RESUMEN
BACKGROUND: Four randomised controlled trials (RCTs) in postmenopausal women with advanced breast cancer (ABC) comparing aromatase inhibitors (AIs) versus the selective estrogen receptor modulator tamoxifen, each individually reported significantly longer progression-free survival (PFS) but none showed a significant difference in overall survival (OS). In these trials between 6.8% and 55% of tumours were hormone receptor (HR) status unknown or negative. This meta-analysis restricted the comparison to HR-positive (HR+) tumours. METHODS: Anonymised individual patient data were obtained from three RCTs, EORTC (exemestane versus tamoxifen), Study 0027 and Study 0030 (both anastrozole versus tamoxifen). For the remaining RCT (Femara Study PO25; letrozole versus tamoxifen), odds ratio (OR) or hazard ratio (HzR), with confidence intervals were obtained from the clinical study report, for patients with HR+ tumours, in addition to published data. In total, data were obtained from 2296 patients; 1560 (68%) had HR+ ABC. FINDINGS: The OR for clinical benefit rate was 1.56, in favour of AIs (p < 0.001). The duration of clinical benefit was not significantly increased by AIs (HzR 0·88; p = 0.08). For PFS the HzR (0.82) was in favour of AIs (p = 0·007). However, for OS the HzR (1.05) was not significantly different between AIs and tamoxifen (p = 0.42). INTERPRETATION: Although third generation AIs put significantly more patients into 'clinical benefit', their tumours were not controlled for significantly longer. Overall, while this resulted in a significantly greater PFS in favour of the AIs, this did not translate into improvement in OS.
Asunto(s)
Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Posmenopausia , Receptores de Estrógenos/análisis , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/uso terapéutico , Anciano , Inhibidores de la Aromatasa/efectos adversos , Neoplasias de la Mama/química , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Persona de Mediana Edad , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como Asunto , Moduladores Selectivos de los Receptores de Estrógeno/efectos adversos , Tamoxifeno/efectos adversos , Factores de TiempoRESUMEN
Endocrine therapy (ET) is recommended as first-line therapy for the majority of patients with hormone receptor-positive (HR+), human epidermal growth factor 2-negative advanced breast cancer (ABC); however, the efficacy of ET in patients with visceral metastases (VM) versus patients whose disease is limited to non-visceral metastases (non-VM) is debated. Meta-analyses including available data from randomised controlled trials of first- and second-line endocrine monotherapies for patients with HR+ ABC were performed to address this question. In one and two-stage meta-analyses, progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and duration of clinical benefit (DoCB) outcomes were analysed. In the first-line meta-analysis (seven trials; n = 1988) tamoxifen and fulvestrant significantly improved PFS, OS and CBR for patients with non-VM versus those whose disease included VM. The most substantial hazard ratios were observed for fulvestrant 500 mg; 0.56 (95% confidence interval [CI] 0.45-0.70) and 0.55 (95% CI 0.42-0.72) for PFS and OS, respectively. In the second-line meta-analysis (seven trials; n = 2324), all ET combined was more effective (in terms of PFS, OS and DoCB) for non-VM versus VM. In both meta-analyses, patients with non-liver VM had better clinical outcomes than patients with liver VM for all types of ET. Patients whose disease included non-VM sites had better clinical outcomes with endocrine monotherapy compared with patients whose disease included VM. These findings may facilitate better informed treatment decision-making.
RESUMEN
Adjuvant! Online (Adjuvant!) is a user-friendly, web-based tool that provides estimates of adjuvant therapy outcomes for individual patients. While reliable evidence underpins estimates for most patient cohorts, there is a paucity of data on the effect of adding chemotherapy to complete estrogen blockade for premenopausal women with estrogen-receptor positive breast cancer. International Breast Cancer Study Group (IBCSG) Trial 11-93 enrolled 174 premenopausal women with estrogen-receptor positive, node-positive breast cancer. Among these patients, 55% had one positive axillary lymph node and 97% had three or fewer positive nodes. Patients were randomized to receive ovarian function suppression plus 5 years of tamoxifen with or without anthracycline-based chemotherapy. Estimated hazard rates and corresponding 10-year relapse-free survival percentages obtained from Trial 11-93 data were compared with those predicted using Adjuvant!. The 10-year relapse-free survival percentages predicted from Adjuvant! were 64.4% (95% CI, 61.9-67.2%) for endocrine therapy alone and 74.9% (95% CI, 73.1-76.8%) for chemoendocrine therapy. By contrast, these estimates in Trial 11-93 were 76.4% (95% CI, 65.8-84.0%) for endocrine therapy alone and 74.9% (95% CI, 64.5-82.7%) for chemoendocrine therapy. The Adjuvant! estimate for the endocrine-alone control group is lower than that observed in Trial 11-93 (P = 0.03), while the estimates for the two chemoendocrine therapy groups are similar. Adjuvant! appears to underestimate the effectiveness of adjuvant endocrine therapy alone for premenopausal women with endocrine responsive breast cancer, thus overestimating the added benefit, if any, from chemotherapy for this patient population.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Programas Informáticos , Adulto , Quimioterapia Adyuvante , Moduladores de los Receptores de Estrógeno , Femenino , Humanos , Internet , Persona de Mediana Edad , Premenopausia , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Estrógenos/biosíntesis , Receptores de Estrógenos/genética , Factores de Riesgo , Tamoxifeno/administración & dosificación , Resultado del TratamientoRESUMEN
PURPOSE: Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. PATIENTS AND METHODS: Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment. RESULTS: A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation. CONCLUSION: Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.
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Androstadienos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Inhibidores de la Aromatasa/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Tamoxifeno/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Androstadienos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ensayos Clínicos Fase III como Asunto , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedades de los Genitales Femeninos/inducido químicamente , Humanos , Cooperación Internacional , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Enfermedades Musculoesqueléticas/inducido químicamente , Evaluación de Resultado en la Atención de Salud/métodos , Pronóstico , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Tamoxifeno/uso terapéutico , Sistema Vasomotor/efectos de los fármacos , Sistema Vasomotor/patologíaRESUMEN
PURPOSE: To examine the association of baseline body mass index (BMI) with the risk of recurrence or death in postmenopausal women with early-stage breast cancer receiving adjuvant tamoxifen or letrozole in the Breast International Group (BIG) 1-98 trial at 8.7 years of median follow-up. PATIENTS AND METHODS: This report analyzes 4,760 patients with breast cancer randomly assigned to 5 years of monotherapy with letrozole or tamoxifen in the BIG 1-98 trial with available information on BMI at randomization. Multivariable Cox modeling assessed the association of BMI with disease-free survival, overall survival (OS), breast cancer-free interval, and distant recurrence-free interval and tested for treatment-by-BMI interaction. Median follow-up was 8.7 years. RESULTS: Seventeen percent of patients have died. Obese patients (BMI ≥ 30 kg/m(2)) had slightly poorer OS (hazard ratio [HR] = 1.19; 95% CI, 0.99 to 1.44) than patients with normal BMI (< 25 kg/m(2)), whereas no trend in OS was observed in overweight (BMI 25 to < 30 kg/m(2)) versus normal-weight patients (HR = 1.02; 95% CI, 0.86 to 1.20). Treatment-by-BMI interactions were not statistically significant. The HRs for OS comparing obese versus normal BMI were HR = 1.22 (95% CI, 0.93 to 1.60) and HR = 1.18 (95% CI, 0.91 to 1.52) in the letrozole and tamoxifen groups, respectively. CONCLUSION: There was no evidence that the benefit of letrozole over tamoxifen differed according to patients' BMI.
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Antineoplásicos Hormonales/uso terapéutico , Índice de Masa Corporal , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Recurrencia Local de Neoplasia/etiología , Nitrilos/uso terapéutico , Obesidad/complicaciones , Tamoxifeno/uso terapéutico , Triazoles/uso terapéutico , Adulto , Anciano , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Moduladores de los Receptores de Estrógeno/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Letrozol , Persona de Mediana Edad , Oportunidad Relativa , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de Riesgo , Resultado del TratamientoRESUMEN
PURPOSE: This phase III randomized open-label clinical trial was designed to evaluate the efficacy and safety of the steroidal aromatase inactivator exemestane versus the antiestrogen tamoxifen as first-line treatment for metastatic breast cancer (MBC) in postmenopausal women. PATIENTS AND METHODS: The study was conducted at 81 centers and enrolled postmenopausal patients with measurable hormone-sensitive metastatic or locally advanced breast cancer. Prior adjuvant chemotherapy and/or tamoxifen were allowed. One previous chemotherapy regimen and no prior hormone therapy for advanced disease were permitted. Patients were randomly assigned to receive exemestane 25 mg or tamoxifen 20 mg orally once daily until disease progression or unacceptable toxicity occurred. RESULTS: A total of 371 patients enrolled at 79 sites (182 exemestane, 189 tamoxifen) were included in the analysis. Both treatments were generally well tolerated without major toxicity. Overall response rate was greater for exemestane than for tamoxifen treatment (46% v 31%; odds ratio = 1.85; 95% CI, 1.21 to 2.82; P = .005). Median progression-free survival (PFS) was longer with exemestane (9.9 months; 95% CI, 8.7 to 11.8 months) than with tamoxifen (5.8 months; 95% CI, 5.3 to 8.1 months). However, these early differences (Wilcoxon P = .028) did not translate to a longer-term benefit in PFS, the primary study end point (log-rank P = .121). There was also no difference in survival between both study arms. CONCLUSION: Exemestane is an effective and well-tolerated first-line hormonal treatment for postmenopausal women with MBC and offers significant early improvement in time to tumor progression when compared with tamoxifen.
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Androstadienos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Posmenopausia , Tamoxifeno/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias Óseas/secundario , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Antagonistas de Estrógenos/uso terapéutico , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Neoplasias de los Tejidos Blandos/secundario , Resultado del TratamientoRESUMEN
PURPOSE: To explore potential differences in efficacy, treatment completion, and adverse events (AEs) in elderly women receiving adjuvant tamoxifen or letrozole for five years in the Breast International Group (BIG) 1-98 trial. METHODS: This report includes the 4,922 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial. The median follow-up was 40.4 months. Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was used to examine the patterns of differences in disease-free survival and incidences of AEs according to age. In addition, three categoric age groups were defined: "younger postmenopausal" patients were younger than 65 years (n = 3,127), "older" patients were 65 to 74 years old (n = 1,500), and "elderly" patients were 75 years of age or older (n = 295). RESULTS: Efficacy results for subpopulations defined by age were similar to the overall trial results: Letrozole significantly improved disease-free survival (DFS), the primary end point, compared with tamoxifen. Elderly patients were less likely to complete trial treatment, but at rates that were similar in the two treatment groups. The incidence of bone fractures, observed more often in the letrozole group, did not differ by age. In elderly patients, letrozole had a significantly higher incidence of any grade 3 to 5 protocol-specified non-fracture AE compared with tamoxifen (P = .002), but differences were not significant for thromboembolic or cardiac AEs. CONCLUSION: Adjuvant treatment with letrozole had superior efficacy (DFS) compared with tamoxifen in all age groups. On the basis of a small number of patients older than 75 years (6%), age per se should not unduly affect the choice of adjuvant endocrine therapy.