RESUMEN
Background We examined the efficacy of mirtazapine in preventing delayed nausea and vomiting following highly emetogenic chemotherapy (HEC). Patients and methods Patients who had experienced delayed emesis and would be subsequently scheduled for at least three more cycles of the same chemotherapy were randomly assigned to either a mirtazapine (15 mg daily on days 2-4) or a control group. In addition, both groups received a standard triplet regimen comprising aprepitant, a 5-HT3 receptor antagonist, and dexamethasone (7.5 mg on days 2-4). The chemotherapy regimens were either an epirubicin plus cyclophosphamide regimen or cisplatin-containing regimens. The primary end point was a complete response (no emesis and no rescue treatment) to the delayed phase (25-120 h post-chemotherapy) during Cycle 1. The impact on quality of life (QOL) was assessed using the Functional Living Index-Emesis (FLIE) questionnaire. Results Of 95 enrolled patients, 46 were assigned to the mirtazapine group and 49 to the control group. The complete response rate in the delayed phase during Cycle 1 was significantly higher with mirtazapine than in the control group (78.3% versus 49.0%, P = 0.003). The main adverse effects of mirtazapine were mild to moderate somnolence and weight gain. Mean total FLIE scores were similar between the two arms. Conclusions This is the first randomized prospective study to show that adding mirtazapine has a substantial and statistically significant benefit with good tolerance in patients with breast cancer who have experienced delayed emesis following the same prior HEC. (Trial registration: ClinicalTrials.gov NCT02336750).
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Antieméticos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Antagonistas de Dopamina/uso terapéutico , Mirtazapina/uso terapéutico , Náusea/prevención & control , Vómitos/prevención & control , Antieméticos/efectos adversos , Aprepitant/uso terapéutico , Cisplatino/efectos adversos , Ciclofosfamida/efectos adversos , Dexametasona/uso terapéutico , Antagonistas de Dopamina/efectos adversos , Epirrubicina/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Mirtazapina/efectos adversos , Náusea/inducido químicamente , Calidad de Vida , Antagonistas del Receptor de Serotonina 5-HT3/uso terapéutico , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
BACKGROUND: Bevacizumab combined with modified FOLFOX6 is a standard regimen for colorectal cancer. The present study was to determine the efficacy and safety of bevacizumab-modified FOLFOX6 regimen in heavily pretreated patients with human epidermal growth factor receptor 2 (HER2/neu)-negative MBC. METHODS: Bevacizumab, 5 mg/kg every two weeks or 7.5 mg/kg every three weeks, was administered with modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 400 mg/m2 on day 1, followed by 5-FU 2400 mg/m2 intravenous infusion over 46 hours every 2 weeks) to patients who failed at least 1 chemotherapy regimen in the metastatic setting. The primary objective was progression free survival (PFS). Secondary objectives included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), safety, and the change of tumor size and Eastern Cooperative Oncology Group (ECOG) performance status. RESULTS: 69 patients were enrolled. The median PFS was 6.8 months (95% CI, 5.0 to 8.5 months), ORR was 50.0% and median OS was 10.5 months (95% CI, 7.9 to 13.1 months). Patients showing objective responses had a 4.2-month median PFS gain and 5.7-month median OS gain compared with those who did not (P < 0.05). Grade 3 or 4 adverse events occurring in more than one patient were neutropenia (53/69, 76.8%), leukopenia (36/69, 52.2%), thrombocytopenia (13/69, 18.8%), anemia (3/69, 4.3%) and hypertension (3/69, 4.3%). CONCLUSIONS: Adding bevacizumab to modified FOLFOX6 does have significant anti-tumor activity and good safety profile in heavily pretreated HER2/neu-negative MBC patients. Further trials are required to confirm whether the high ORR can translate into a long-term PFS and even OS benefit. TRIAL REGISTRATION: www.clinicaltrials.gov NCT01658033.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Estimación de Kaplan-Meier , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Receptor ErbB-2 , Retratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: Platinum chemotherapy has a role in the treatment of metastatic triple-negative breast cancer but its full potential has probably not yet been reached. We assessed whether a cisplatin plus gemcitabine regimen was non-inferior to or superior to paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer. METHODS: For this open-label, randomised, phase 3, hybrid-designed trial undertaken at 12 institutions or hospitals in China, we included Chinese patients aged 18-70 years with previously untreated, histologically confirmed metastatic triple-negative breast cancer, and an ECOG performance status of 0-1. These patients were randomly assigned (1:1) to receive either cisplatin plus gemcitabine (cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) or paclitaxel plus gemcitabine (paclitaxel 175 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) given intravenously every 3 weeks for a maximum of eight cycles. Randomisation was done centrally via an interactive web response system using block randomisation with a size of eight, with no stratification factors. Patients and investigator were aware of group assignments. The primary endpoint was progression-free survival and analyses were based on all patients who received at least one dose of assigned treatment. The margin used to establish non-inferiority was 1·2. If non-inferiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine was achieved, we would then test for superiority. The trial is registered with ClinicalTrials.gov, number NCT01287624. FINDINGS: From Jan 14, 2011, to Nov 14, 2013, 240 patients were assessed for eligibility and randomly assigned to treatment (120 in the cisplatin plus gemcitabine group and 120 in the paclitaxel plus gemcitabine group). 236 patients received at least one dose of assigned chemotherapy and were included in the modified intention-to-treat analysis (118 per group). After a median follow-up of 16·3 months (IQR 14·4-26·8) in the cisplatin plus gemcitabine group and 15·9 months (10·7-25·4) in the paclitaxel plus gemcitabine group, the hazard ratio for progression-free survival was 0·692 (95% CI 0·523-0·915; pnon-inferiority<0·0001, psuperiority=0·009, thus cisplatin plus gemcitabine was both non-inferior to and superior to paclitaxel plus gemcitabine. Median progression-free survival was 7·73 months (95% CI 6·16-9·30) in the cisplatin plus gemcitabine group and 6·47 months (5·76-7·18) in the paclitaxel plus gemcitabine group. Grade 3 or 4 adverse events that differed significantly between the two groups included nausea (eight [7%] vs one [<1%]), vomiting (13 [11%] vs one [<1%]), musculoskeletal pain (none vs ten [8%]), anaemia (39 [33%] vs six [5%]), and thrombocytopenia (38 [32%] vs three [3%]), for the cisplatin plus gemcitabine compared with the paclitaxel plus gemcitabine groups, respectively. In addition, patients in the cisplatin plus gemcitabine group had significantly fewer events of grade 1-4 alopecia (12 [10%] vs 42 [36%]) and peripheral neuropathy (27 [23%] vs 60 [51%]), but more grade 1-4 anorexia (33 [28%] vs 10 [8%]), constipation (29 [25%] vs 11 [9%]), hypomagnesaemia (27 [23%] vs five [4%]), and hypokalaemia (10 [8%] vs two [2%]). Serious drug-related adverse events were seen in three patients in the paclitaxel plus gemcitabine group (interstitial pneumonia, anaphylaxis, and severe neutropenia) and four in the cisplatin plus gemcitabine group (pathological bone fracture, thrombocytopenia with subcutaneous haemorrhage, severe anaemia, and cardiogenic syncope). There were no treatment-related deaths. INTERPRETATION: Cisplatin plus gemcitabine could be an alternative or even the preferred first-line chemotherapy strategy for patients with metastatic triple-negative breast cancer. FUNDING: Shanghai Natural Science Foundation.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cisplatino/administración & dosificación , Desoxicitidina/análogos & derivados , Paclitaxel/administración & dosificación , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , China , Cisplatino/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/efectos adversos , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/patología , GemcitabinaRESUMEN
Apatinib is an oral, highly potent tyrosine-kinase inhibitor targeting VEGFR2. Phase I study showed the recommended dose of 750 mg/day with substantial antitumor activity. This phase II study aims to evaluate the optimum dose level for the efficacy and safety of apatinib monotherapy in heavily pretreated patients with metastatic triple negative breast cancer (mTNBC) in China. Phase IIa was first performed among 25 patients previously treated with anthracycline and/or taxane. All patients received apatinib 750 mg/day p.o. in a 4-week cycle. Subsequently, a phase IIb study of 59 patients was activated, with the endpoint progression-free survival (PFS). The dosage of drug for the Phase IIb was determined according to safety, tolerability and efficacy from the phase IIa study. As a result of toxicity associated with the 750 mg dose in phase IIa, the recommended initial dose of apatinib in the phase IIb was 500 mg/day. In phase IIb, grade 3/4 hematologic toxicities were thrombocytopenia (13.6%), leukopenia (6.8%), neutropenia (3.4%) and anemia (1.7%). The most frequent grade 3/4 nonhematologic toxicities were hand-foot syndrome, proteinuria, hypertension, and increased ALT. In the 56 evaluable patients, overall response rate and clinical benefit rate (CBR) were 10.7 and 25.0%, respectively. Median PFS and overall survival were 3.3 (95% CI 1.7-5.0) and 10.6 (95% CI 5.6-15.7) months, respectively. Our results indicate that apatinib dose of 500 mg rather than 750 mg is the recommended starting dose for the heavily pretreated mTNBC patients with measurable rate of partial response and PFS.
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Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Piridinas/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Antineoplásicos/farmacología , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/secundario , Metástasis Linfática , Persona de Mediana Edad , Piridinas/farmacología , Neoplasias de la Mama Triple Negativas/sangre , Neoplasias de la Mama Triple Negativas/mortalidad , Neoplasias de la Mama Triple Negativas/patología , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
AIM: The objectives of this study were to determine if the baseline SUVmax measured by F-FDG PET/CT correlates with molecular subtype and to explore the impact of baseline SUVmax on the survival of patients with metastatic breast cancer (MBC). METHODS: Patients with MBC were screened with PET/CT from February 2007 until December 2010. Multivariate linear regression analysis was performed to identify independent variable correlation with SUVmax. Prognostic variables identified by univariate analysis, with P < 0.1, were analyzed in the multivariate Cox model. RESULTS: A total of 244 MBC patients were eligible for this study. Multivariate linear regression analysis showed that molecular subtype, visceral metastasis, and number of metastatic organs could be used to predict the logarithmic values of SUVmax (lgSUVmax) for previous untreated MBC patients, whereas for those with 1 or more line previous treatment, the number of metastatic organs was identified as the only independent variable correlating with lgSUVmax. Cox regression analysis indicated that only in patients with previously untreated MBC did baseline SUVmax (continuous variable) act as an independent prognostic factor (hazard ratio = 1.049 for progression-free survival, 1.124 for overall survival). CONCLUSIONS: Baseline SUVmax correlates with molecular subtypes only in previously untreated MBC patients. PET/CT imaging can be used as a potential prognostic tool for patients with newly diagnosed MBC.
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Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/secundario , Fluorodesoxiglucosa F18/farmacocinética , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , CintigrafíaRESUMEN
BACKGROUND: Whether PET scan maximum standard uptake value (SUVmax) could differentiate luminal A from luminal B and help predict the survival of metastatic breast cancer (MBC) patients with luminal subtype is still unknown and need to be investigated. METHODS: 305 MBC patients with luminal subtypes were screened with PET/CT. Eligible patients were prospectively followed up. RESULTS: In total, 134 patients were eligible for this study. SUVmax was significantly related to the number of metastatic sites and presence of visceral metastasis on univariate analysis. SUVmax could not effectively differentiate patients with luminal A from luminal B subtype. Although luminal subtype at diagnosis could predict the relapse-free interval, it could not predict progression-free survival (PFS) or overall survival (OS) after developing relapse. In contrast, SUVmax was predictive of both PFS and OS and this effect was maintained in multivariate COX regression model. CONCLUSIONS: SUVmax of MBC did not correlate with molecular subtypes of primary tumor. While molecular subtype may be a valuable prognostic factor at primary diagnosis of breast cancer, the SUVmax, rather than molecular subtype, does have a potential to predict independently in multivariate analysis for the PFS and OS in patients with metastatic disease of luminal subtype.
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Neoplasias de la Mama/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Radiofármacos , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Metástasis Linfática , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Radiofármacos/farmacocinética , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
Zoledronic acid has direct and indirect antitumor effects. However, the optimal regimen for breast cancer patients remains to be determined. This study aimed to compare biomarker changes between a weekly low dose (metronomic arm) and a conventional dosage of zoledronic acid (conventional arm), and to explore correlations between biomarkers and progression-free survival (PFS). Sixty breast cancer patients with bone metastases were randomized to receive either zoledronic acid 1 mg IV weekly for 4 doses or a single dose of zoledronic acid 4 mg IV. Administration of other treatments was delayed for 1 month. Serial blood samples were collected on days 1, 15, 29, and at 3 months. Serum VEGF alteration was the primary endpoint. Compared to the conventional arm, the metronomic arm resulted in a significantly greater reduction in serum levels of VEGF and N-telopeptide of type I collagen (NTx) over time during the first month of treatment. Serum CA 15-3 level stabilized over time in the metronomic arm, but increased in the conventional arm. Independent prognostic factors for PFS included chemotherapy received (HR, 8.042; P = 0.000), estrogen receptor status (HR, 2.837; P = 0.020), VEGF levels at 3 months after intervention (HR, 2.026; P = 0.045), and baseline NTx (HR, 1.051; P = 0.001). Metronomic low-dose zoledronic acid is more effective than the conventional regimen and generates sustained reductions in circulating VEGF and NTx levels, as well as stabilization of serum CA 15-3 levels (ClinicalTrials.gov number, NCT00524849).
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Antineoplásicos/administración & dosificación , Biomarcadores de Tumor/sangre , Conservadores de la Densidad Ósea/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Difosfonatos/administración & dosificación , Imidazoles/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Antineoplásicos/efectos adversos , Conservadores de la Densidad Ósea/efectos adversos , Neoplasias Óseas/sangre , Neoplasias Óseas/mortalidad , Neoplasias Óseas/secundario , Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , China , Colágeno Tipo I/sangre , Difosfonatos/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Imidazoles/efectos adversos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Mucina-1/sangre , Péptidos/sangre , Factores de Tiempo , Resultado del Tratamiento , Ácido ZoledrónicoRESUMEN
Recent pre-clinical models suggest that radiation can promote tumor aggressiveness. We hypothesized that if this were occurring clinically, locoregional recurrences (LRRs) after postmastectomy radiation therapy (PMRT) would lead to lower survival than LRR after mastectomy alone. This study used two independent datasets to compare survival after LRR in women treated with versus without PMRT. Data from 229 LRR cases among 1,500 patients enrolled on prospective trials at the MD Anderson Cancer Center (MDA), and 66 LRR cases among 318 patients enrolled in the British Columbia Cancer Agency (BCCA) PMRT randomized trial were analyzed. In the MDA non-randomized dataset, 189/1031 had LRR after mastectomy alone and 40/469 had LRR after PMRT. In the randomized BC trial dataset, 52/158 had LRR after mastectomy alone and 14/160 had LRR after PMRT. In both datasets, survival was calculated from the time of LRR to death. Analysis of MDA data shows that in all LRR cases regardless of distant metastasis (DM), 5/10-year OS were 50/34% without PMRT and 27/19% after PMRT (P = 0.006). However, PMRT-treated patients had increased risk factors for DM (advanced T and N stages) and more PMRT-treated patients developed DM prior to LRR (63 vs. 34%, P = 0.005). Analyzing only patients will an isolated LRR (without previous or simultaneous, DMV), there was no OS difference between groups (P = 0.33). Analysis of BCCA data shows that distributions of T and N stages were similar in patients with LRR after mastectomy alone versus after PMRT. DM free survival after any LRR and after isolated LRR were similar in mastectomy alone versus PMRT-treated patients (P = 0.75, P = 0.26, respectively). Overall survival after any LRR and after isolated LRR were also similar in the two groups (P = 0.93, P = 0.28, respectively). Patients who develop LRR after mastectomy alone have high rates of DM and poor OS but these rates are not affected by the use of PMRT at the time of primary treatment. These data do not support the hypothesis that irradiation promotes biologically aggressive local recurrences.
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Neoplasias de la Mama/terapia , Mastectomía , Recurrencia Local de Neoplasia/mortalidad , Adulto , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/secundario , Colombia Británica , Quimioterapia Adyuvante , Distribución de Chi-Cuadrado , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Recurrencia Local de Neoplasia/etiología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Radioterapia Adyuvante/efectos adversos , Radioterapia Adyuvante/mortalidad , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Tasa de Supervivencia , Texas , Factores de Tiempo , Resultado del TratamientoRESUMEN
For this review, the authors appraised the evidence for adjuvant trastuzumab therapy in early breast cancer. There was level 1 evidence to support the routine use of 1 year of adjuvant trastuzumab in conjunction with chemotherapy for women with human epidermal growth factor receptor 2 (HER-2)-positive early breast cancer. The relative benefits of concurrent versus sequential administration remained unclear; however concurrent administration permitted the earliest possible intervention with trastuzumab with possible superiority. There was evidence to support the use of trastuzumab in both lymph node-positive and high-risk lymph node-negative patients, and preliminary data suggested that all patient subgroups that were eligible for the trials benefit equally from trastuzumab. Adjuvant trastuzumab was associated with a risk of cardiotoxicity, the long-term impact of which remains largely unknown. Routine cardiac risk assessment considering left ventricular ejection fraction, age, and prior history of cardiac events is recommended along with the selection of trastuzumab-based regimens that minimize cardiotoxicity. Trastuzumab acquisition costs for 1 year of therapy were the largest component of treatment costs.
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Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Sistemas de Liberación de Medicamentos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/economía , Anticuerpos Monoclonales Humanizados , Ensayos Clínicos como Asunto , Terapia Combinada , Femenino , Costos de la Atención en Salud , Corazón/efectos de los fármacos , Humanos , Calidad de Vida , TrastuzumabRESUMEN
PURPOSE: To examine the power of the nodal ratio (NR) of positive/excised nodes in predicting postmastectomy locoregional recurrence (LRR) in patients with 1-3 positive nodes (N+) and in identifying cohorts at similar risk across independent data sets. METHODS AND MATERIALS: Data from 82 patients with 1-3 N+ treated without postmastectomy radiotherapy (PMRT) in the British Columbia (BC) randomized trial were compared with data from 462 patients treated without PMRT in prospective chemotherapy trials at the M. D. Anderson Cancer Center (MDACC). Kaplan-Meier LRR curves were compared between centers using the absolute number of N+ and nodal ratios. RESULTS: The median number of excised nodes was 10 in BC and 16 in MDACC (p < 0.001). Examining LRR by number of N+, the 10-year LRR rate for patients with 1-3 N+ was higher in BC compared with MDACC (21.5% vs. 12.6%; p = 0.02). However, when examining LRR using NR, no differences were found between institutions. In patients with NR < or = 0.20, the 10-year LRR rate was 17.7% BC vs. 10.9% MDACC (p = 0.27). In patients with NR > or = 0.20, the 10-year LRR rate was 28.7% BC vs. 22.7% MDACC (p = 0.32). On Cox regression analysis, NR was a stronger prognostic factor compared with number of N +. CONCLUSIONS: In patients with 1-3 N+, evaluating nodal positivity using NR reduced inter-institutional differences in LRR estimates that may exist due to variations in numbers of nodes excised. Nodal ratio >0.20 was associated with LRR >20%, warranting PMRT consideration. Nodal ratio may be useful for extrapolating data from prospective trials to clinical practices in which axillary staging extent vary.
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Neoplasias de la Mama/patología , Escisión del Ganglio Linfático , Recurrencia Local de Neoplasia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Axila , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Ciclofosfamida/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Metástasis Linfática , Mastectomía Radical Modificada , Metotrexato/administración & dosificación , Persona de Mediana Edad , Estudios Prospectivos , Análisis de RegresiónRESUMEN
PURPOSE: Prognostication of breast cancer using clinicopathologic variables, although useful, remains imperfect. Many reports suggest that gene expression profiling can refine the current approach. Alternatively, it has been shown that panels of proteins assessed by immunohistochemistry might also be useful in this regard. We evaluate the prognostic potential of a panel of markers by immunohistochemistry in a large case series to establish if either a single marker or a panel could improve the prognostic power of the Nottingham Prognostic Index (NPI). We validated the results in an independent series. EXPERIMENTAL DESIGN AND RESULTS: The expression of 13 biomarkers was evaluated in 930 breast cancers on a tissue microarray. Eight markers [estrogen receptor (ER), progesterone receptor (PR), Bcl-2, cyclin E, p53, MIB-1, cytokeratin 5/6, and HER2] showed a significant association with survival at 10 years on univariate analysis. On multivariate analysis that included these eight markers and the NPI, only the NPI [hazard ratio (HR), 1.35; 95% confidence interval (95% CI), 1.16-1.56; P = 0.0005], ER (HR, 0.59; 95% CI, 0.39-0.88; P = 0.011), and Bcl-2 (HR, 0.68; 95% CI, 0.46-0.99; P = 0.055) were significant. In a subsequent multivariate analysis that included the NPI, ER, and Bcl-2, only Bcl-2 (HR, 0.62; 95% CI, 0.44-0.87; P = 0.006) remained independent of NPI (HR, 1.50; 95% CI, 1.16-1.56; P = 0.004). In addition, Bcl-2, used as a single marker, was more powerful than the use of a panel of markers. Based on these results, an independent series was used to validate the prognostic significance of Bcl-2. ER and PR were also evaluated in this validation series. Bcl-2 (HR, 0.83; 95% CI, 0.71-0.96; P = 0.018) retained prognostic significance independent of the NPI (HR, 2.04; 95% CI, 1.67-2.51; P < 0.001) with an effect that was maximal in the first 5 years. CONCLUSION: Bcl-2 is an independent predictor of breast cancer outcome and seems to be useful as a prognostic adjunct to the NPI, particularly in the first 5 years after diagnosis.
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Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Distribución de Chi-Cuadrado , Ciclina E/análisis , Femenino , Humanos , Inmunohistoquímica/métodos , Queratinas/análisis , Antígeno Ki-67/análisis , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Receptor ErbB-2/análisis , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/análisisRESUMEN
BACKGROUND: The British Columbia randomized radiation trial was designed to determine the survival impact of locoregional radiation therapy in premenopausal patients with lymph node-positive breast cancer treated by modified radical mastectomy and adjuvant chemotherapy. Three hundred eighteen patients were assigned to receive no further therapy or radiation therapy (37.5 Gy in 16 fractions). Previous analysis at the 15-year follow-up showed that radiation therapy was associated with a statistically significant improvement in breast cancer survival but that improvement in overall survival was of only borderline statistical significance. We report the analysis of data from the 20-year follow-up. METHODS: Survival was analyzed by the Kaplan-Meier method. Relative risk estimates were calculated by the Wald test from the proportional hazards regression model. All statistical tests were two-sided. RESULTS: At the 20 year follow up (median follow up for live patients: 249 months) chemotherapy and radiation therapy, compared with chemotherapy alone, were associated with a statistically significant improvement in all end points analyzed, including survival free of isolated locoregional recurrences (74% versus 90%, respectively; relative risk [RR] = 0.36, 95% confidence interval [CI] = 0.18 to 0.71; P = .002), systemic relapse-free survival (31% versus 48%; RR = 0.66, 95% CI = 0.49 to 0.88; P = .004), breast cancer-free survival (48% versus 30%; RR = 0.63, 95% CI = 0.47 to 0.83; P = .001), event-free survival (35% versus 25%; RR = 0.70, 95% CI = 0.54 to 0.92; P = .009), breast cancer-specific survival (53% versus 38%; RR = 0.67, 95% CI = 0.49 to 0.90; P = .008), and, in contrast to the 15-year follow-up results, overall survival (47% versus 37%; RR = 0.73, 95% CI = 0.55 to 0.98; P = .03). Long-term toxicities, including cardiac deaths (1.8% versus 0.6%), were minimal for both arms. CONCLUSION: For patients with high-risk breast cancer treated with modified radical mastectomy, treatment with radiation therapy (schedule of 16 fractions) and adjuvant chemotherapy leads to better survival outcomes than chemotherapy alone, and it is well tolerated, with acceptable long-term toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/radioterapia , Ganglios Linfáticos/efectos de la radiación , Mastectomía Radical Modificada , Recurrencia Local de Neoplasia/prevención & control , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Colombia Británica , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática , Metotrexato/administración & dosificación , Recurrencia Local de Neoplasia/mortalidad , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante/efectos adversos , Medición de Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Expression profiling studies classified breast carcinomas into estrogen receptor (ER)+/luminal, normal breast-like, HER2 overexpressing, and basal-like groups, with the latter two associated with poor outcomes. Currently, there exist clinical assays that identify ER+/luminal and HER2-overexpressing tumors, and we sought to develop a clinical assay for breast basal-like tumors. EXPERIMENTAL DESIGN: To identify an immunohistochemical profile for breast basal-like tumors, we collected a series of known basal-like tumors and tested them for protein patterns that are characteristic of this subtype. Next, we examined the significance of these protein patterns using tissue microarrays and evaluated the prognostic significance of these findings. RESULTS: Using a panel of 21 basal-like tumors, which was determined using gene expression profiles, we saw that this subtype was typically immunohistochemically negative for estrogen receptor and HER2 but positive for basal cytokeratins, HER1, and/or c-KIT. Using breast carcinoma tissue microarrays representing 930 patients with 17.4-year mean follow-up, basal cytokeratin expression was associated with low disease-specific survival. HER1 expression was observed in 54% of cases positive for basal cytokeratins (versus 11% of negative cases) and was associated with poor survival independent of nodal status and size. c-KIT expression was more common in basal-like tumors than in other breast cancers but did not influence prognosis. CONCLUSIONS: A panel of four antibodies (ER, HER1, HER2, and cytokeratin 5/6) can accurately identify basal-like tumors using standard available clinical tools and shows high specificity. These studies show that many basal-like tumors express HER1, which suggests candidate drugs for evaluation in these patients.
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Neoplasias de la Mama/patología , Neoplasias Basocelulares/patología , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Femenino , Humanos , Inmunohistoquímica/métodos , Queratinas/análisis , Invasividad Neoplásica , Neoplasias Basocelulares/genética , Neoplasias Basocelulares/mortalidad , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptor ErbB-2/análisis , Receptor ErbB-2/genética , Receptores de Estrógenos/análisis , Receptores de Estrógenos/genética , Análisis de SupervivenciaRESUMEN
BACKGROUND: The antiestrogen tamoxifen has potent activity against estrogen receptor-positive breast cancer, but two nonsteroidal aromatase inhibitors, letrozole and anastrozole, show considerable advantages over tamoxifen with respect to patient survival and tolerability. To determine the optimal way to use letrozole and tamoxifen, we studied their effects on a breast tumor xenograft model, MCF-7Ca, that is responsive to both antiestrogens and aromatase inhibitors. METHODS: Female ovariectomized BALB/c athymic nude mice carrying xenograft tumors were treated daily subcutaneously with one of the following first-line therapies for varying durations: no drug (control), tamoxifen (100 microg/day) alone, letrozole (10 microg/day) alone, both drugs at the same time, or alternating 4-week courses of each drug (beginning with a course of tamoxifen or beginning with a course of letrozole). Tumor volumes and weights were estimated using linear mixed-effects models. The time to tumor doubling was calculated, and tumor weights in the treatment groups were compared, with adjustments for multiple comparisons being made with either Tukey's or Dunnett's procedure. Second-line therapies (with tamoxifen, letrozole, or fulvestrant) were initiated when tumors doubled in size under first-line therapies. All statistical tests were two-sided. RESULTS: The times for doubling of tumor volume were as follows: control, 3-4 weeks; tamoxifen alone, 16 weeks; tamoxifen alternating with letrozole, 17-18 weeks; tamoxifen plus letrozole, 18 weeks; letrozole alternating with tamoxifen, 22 weeks; letrozole alone, 34 weeks. First-line treatment with letrozole was superior to treatment with tamoxifen alone or with the two drugs combined (at week 16, both P<.001). Alternating tamoxifen and letrozole and alternating letrozole and tamoxifen were also not as effective as letrozole alone (at week 16, P =.002 and P<.001, respectively). Tumors progressing on tamoxifen remained sensitive to second-line therapy with letrozole compared with those remaining on tamoxifen at the end of treatment (week 28, P<.001), whereas tumors progressing on letrozole were unaffected by second-line treatment with the antiestrogens tamoxifen or fulvestrant. CONCLUSIONS: First-line letrozole therapy extends time for tumor progression in this model relative to the other treatment regimens tested. However, further studies are needed to determine the most effective second-line therapy for tumors that progress on letrozole.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de la Aromatasa , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores Enzimáticos/administración & dosificación , Moduladores de los Receptores de Estrógeno/administración & dosificación , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Nitrilos/administración & dosificación , Tamoxifeno/administración & dosificación , Triazoles/administración & dosificación , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Esquema de Medicación , Inhibidores Enzimáticos/sangre , Moduladores de los Receptores de Estrógeno/sangre , Femenino , Humanos , Letrozol , Modelos Lineales , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nitrilos/sangre , Tamaño de los Órganos/efectos de los fármacos , Ovariectomía , Tamoxifeno/sangre , Trasplante Heterólogo , Triazoles/sangre , Útero/efectos de los fármacosRESUMEN
This study was to determine if the use of regional radiotherapy (RT) changed in British Columbia after publication of new randomized trial data in 1997. Women with pathologic T1-3N1, nonmetastatic breast cancer treated with a mastectomy or breast-conserving surgery (BCS) were included. The use of regional RT was compared in two cohorts: cohort 1, July 1, 1995-June 30, 1997 (n = 834); and cohort 2, July 1, 1998-June 30, 2000 (n = 1072). All p-values were two-sided. Adjuvant systemic therapy was given to 96% and 95% of women in cohorts 1 and 2, respectively. Forty-five percent of cohort 1 and 48% of cohort 2 had BCS. Regional RT was received by 44% of cohort 1 and 66% of cohort 2 (p < 0.001). Eighty-eight percent and 90% of women with four or more positive nodes in cohorts 1 and 2 received regional RT, respectively. For women in cohorts 1 and 2 with one to three positive nodes, regional RT use increased from 32% to 54% after mastectomy, and from 23% to 59% after BCS, respectively (p < 0.001 for both). Publication of randomized trials and a coordinated guideline implementation process in British Columbia was associated with a significant increase in the use of regional RT in women with one to three positive nodes.
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Neoplasias de la Mama/radioterapia , Evaluación de Resultado en la Atención de Salud , Radioterapia Adyuvante/estadística & datos numéricos , Anciano , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Colombia Británica/epidemiología , Estudios de Cohortes , Femenino , Humanos , Metástasis Linfática , Mastectomía , Mastectomía Segmentaria , Persona de Mediana Edad , Estadificación de Neoplasias , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Urokinase plasminogen activator (uPA) expression in breast cancer is associated with relapse and a reduction in disease-specific survival. Thus, efforts are under way to identify uPA inhibitors. By screening a chemical library of >1000 compounds, 17-allyaminogeldanamycin (17AAG) was identified as a potent inhibitor of uPA by the National Cancer Institute and is now in Phase I clinical trials. At this time, it remains unclear how 17AAG blocks uPA; one possibility is through disruption of the insulin-like growth factor I receptor (IGF-IR) pathway. This would be consistent with studies from our laboratory showing that activation of IGF-IR results in the induction of uPA protein. In the study described herein, we observed that IGF-IR and uPA were highly expressed in 87 and 55% of breast cancer by screening tumor tissue microarrays representing 930 cases. A significant proportion (52.1% = 354 of 680 cases, P < 0.0001) of the patients had tumors expressing both proteins. uPA alone (P = 0.033) or in combination with IGF-IR (P = 0.0104) was indicative of decreased disease-specific survival. Next, we demonstrated that treating MDA-MB-231 cells with increasing concentrations of 17AAG resulted in IGF-IR degradation (IC(50) = 1.0 micro M) and blocked signal transduction through the Akt and mitogen-activated protein kinase pathways. Finally, we found that 17AAG had a robust inhibitory effect on the production of uPA mRNAand protein in the presence of IGF-I. Thus, our study raises the possibility that 17AAG could prove to be an effective therapeutic agent for a large number of breast cancer patients by inhibiting the IGF-IR and ultimately uPA.
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Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica/genética , Receptor IGF Tipo 1/genética , Rifabutina/análogos & derivados , Rifabutina/uso terapéutico , Activador de Plasminógeno de Tipo Uroquinasa/genética , Antineoplásicos/uso terapéutico , Secuencia de Bases , Benzoquinonas , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Cartilla de ADN , Femenino , Estudios de Seguimiento , Humanos , Lactamas Macrocíclicas , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , ARN Mensajero/genética , Análisis de Supervivencia , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
The BRCA2 gene is mutated in familial breast and ovarian cancer, and its product is implicated in DNA repair and transcriptional regulation. Here we identify a protein, EMSY, which binds BRCA2 within a region (exon 3) deleted in cancer. EMSY is capable of silencing the activation potential of BRCA2 exon 3, associates with chromatin regulators HP1beta and BS69, and localizes to sites of repair following DNA damage. EMSY maps to chromosome 11q13.5, a region known to be involved in breast and ovarian cancer. We show that the EMSY gene is amplified almost exclusively in sporadic breast cancer (13%) and higher-grade ovarian cancer (17%). In addition, EMSY amplification is associated with worse survival, particularly in node-negative breast cancer, suggesting that it may be of prognostic value. The remarkable clinical overlap between sporadic EMSY amplification and familial BRCA2 deletion implicates a BRCA2 pathway in sporadic breast and ovarian cancer.