (LD). A sequential design was used for patient accrual, with the objective of determining the maximum tolerated dose (MTD) and the recommended dose (RD) of vinflunine in 3 groups of increasing LD levels. Vinflunine and its only active metabolite 4-O-deacetylvinflunine were quantified in serial whole blood samples. PK parameters were derived and compared between LD groups and with a reference PK database. Vinflunine and 4-O-deacetylvinflunine PK parameters were not affected in any of the explored LD levels. Geometric mean values for vinflunine total clearance were 47.8, 37.5 and 45.4 L/h in the 3 groups of increasing degrees of LD, as compared to 42.5 L/h in reference patients with no LD. No relationship was found between vinflunine clearance and the presence or absence of cirrhosis, nor was it found with the presence or absence of liver metastasis or with liver-related biochemical parameters. Based on the observed tolerability profile, the recommended doses of i.v. vinflunine are 320 mg/m(2), 250 mg/m(2) or 200 mg/m(2) for patients with increasing degrees of liver dysfunction.
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Antineoplásicos Fitogénicos/farmacocinética , Hepatopatías/tratamiento farmacológico , Neoplasias/sangre , Moduladores de Tubulina/farmacocinética , Vinblastina/análogos & derivados , Adulto , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Bilirrubina/sangre , Femenino , Humanos , Infusiones Intravenosas , Hepatopatías/sangre , Hepatopatías/complicaciones , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Resultado del Tratamiento , Moduladores de Tubulina/administración & dosificación , Moduladores de Tubulina/efectos adversos , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , Vinblastina/farmacocinética , gamma-Glutamiltransferasa/sangreRESUMEN
BACKGROUND: This phase I cohort study investigated aflibercept (vascular endothelial growth factor (VEGF) trap) plus docetaxel and cisplatin in patients with advanced solid tumours. METHODS: Patients received intravenous aflibercept 4, 5, or 6 mg kg(-1) with docetaxel and cisplatin (75 mg m(-2) each) on day 1 of a 3-week cycle until progressive disease or unacceptable toxicity. Primary objectives were determining cycle 1 dose-limiting toxicities (DLTs) and the aflibercept recommended phase II trial dose (RP2D) for this combination. RESULTS: During the dose-escalation phase (n=16), there were two DLTs of febrile neutropenia (at 4 and 5 mg kg(-1)). Granulocyte colony-stimulating factor prophylaxis was subsequently recommended. The RP2D of aflibercept was established at 6 mg kg(-1) and administered to 14 additional patients. The most frequent grade 3/4 adverse events (AEs) were neutropenia (43.3%), stomatitis (20.0%), asthenia/fatigue (20.0%), and hypertension (16.7%). All-grade AEs associated with VEGF blockade included epistaxis (83.3%), dysphonia (70.0%), proteinuria (53.3%), and hypertension (50.0%). There were five partial responses (16.7%) and 18 cases of stable disease (60.0%) (lasting >3 months in 10 patients). There were no pharmacokinetic (PK) interactions between the three drugs. CONCLUSION: Aflibercept 6 mg kg(-1) with docetaxel and cisplatin 75 mg m(-2) every 3 weeks is the RP2D based on tolerability, antitumour activity, and PKs.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Neoplasias/tratamiento farmacológico , Proteínas Recombinantes de Fusión/administración & dosificación , Taxoides/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Docetaxel , Esquema de Medicación , Fatiga/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Receptores de Factores de Crecimiento Endotelial VascularRESUMEN
BACKGROUND: The aim of this study is to evaluate the impact of the different breast cancer subtypes on the tumor (18)F-FDG uptake at baseline and on its changes after the first course of neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: One hundred and fifteen women with newly diagnosed, large or locally advanced breast cancer undergoing NAC were included. Estrogen receptor (ER), progesterone receptor (PR) and HER2 status were used to define three major tumor subtypes: triple negative (TN) (ER-/PR-/HER2-), luminal (ER+ and/or PR+; HER2-) and HER2 positive (HER2+). Using Fluorine-18 fluorodeoxyglucose positron emission tomography, the tumoral standard uptake value (SUV) maximal index was measured at baseline and just before the second course of NAC. RESULTS: TN tumors presented the highest baseline SUV (11.3 ± 8.5; P < 0.0001). The decrease of SUV after the first course of NAC (ΔSUV) was significantly higher in TN and HER2-positive subtypes (-45% ± 25% and -57% ± 30%, respectively) than in luminal one (-19% ± 35%; P < 0.0001). ΔSUV was a predictive factor of the pathological complete response only in HER2-positive tumors (cut-off = -75%; P < 0.03) with an accuracy of 76%. CONCLUSION: The baseline (18)F-FDG tumoral uptake but also its early response to NAC is different according to the immunohistological subtypes of breast cancer.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Fluorodesoxiglucosa F18/metabolismo , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/metabolismo , Quimioterapia Adyuvante , Femenino , Humanos , Imagen Multimodal , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Even though neoadjuvant chemotherapy has shown no benefits on overall survival (OS), it is being widely used in the treatment of breast cancer. This is based on the assumption that it may diminish the mastectomy rate and therefore be clinically relevant for patients. Our objective was to assess the impact of neoadjuvant chemotherapy on OS and on the rate of mastectomy in patients with non-metastatic primary operable breast carcinoma in routine practice. METHODS: The Cote d'Or district breast cancer registry was used to analyse the OS and mastectomy rate in patients with invasive primary operable unilateral breast cancer diagnosed between 1982 and 2006. We performed Cox proportional hazard ratio (HR) analyses for OS and multivariate logistic regression for the mastectomy rate for the overall population. Different matching methods based on the propensity score were used as sensitivity analyses to ensure that corrections for selection bias were adequate. RESULTS: We analysed 1578 patients, among whom 174 had received neoadjuvant chemotherapy. Median follow-up was 11.1 years. There was no difference between the two treatment groups for OS (HR=1.08 (95% confidence interval (CI): 0.77-1.51 for neoadjuvant chemotherapy)). The mastectomy rate was higher among patients treated with neoadjuvant chemotherapy (odds ratio 1.54 (95%CI: 1.03-2.31)). Sensitivity analyses confirmed these results: for OS, there was no difference between the two populations precisely matched using propensity scores (HR 1.08; 95%CI: 0.671-1.65). CONCLUSION: Despite long term follow-up, neoadjuvant chemotherapy provided no benefit for either OS or the mastectomy rate in our population.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Mastectomía/métodos , Neoplasias de la Mama/patología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Puntaje de Propensión , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Predictive markers of response to chemotherapy are lacking in breast cancer patients. Forkhead Box Protein 3 (FOXP3) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent. So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival (OS) benefit over anthracyclines alone, in patients with FOXP3-negative tumors. PATIENTS AND METHODS: Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel (Taxotere) to anthracyclines in patients with localized breast cancer. Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells. RESULTS: Four hundred and five tumors were found to express FOXP3 (37%). FOXP3 expression in breast cancer cells was associated with better OS (P = 0.003). Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy, but not in patients treated with sequential anthracycline-taxane. Moreover, in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy. CONCLUSION: FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer.
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Antraciclinas/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Factores de Transcripción Forkhead/metabolismo , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Quimioterapia Adyuvante , Femenino , HumanosRESUMEN
BACKGROUND: To determine the recommended doses of lapatinib (LPT) combined with vinorelbine (VNR) in women with human epidermal growth factor receptor 2-overexpressing advanced breast cancer pretreated with trastuzumab. METHODS: In this phase I study, women were treated with oral daily LPT and i.v. VNR infused on days 1 and 8 every 3 weeks. Dose levels (DL) of LPT (mg)/VNR (mg m(-2)) ranged from 750/20 to 1250/30. The primary end point was feasibility based on maximal tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic interactions were investigated. RESULTS: Of 33 patients included, 29 were evaluable. Two DLT occurred at DL4 (1000/25) meeting the MAD criteria. Despite an additional intermediate DL3' (1250/22.5), MTD was reached at DL3 (1000/22.5). Grade 3-4 neutropenia was the most common toxicity (34% and 38% of patients, respectively). Other significant toxicities included grade 3-4 diarrhoea (3% each), and grade 3 asthenia (10%). Although not statistically significant, LPT (at 1000 or 1250 mg) decreased the VNR clearance by 30-40% compared with DL1. CONCLUSION: The MTD LPT 1000 mg/VNR 22.5 mg m(-2) (DL3) is recommended for additional development. Pharmacokinetic interactions might increase the exposure to VNR and consequently alter the hematological tolerance.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quinazolinas/administración & dosificación , Receptor ErbB-2/metabolismo , Vinblastina/análogos & derivados , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Esquema de Medicación , Resistencia a Antineoplásicos , Estudios de Factibilidad , Femenino , Humanos , Lapatinib , Dosis Máxima Tolerada , Persona de Mediana Edad , Trastuzumab , Vinblastina/administración & dosificación , VinorelbinaRESUMEN
BACKGROUND: This phase II study evaluated single-agent bosutinib in pretreated patients with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Patients received oral bosutinib 400 mg/day. The primary end point was the progression-free survival (PFS) rate at 16 weeks. Secondary end points included objective response rate, clinical benefit rate, 2-year overall survival rate, safety, and changes in levels of bone resorption/formation biomarkers. RESULTS: Seventy-three patients were enrolled and treated. Median time from diagnosis of metastatic disease to initiation of bosutinib treatment was 24.5 months. For the intent-to-treat population, the PFS rate at 16 weeks was 39.6%. Unexpectedly, all responding patients (n = 4) were hormone receptor positive. The clinical benefit rate was 27.4%. The 2-year overall survival rate was 26.4%. The main toxic effects were diarrhea (66%), nausea (55%), and vomiting (47%). Grade 3-4 laboratory aminotransferase elevations occurred in 14 (19%) patients. Myelosuppression was minimal. No consistent changes in the levels of bone resorption/formation biomarkers were seen. CONCLUSIONS: Bosutinib showed promising efficacy in prolonging time to progression in chemotherapy-pretreated patients with locally advanced or metastatic breast cancer. Bosutinib was generally well tolerated, with a safety profile different from that of the Src/Abl tyrosine kinase inhibitor dasatinib in a similar patient population.
Asunto(s)
Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Nitrilos/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/uso terapéutico , Terapia Recuperativa/métodos , Adulto , Anciano , Remodelación Ósea/efectos de los fármacos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Estadificación de Neoplasias , Proteínas Tirosina Quinasas/antagonistas & inhibidoresRESUMEN
PURPOSE: A phase I study was performed to determine the maximal tolerated dose (MTD), recommended dose (RD), safety and efficacy of vinflunine when combined with capecitabine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes, with pharmacokinetic blood sampling to test potential drug-drug interactions. PATIENTS AND METHODS: Sixteen patients with MBC who had received anthracyclines and taxanes in the neo/adjuvant setting, if progression occurred during or within 12 months of chemotherapy completion, and/or as first-line chemotherapy of MBC were enrolled. Vinflunine (VFL) was given on day 1 with capecitabine (CAPE) twice daily from days 1 to 14, every 3 weeks. Three dose levels (DL) were investigated (DL1: VFL 280 mg/m² and CAPE 1,650 mg/m²/day, DL2: VFL 320 mg/m² and CAPE 1,650 mg/m²/day and DL3: VFL 280 mg/m² and CAPE 2,000 mg/m²/day). RESULTS: The RD was established as vinflunine 280 mg/m² on day 1 plus capecitabine 1,650 mg/m²/day on days 1 to 14 given every 3 weeks. Dose-limiting toxicities were grade 4 neutropenia lasting at least 7 days for 2 patients, anorexia with fatigue for 1 patient and diarrhoea with fatigue, anorexia and febrile neutropenia for 1 patient. Neutropenia was the main toxicity of the combination, it was reported in 15 patients (93.8%) with grade 3 in 7 patients (43.8%) and 22.6% of cycles and grade 4 in 7 patients (43.8%) and 19.8% of cycles. Complications were rare with only one patient experiencing febrile neutropenia at DL exceeding the RD. The most frequent non-haematological toxicities were fatigue and gastrointestinal disorders; however, no grade 3 or 4 episode was observed at the RD. Hand-foot syndrome was reported in 5 patients (31.3%) and 22.6% of cycles, no episode of grade 3 was seen. Concerning pharmacokinetics, no modifications were detected for VFL, while slight accumulation between days 1 and 14 was observed for 5-FU formed from CAPE. The risk of clinical significant drug-drug interaction was considered weak. Objective partial responses were reported in 7 patients, yielding a response rate of 43.8% in the all-treated population according to the investigator assessment. CONCLUSIONS: The combination of vinflunine and capecitabine is safe and showed promising antitumour activity in MBC patients who have failed prior anthracyclines and taxanes. Further clinical development of this combination is warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Antraciclinas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/análogos & derivados , Fluorouracilo/farmacocinética , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Taxoides/farmacología , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , Vinblastina/análogos & derivados , Vinblastina/farmacocinéticaRESUMEN
BACKGROUND: A dose-dense strategy has been considered to improve results of adjuvant chemotherapy for breast cancer. This randomised phase II trial investigated the feasibility of this approach with sequential anthracyclines and taxanes-based chemotherapy. METHODS: Patients with high-risk node-positive breast cancer were treated with three cycles of fluorouracil 500 mg m(-2), epirubicin 100 mg m(-2), cyclophosphamide 500 mg m(-2) (FEC 100) followed by three cycles of docetaxel 100 mg m(-2) delivered at 2-weekly intervals supported by primary prophylaxis with filgrastim. All patients were randomised to either uninterrupted treatment (arm A) or to have a 2-week additional period of rest between the FEC and docetaxel (arm B). The primary endpoint was the rate of success of chemotherapy delivery. Using a two-stage Fleming design, 120 patients were required with one interim analysis. RESULTS: In March 2005, enrolment was stopped into arm A after the observation of severe skin toxicities. Following the planned interim analysis, the study was closed because of the high rate of grade 3/4 skin toxicities in both arms (arm A: 32.4% and arm B: 18.9%). CONCLUSION: Sequential dose-dense FEC 100 followed by docetaxel 100 mg m(-2) is not feasible. Feasibility still depends largely on several factors including the choice of drugs, dosage and sequence of administration.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Relación Dosis-Respuesta a Droga , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Persona de Mediana EdadRESUMEN
BACKGROUND: In HER2-overexpressing breast cancer, accumulating preclinical evidences suggest that some chemotherapies, like trastuzumab, but also taxanes, are able to trigger a T helper 1 (Th1) anticancer immune response that contribute to treatment success. T helper 1 immune response is characterised by the expression of the transcription factor T-bet in CD4 T lymphocytes. We hypothesised that the presence of such T cells in the tumour immune infiltrates following neoadjuvant chemotherapy would predict patient survival. METHODS: In a series of 102 consecutive HER2-overexpressing breast cancer patients treated by neoadjuvant chemotherapy incorporating antracyclines or taxane and trastuzumab, we studied by immunohistochemistry the peritumoral lymphoid infiltration by T-bet+ lymphocytes before and after chemotherapy in both treatment groups. Kaplan-Meier analysis and Cox modelling were used to assess relapse-free survival (RFS). RESULTS: Fifty-eight patients have been treated with trastuzumab-taxane and 44 patients with anthracyclines-based neoadjuvant chemotherapy. The presence of T-bet+ lymphocytes in peritumoral lymphoid structures after chemotherapy was significantly more frequent in patients treated with trastuzumab-taxane (P=0.0008). After a median follow-up of 40 months, the presence of T-bet+ lymphocytes after neoadjuvant chemotherapy confers significantly better RFS (log-rank test P=0.011) only in patients treated with trastuzumab-taxane. In this population, multivariate Cox regression model showed that only the presence of T-bet+ lymphocytes in peritumoral lymphoid structures after neoadjuvant chemotherapy was independently associated with improved RFS (P=0.04). CONCLUSION: These findings indicate that the tumour infiltration by T-bet+ Th1 lymphocytes following neoadjuvant trastuzumab-taxane may represent a new independent prognostic factor of improved outcome in HER2-overexpressing breast carcinoma.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Linfocitos T CD4-Positivos/metabolismo , Genes erbB-2 , Tejido Linfoide/metabolismo , Proteínas de Dominio T Box/metabolismo , Taxoides/administración & dosificación , Antraciclinas , Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Docetaxel , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Pronóstico , TrastuzumabRESUMEN
BACKGROUND: We analysed whether the level of human epidermal growth factor receptor-2 (HER-2) amplification significantly influenced either pathological complete response (pCR) or recurrence-free survival (RFS) and overall survival (OS) after trastuzumab-based neoadjuvant therapy. METHODS: In all, 99 patients with an HER-2-amplified breast tumour treated with trastuzumab-based neoadjuvant therapy were included. Tumours were classified as low amplified (LA; 6-10 signals per nuclei) or highly amplified (HA; >10 signals). Pathological response was assessed according to Chevallier's classification (pCR was defined as grade 1 or 2). Median follow-up lasted 46 months (6-83). Cox uni- and multivariate analyses were performed. RESULTS: In all, 33 tumour samples were LA and 66 were HA. The pCR in HA tumours was significantly higher than in LA tumours (55% vs 24%, P=0.005), whereas no association was found between the pCR rate and tumour stage, grade or hormone receptor status. In multivariate analysis, the pathological nodal status (P=0.005) and adjuvant trastuzumab (P=0.037) were independently associated with RFS, whereas the level of HER-2 amplification nearly reached statistical significance (P=0.057). There was no significant difference between LA and HA tumours for OS (P=0.22, log-rank). CONCLUSION: The level of HER-2 gene amplification significantly influenced pCR but not RFS or OS in non-metastatic breast cancer treated with trastuzumab-based neoadjuvant therapy. However, RFS in patients with HA tumours tended to be shorter.