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BACKGROUND: Adjuvant treatment in breast cancer patients especially with aromatase inhibitors (AIs) has adverse effects on bone metabolism resulting in an increased occurrence of fractures. In order to demonstrate this occurrence, long-term follow-up studies are necessary. From several national registries in Denmark, it is possible to link data from different sources and analyze this issue. METHODS: A study cohort of 68,842 breast cancer patients prospectively diagnosed and registered in the Danish Breast Cancer Cooperative Group's database during the period 1995-2012 formed the basis of the analysis. These data were matched with data on all types of fractures from the Danish National Patient Register and vital data from the Danish Civil Registration System. RESULTS: After data cleaning 66,502 patients were available for analysis and 16,360 of these had incurred 20,341 fractures with 13,182 patients having just one fracture. These fractures were distributed over 214 specific fracture sites. An extended multivariable Cox regression model revealed significant association between the occurrence of fractures and age, menopause, Charlson comorbidity index (CCI) and endocrine therapy such that late menopause and tamoxifen treatment were associated with a lower occurrence and AI treatment, age and CCI were associated with a higher occurrence of fractures. CONCLUSION: Before advising adjuvant therapy with AIs fragile patients with chronic diseases should receive special attention in order to reduce the incidence of fractures in this vulnerable group of patients.
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Neoplasias de la Mama/epidemiología , Fracturas Óseas/epidemiología , Factores de Edad , Anciano , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/terapia , Estudios de Cohortes , Comorbilidad , Dinamarca/epidemiología , Femenino , Humanos , Menopausia , Persona de Mediana Edad , Análisis Multivariante , Sistema de RegistrosRESUMEN
BACKGROUND: The Copenhagen Breast Cancer Trial (CBCT) randomly assigned patients with early breast cancer to two years of tamoxifen or placebo and we evaluated the effect over the following four decades. PATIENT AND METHODS: Between 1975 and 1978, 327 patients with primary breast cancer were randomly assigned to two years of daily placebo or tamoxifen. Survival statistics was collected from the Danish Civil Registration System. RESULTS: The five-year invasive breast cancer recurrence (BCR) rate was 43.2% in the placebo arm and 31.9% in the tamoxifen arm. Compared with the placebo arm the hazard ratio for a BCR event was 0.73 in the tamoxifen arm (p = .07). With an estimated median follow-up on overall survival of 40.9 years, 154 and 145 patients had died in the placebo and tamoxifen arm, respectively. After adjustment for baseline characteristics a significant reduction in mortality was obtained from tamoxifen (HR 0.79; p = .04). CONCLUSION: Two years of adjuvant tamoxifen resulted in a sustained reduction in mortality in pre- and postmenopausal high-risk breast cancer patients with long-term follow-up data.
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Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/uso terapéutico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adulto , Anciano , Neoplasias de la Mama/patología , Dinamarca/epidemiología , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Mastectomía , Persona de Mediana Edad , Radioterapia AdyuvanteRESUMEN
BACKGROUND: Since 40 years, Danish Breast Cancer Cooperative Group (DBCG) has provided comprehensive guidelines for diagnosis and treatment of breast cancer. This population-based analysis aimed to describe the plurality of modifications introduced over the past 10 years in the national Danish guidelines for the management of early breast cancer. By use of the clinical DBCG database we analyze the effectiveness of the implementation of guideline revisions in Denmark. METHODS: From the DBCG guidelines we extracted modifications introduced in 2007-2016 and selected examples regarding surgery, radiotherapy (RT) and systemic treatment. We assessed introduction of modifications from release on the DBCG webpage to change in clinical practice using the DBCG clinical database. RESULTS: Over a 10-year period data from 48,772 patients newly diagnosed with malignant breast tumors were entered into DBCG's clinical database and 42,197 of these patients were diagnosed with an invasive carcinoma following breast conserving surgery (BCS) or mastectomy. More than twenty modifications were introduced in the guidelines. Implementations, based on prospectively collected data, varied widely; exemplified with around one quarter of the patients not treated according to a specific guideline within one year from the introduction, to an almost immediate full implantation. CONCLUSIONS: Modifications of the DBCG guidelines were generally well implemented, but the time to full implementation varied from less than one year up to around five years. Our data is registry based and does not allow a closer analysis of the causes for delay in implementation of guideline modifications.
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Neoplasias de la Mama/terapia , Guías de Práctica Clínica como Asunto , Antineoplásicos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Dinamarca , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Escisión del Ganglio Linfático , Mastectomía Segmentaria , Radioterapia Adyuvante , Receptor ErbB-2/antagonistas & inhibidores , Sistema de RegistrosRESUMEN
Background Breast cancer mortality has declined from 1995 through 2012 which may be attributed to earlier diagnosis, changes in lifestyle risk factors, and improved treatments. To a large extent the relative contribution of these modalities are unknown. Mammography screening was introduced late in Denmark; in 1995 around 20% of the Danish female population aged 50-69 was covered by population-based screening, and this was in 2008 extended to the entire population. Breast conserving surgery gradually replaced mastectomy, and sentinel node biopsy was introduced. In the same period adjuvant treatment was extended considerable. Methods A population-based study of 68 842 breast cancer patients registered in the clinical database of the Danish Breast Cancer Cooperative Group in 1995-2012. Comprehensive data on prognostic factors, comorbidity and treatment together with complete follow-up for survival were used to evaluate improvements in mortality and standardized mortality rate in successive time periods. Results The results from this study demonstrated a significant improvement in prognosis in successive time periods covering 1995-2012. Apart from patients with a high Charlson Comorbidity Index (CCI) improvements were seen in all subgroups of patients. Prognostic factors were more favorable in the latest time period accordingly to the introduction of nationwide screening. In the study period adjuvant treatment was extended considerable. Conclusion The impact of screening was by nature of limited magnitude. The modified treatment strategies implemented by the use of nationwide guidelines seemed to have a major impact on the substantial survival improvements.
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Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Adyuvantes Inmunológicos/uso terapéutico , Adolescente , Adulto , Anciano , Neoplasias de la Mama/terapia , Comorbilidad , Dinamarca/epidemiología , Detección Precoz del Cáncer , Femenino , Humanos , Mamografía , Tamizaje Masivo , Mastectomía Segmentaria , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Omission of chemotherapy may affect mortality in postmenopausal high-risk women despite appropriate adjuvant endocrine therapy for estrogen receptor (ER) positive breast cancer. The aim of this study was to determine how all-cause mortality rate in these patients compares to that of the general female population. Furthermore, to identify a subset without excess mortality using clinical and pathological characteristics. PATIENTS AND METHODS: From the population-based database of the Danish Breast Cancer Cooperative Group we included 6529 postmenopausal patients with ER positive high-risk breast cancer who in 1996 through 2004 by nationwide guidelines were allocated to five years of tamoxifen, an aromatase inhibitor (AI) or both in sequence. Multivariate categorical and fractional polynomials (MFP) models were used to construct prognostic subsets by clinicopathologic characteristics. RESULTS: In a multivariate model excess mortality was inversely (p < 0.0001) associated with increasing age at surgery while recurrence-free survival (RFS) was not. Non-adherence to endocrine therapy was associated with excess mortality (p = 0.0008) while treatment with an AI was associated with a less pronounced mortality excess (p = 0.03). A prognostic standard mortality rate (SMR) index (PSI) was built using the regression coefficients obtained in the MFP model, and the same risk factors were used to construct a flowchart algorithm. Both allocated 75% to a group with increased all-cause mortality as compared to the general female population, but the SMR was significantly increased (SMR 1.38; 95% CI 1.16-1.65) in 462 patients who were allocated to low-risk group by the Flowchart algorithm and to a high-risk group by PSI. CONCLUSION: Only one quarter of postmenopausal ER positive breast cancer patients are free of excess mortality when omitting adjuvant chemotherapy. Patients should be informed about importance of adherence to adjuvant endocrine therapy and inclusion of an AI. A PSI may better guide recommendations regarding adjuvant chemotherapy.
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Algoritmos , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Cumplimiento de la Medicación , Anciano , Inhibidores de la Aromatasa/uso terapéutico , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Posmenopausia , Modelos de Riesgos Proporcionales , Receptores de Estrógenos/metabolismo , Tamoxifeno/uso terapéuticoRESUMEN
The estrogen receptor (ER) is the target of tamoxifen, but endocrine therapies do not benefit all patients with ER positive tumors. We therefore hypothesized that copy number changes in the ESR1 gene, encoding ER, confer resistance. Within a consecutive series of ER positive, postmenopausal patients allocated to 5 years tamoxifen, we identified 61 patients with recurrence less than 4 years and 48 patients without recurrence at least 7 years after initiation of adjuvant tamoxifen. Archival tissue containing primary tumor was collected from 97 patients (89%). Tumor samples were analyzed for ESR1 copy number changes using FISH with a probe covering the ESR1 gene at 6q25 and a reference probe covering the centromere of chromosome 6. The assay was validated in a material of 120 normal breast samples. FISH analysis for ESR1 was successful in 91 patients (94%). Amplification (ratio ESR1/CEN-6 ≥ 2.0) was observed in 11 of 50 (22%) patients with early recurrence, compared to two of 41 (5%) patients without recurrence. The difference is statistically significant (P = 0.033). In both groups, two patients with ESR1 deletion (ratio ESR1/CEN-6 < 0.8) were identified. ESR1 amplification was significantly associated with poor disease-free survival (P = 0.0054) and overall survival (P = 0.0004). This pilot study supports our hypothesis that ESR1 amplification is associated with a poorer outcome following adjuvant treatment with tamoxifen in ER positive early breast cancer. This study also revealed the existence of ESR1 deletions. The prognostic and predictive impact of ESR1 copy number changes needs further exploration in clinical trials.
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Antineoplásicos Hormonales/uso terapéutico , Resistencia a Antineoplásicos/genética , Receptor alfa de Estrógeno/genética , Amplificación de Genes/genética , Posmenopausia , Tamoxifeno/uso terapéutico , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Quimioterapia Adyuvante , Femenino , Eliminación de Gen , Orden Génico , Humanos , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Análisis de SupervivenciaRESUMEN
The DBCG89D trial randomized high-risk early breast cancer patients to adjuvant CMF (cyclophosphamide, methotrexate and fluorouracil) or CEF (cyclophosphamide, epirubicin and fluorouracil). Prosigna assays were performed by researchers with no access to clinical data. Time to distant recurrence (DR) was the primary endpoint, time to recurrence (TR) and overall survival (OS) secondary. Among the 980 Danish patients enrolled, Prosigna results were obtained in 686. Continuous ROR score was associated with DR for CMF (adjusted hazard ratio (HR) 1.20, 95% CI 1.09-1.33), and for CEF (HR 1.04, 95% CI 0.92-1.18), P interaction = 0.06. DR was significantly longer in CEF compared to CMF treated patients with Her2-enriched tumors (HR 0.58, 95% CI 0.38-0.86), but not in patients with luminal tumors. Heterogeneity of treatment effect was significant for TR and OS. In this prospective-retrospective analysis, patients with Her2-enriched breast cancer derived substantial benefit from anthracycline chemotherapy whereas anthracyclines are not an essential component of chemotherapy for patients with luminal subtypes. The benefit of CEF vs. CMF correlated with increasing ROR Score.
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BACKGROUND: New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved in the synthesis of aromatase, has been suggested as a surrogate marker for aromatase expression. METHODS: Primary tumor material was retrospectively collected from 88 patients who participated in a randomized clinical trial comparing the AI letrozole to the anti-estrogen tamoxifen for first-line treatment of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression. RESULTS: Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP. CONCLUSION: TMAs are not suitable for IHC analysis of in situ aromatase expression and we did not find COX-2 expression in carcinoma cells to be a surrogate marker for aromatase. In situ aromatase expression in tumor cells is associated with ER expression and may thus point towards good prognosis. Aromatase expression in cancer cells is not predictive of response to endocrine therapy, indicating that in situ estrogen synthesis may not be the major source of intratumoral estrogen. However, aromatase expression in combination with high PR expression may select letrozole treated patients with longer TTP. TRIAL REGISTRATION: Sub-study of trial P025 for advanced breast cancer.
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Aromatasa/biosíntesis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Nitrilos/uso terapéutico , Receptores de Estrógenos/biosíntesis , Tamoxifeno/uso terapéutico , Triazoles/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/enzimología , Carcinoma in Situ/tratamiento farmacológico , Carcinoma in Situ/enzimología , Carcinoma in Situ/metabolismo , Ciclooxigenasa 2/biosíntesis , Femenino , Humanos , Inmunohistoquímica , Letrozol , Receptores de Progesterona/biosíntesis , Estudios Retrospectivos , Análisis de Matrices TisularesRESUMEN
INTRODUCTION: The purpose of this study was to evaluate the association between response at recurrence to letrozole versus tamoxifen and the expression of estrogen regulated proteins individually and combined in an "ER activity profile" in primary tumor tissue. Our hypothesis is that letrozole may be more effective than tamoxifen for treatment of tumors with high intratumoral estrogen content, whereas tamoxifen may be more efficient for treatment of tumors with high levels of the estrogen receptor (ER) and low intratumoral estrogen content. MATERIALS AND METHODS: For this study, we produced tissue microarrays from formalin fixed paraffin embedded primary tumor material from a subgroup of patients (9.4%), who have participated in the international, randomized, phase III clinical trial PO25 comparing letrozole with tamoxifen in 907 patients with advanced breast cancer. The expression levels of ER, the progesterone receptor (PR), the anti-apoptotic protein Bcl-2 and the Insulin like Growth Factor Receptor I (IGF-IR) were determined by semi-quantitative immunohistochemistry. RESULTS: Response to letrozole and tamoxifen treatment, measured as time to progression (TTP), was independent of primary tumor expression level of ER, Bcl-2 and IGF-IR. However, high expression of PR as well as high expression of three different ER activity profiles; ER/PR/Bcl-2, ER/PR/IGF-IR and ER/PR/Bcl-2/IGF-IR identified letrozole treated patients with significantly longer TTP. The ER activity profile including ER, PR, Bcl-2 and IGF-IR showed a trend towards being a selection criterion for letrozole versus tamoxifen therapy. DISCUSSION: This small sub-study supports our hypothesis that letrozole is superior to tamoxifen primarily in patients expressing high levels of estrogen regulated proteins in the primary tumor tissue. Furthermore, it seems that the "ER activity profile" with high PR, IGF-IR and Bcl-2 is a promising selection criterion, regarding prediction of response to letrozole versus tamoxifen.
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Antineoplásicos Hormonales/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Nitrilos/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/uso terapéutico , Triazoles/uso terapéutico , Adulto , Anciano , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Letrozol , Análisis por Micromatrices , Persona de Mediana Edad , Selección de Paciente , Proyectos Piloto , Valor Predictivo de las Pruebas , Resultado del TratamientoRESUMEN
It is an open question if chemotherapy (CT) per se imposes adverse effects on salivary gland function. The aim of the present study was to investigate effects of CT on salivary function in breast cancer patients during and after adjuvant CT. Forty-five breast cancer patients, eligible for adjuvant CT with CEF or CMF (cyclophosphamide, epirubicin or methotrexate, 5-fluorouracil) were followed before, during, six months and one year after CT. Findings were compared to those in a control group of 31 breast cancer patients not receiving CT. Flow rates and compositions of unstimulated and stimulated whole saliva as well as stimulated parotid saliva (UWS, SWS and SPS) were measured. Feeling of oral dryness and saliva-related complaints were registered. UWS and SWS flow rates decreased during CT (p<0.001 and p<0.01). UWS remained lower six months after, but reached baseline level within one year. SPS flow rate was not significantly affected, suggesting that the decrease in whole saliva production is accounted for by decreased acinar saliva formation by the submandibular glands. Twenty patients (44%) suffered from hyposalivation (UWS < or = 0.1 ml/min and/or SWS < or = 0.5 ml/min) during CT. Xerostomia scores rose during CT and stayed elevated one year after treatment. CT also induced compositional changes by slightly increasing salivary sodium and chloride concentrations as well as decreasing inorganic phosphate concentrations in spite of lower or unchanged flow rates, implying that ductal modification mechanisms are affected. UWS and SWS total protein output and UWS secretory IgA output decreased in response to CT. Thus, the results suggest that acinar and ductal cell functions are affected by adjuvant CT. These adverse drug reactions are temporary, as salivary findings generally returned to baseline values within one year following treatment.
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Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Glándulas Salivales/efectos de los fármacos , Xerostomía/inducido químicamente , Adulto , Anciano , Neoplasias de la Mama/fisiopatología , Neoplasias de la Mama/radioterapia , Carcinoma Ductal de Mama/fisiopatología , Carcinoma Ductal de Mama/radioterapia , Estudios de Casos y Controles , Quimioterapia Adyuvante/efectos adversos , Distribución de Chi-Cuadrado , Electrólitos/análisis , Femenino , Humanos , Concentración de Iones de Hidrógeno , Inmunoglobulina A Secretora/análisis , Persona de Mediana Edad , Saliva/química , Glándulas Salivales/fisiopatología , Proteínas y Péptidos Salivales/análisis , Salivación/efectos de los fármacos , Tasa de Secreción , Xerostomía/fisiopatologíaRESUMEN
DBCG (Danish Breast Cancer Cooperative Group) constitutes a multidisciplinary organization established in 1975 by the Danish Surgical Society. The purpose involves first and foremost a nation-wide standardization of breast cancer treatment based on novel therapeutic principles, collaboration between experts handling diagnostic work-up, surgery, radiotherapy, medical oncology, and basic research, and, further, complete registration of relevant clinical data in a national data base attached to DBCG. Data are processed by the Secretariat personnel composed of statisticians, data managers, and data secretaries making current analyses of outcome results feasible. DBCG is run by the Executive Committee consisting of expert members appointed by their respective society. From 1978 the DBCG project gained widely accession from participating units, and since then nearly all newly diagnosed breast cancer incident cases are reported and registered in the national data base. Today, the data base includes approximately 80 000 incidents of primary breast cancer. Annually, the Secretariat receives roughly 1.5 million parameters to be entered into the data base. Over time DBCG has generated seven treatment programmes including in situ lesions and primary invasive breast cancer. Probands are subdivided into risk groups based on a given risk pattern and allocated to various treatment programmes accordingly. The scientific initiatives are conducted in the form of register- and cohort analysis or randomized trials in national or international protocolized settings. Yearly, about 4 000 new incident cases of primary invasive breast cancer and about 200 in situ lesions enter the national programmes. Further, about 600 women with hereditary disposition of breast cancer are registered and evaluated on a risk scale. The main achievements resulted in a reduction of relative risk of death amounting up to 20% and increased 5-year overall survival ascending from 60% to roughly 80%. This article is partly based on a Danish paper to be published in the Centenary Jubilee book of the Danish Surgical Society, 2008.
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Neoplasias de la Mama/historia , Neoplasias de la Mama/terapia , Oncología Médica/historia , Sociedades Médicas/historia , Aniversarios y Eventos Especiales , Dinamarca , Femenino , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Oncología Médica/organización & administración , Sociedades Médicas/organización & administraciónRESUMEN
UNLABELLED: A significant reduction in the risk of recurrence and death was achieved three decades ago with adjuvant chemotherapy in patients with operable breast. The major pivotal trials used oral cyclophosphamide (C) days 1-14 with intravenous methotrexate (M) and fluorouracil (F) on days 1 and 8, repeated every 28 days. The classical CMF has later been modified as concerns dose and schedule, without formal comparisons in randomised trials between the classical CMF and the modifications. MATERIAL AND METHODS: Classical CMF was used in the first adjuvant chemotherapy trial performed by the Danish Breast Cancer Cooperative Group (DBCG), and two succeeding randomised trials in premenopausal patients with node positive breast cancer used three-weekly or four-weekly intravenous CMF in one of the treatment arms. RESULTS: Between November 1977 and January 2001 these trials included 2 213 patients who in addition to surgery and radiotherapy received CMF. Ten-year disease-free survival (DFS) rates were 48% following classical CMF, 45% following four-weekly and 47% following three-weekly CMF. Major differences in patient characteristics were observed across these three cohorts, and a multivariate analysis was performed adjusting for the known prognostic factors. In the adjusted analysis a 30% increase in the risk of recurrence was observed for two the intravenous regimens as compared to classical CMF. As concerns survival a significant 40% increase in the risk of death was observed with the four-weekly regimen, while a similar risk of death was observed with the three-weekly intravenous. Classical CMF was associated with a higher risk of amenorrhoea, and this may at least in part explain an observed interaction between age and efficacy. DISCUSSION: This cross trial comparison suggests a detrimental effect in premenopausal patients with node positive breast cancer when shifting from classical CMF to intravenous regimens with lower dose-intensity. Caution is required in the interpretation of these results due to the non-experimental study design.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Metástasis Linfática , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Premenopausia , Tasa de SupervivenciaRESUMEN
INTRODUCTION: Since 30 years DBCG (Danish Breast Cancer Coperative Group) has maintained, on a nation-wide basis, a clinical database of diagnostic procedures, therapeutic interventions, and clinical outcome in patients with primary breast cancer. The present analysis was undertaken to evaluate the development of the prognosis since 1977, and to analyse factors potentially contributing to the change of the prognosis. MATERIAL AND METHODS: All cases of invasive breast cancer reported to DBCG during the period 1977-2006 were included in the present analysis. RESULTS: A total of close to 80 000 patients were registered in the DBCG Database. Since 1977 the prognosis has improved significantly, thus 5 year survival for the total population of patients with primary breast cancer has increased from 65 to 81%. DISCUSSION: According to the present analysis diagnosis at an earlier stage in the natural course of the disease and especially the development of more active systemic treatment modalities have contributed to the improved prognosis.
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Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/terapia , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Terapia Combinada , Dinamarca/epidemiología , Supervivencia sin Enfermedad , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Sistema de Registros , Factores de Riesgo , Resultado del TratamientoRESUMEN
From November 1951 to December 1957, 666 consecutive patients with untreated primary breast cancer admitted to the Radium Center in Copenhagen were randomised before their operability was evaluated into two groups, simple mastectomy with postoperative radiotherapy or extended radical mastectomy. Following physical examination 241 of the patients were excluded, primarily due to tumours deemed inoperable due to clinical criteria (n =107) and due to poor general condition (n =69). Twenty-five years results of disease-free free survival and fifty years results of survival are presented, showing no difference between the two groups. Patients with clinical stage I did significantly better than patients with stage II-III tumours. Patients with grade I tumours had a better survival than patients with grade II-III. The breast cancer associated mortality was lower in premenopausal patients compared to postmenopausal patients. An excess mortality due to breast cancer was evident up to 20-25 years following the primary diagnosis.
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Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Adulto , Anciano , Neoplasias de la Mama/patología , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Mastectomía Radical Extendida , Mastectomía Simple , Persona de Mediana Edad , Posmenopausia , Premenopausia , Tasa de SupervivenciaRESUMEN
The main objective of the present study aims at comparing the long-term efficacy of breast conserving surgery (BCS) vs. mastectomy (M) based on a randomized design. The Danish Breast Cancer Cooperative Group (DBCG) conducted the trial (DBCG-82TM) from January 1983 to March 1989 recruiting 1154 patients with invasive breast carcinoma. Follow-up time ended 1(st) May 2006 with a median follow-up time of 19.6 years (time span 17.1-23.3 years). Eligibility criteria included a one-sided, unifocal, primary operable breast carcinoma, patient age below 70 years, probability of satisfactory cosmetic outcome with BCS, and no evidence of disseminated disease. The patients accrued were grouped into three subsets: correctly randomized, suspicion of randomization error, and declining randomization. The main analyses focus on the subgroup of 793 correctly randomized patients representing 70% of the complete series. 10-year recurrence free survival (RFS) and 20-year overall survival (OS) based on intent to treat did not reveal significant differences in outcome between breast conserving surgery vs. mastectomy, p=0.95 and p=0.10, respectively. Including the complete series comprising 1133 eligible patients based on treatment in fact given similarly no significant difference between surgical options could be traced in outcome of 10-year RFS and 20-year OS, p=0.94 and p=0.24, respectively. The pattern of recurrences as a first event in breast conservation vs. mastectomy did not differ significantly irrespective of site, p=0.27. Looking into the type of local relapse, viz., new primaries vs. true recurrences, it appeared that new primaries were significantly associated to BCS, while true recurrences dominated among M treated patients (p<0.001). In conclusion, long-term data indicate that BCS in eligible patients proves as effective as mastectomy both regarding local tumour control, RFS and OS. Local failures as a first event consistent with new primaries are strongly associated with BCS, whereas true recurrence predominates after mastectomy.
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Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/cirugía , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/radioterapia , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/radioterapia , Quimioterapia Adyuvante , Femenino , Estudios de Seguimiento , Humanos , Mastectomía , Mastectomía Segmentaria , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Radioterapia Adyuvante , Tasa de SupervivenciaRESUMEN
BACKGROUND: Previous analyses of TOP2A and HER2 in the Danish Breast Cancer Coopererative Group (DBCG) trial 89D suggested that TOP2A amplifications and possible also deletions are predictive markers for the effect of adjuvant epirubicin in patients with primary breast cancer. We present an updated and extended statistical analysis, requested for IVD-labeling of TOP2A testing. MATERIAL AND METHODS: In the DBCG trial 89D 980 Danish patients were randomly assigned to nine cycles of intravenous CMF (cyclophosphamide, methotrexate, and fluorouracil) or CEF (cyclophosphamide, epirubicin, and fluorouracil). Archival tumor tissue was collected retrospectively from 806 of these patients in a prospectively designed, biological sub-study, and was successfully analyzed for TOP2A aberrations and HER2 status in 773 samples (96%). Recurrence-free survival (RFS) was the primary endpoint. RESULTS: TOP2A aberrations (amplifications and deletions) were significantly associated with shorter RFS (p<0.0001) and overall survival (OS) (p<0.0001). Deleted cases had worse prognosis than amplified cases. In a Cox proportional hazard model TOP2A was an independent prognostic marker for RFS and OS. Patients with amplifications had a 61% reduction in the risk of an event (p=0.002) and a 51% reduction in the risk of death (p=0.01) if allocated to CEF compared to 6% and 10% in TOP2A normal patients. A similar but non-significant trend (p=0.08) was shown in patients with TOP2A deletions. Clear statistical evidence of a differential benefit, favoring CEF among patients with TOP2A aberrations was found for RFS (p=0.02 for interaction) but not for OS (p=0.14 for interaction). CONCLUSION: In conclusion, this updated analysis of TOP2A aberrations in DBCG trial 89D suggests a differential benefit of adjuvant chemotherapy in patients with primary breast cancer, favoring treatment with epirubicin in patients with TOP2A amplifications, and perhaps deletions. Additional studies are needed to clarify the exact importance of TOP2A deletions on outcome, but deletions have proven to be associated with a very poor prognosis.
Asunto(s)
Antígenos de Neoplasias/genética , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , ADN-Topoisomerasas de Tipo II/genética , Proteínas de Unión al ADN/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Dosificación de Gen , Humanos , Hibridación Fluorescente in Situ , Metotrexato/administración & dosificación , Análisis Multivariante , Proteínas de Unión a Poli-ADP-Ribosa , Receptor ErbB-2/genética , Estudios RetrospectivosRESUMEN
Introduction. Since 30 years, DBCG (Danish Breast Cancer Cooperative Group) has maintained a clinical database allowing the conduct of quality control studies, of randomised trials, examination of the epidemiology of breast cancer and of prognostic and predictive factors. Material and methods. The original database included patients with invasive breast cancer, but has later been expanded to patients with in situ breast cancer and hereditary breast and ovarian cancer families. Results. The multidisciplinary cooperative group has provided successive treatment guidelines and 70% of the 77284 registered patients have been enrolled and received treatment according to these guidelines. The standard treatments and the randomised trials included in the DBCG programmes are all briefly described. Among high-risk patients 48% have participated in randomised trials, and the results of these trials have largely been implemented in the next generation of treatment guidelines. Records within the clinical database of archival tumour tissue have established a basis for translational research and epidemiologic research has been enabled through linkage to other healthcare registries. Discussion. The joint conception of the multidisciplinary breast cancer group and a clinical database has provided improvements in the management of breast cancer patients and has enabled recruitment of patients onto randomised trials.
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Neoplasias de la Mama/clasificación , Neoplasias de la Mama/terapia , Bases de Datos Factuales , Oncología Médica/métodos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma in Situ/genética , Carcinoma in Situ/patología , Carcinoma in Situ/terapia , Terapia Combinada , Femenino , Predicción , Humanos , Oncología Médica/normas , Oncología Médica/tendencias , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Sistema de Registros , Factores de RiesgoRESUMEN
INTRODUCTION: A cohort of premenopausal patients with primary hormone receptor positive breast cancer was prospectively identified to be eligible for the DBCG 89B trial. We perform a long-term follow-up and evaluate the external validity of the trial. MATERIAL AND METHODS: Following registration in a population-based registry, patients were invited to be randomized to ovarian ablation (OA) versus nine courses of three-weekly cyclophosphamide, methotrexate and 5-fluorouracil (CMF). The same procedures were used in all patients, including report forms, central review, querying, and analysis of data. Multivariate analysis was used to adjust for differences in base-line characteristics. RESULTS: Participation in the randomization varied according to center and time period. One thousand six hundred and twenty eight eligible patients were registered and 525 randomized in the DBCG 89B trial. Median estimated follow-up was 9.5 years for disease-free survival and 12.1 years for overall survival. Non-enrolled patients had a disease-free and overall survival similar to randomized patients. Within 5 years of surgery, results were similar following OA and CMF, but disease-free survival was significant inferior with OA more than five years after surgery, adjusted hazard ratio 1.38 (95% CI 1.03 to 1.85; p=0.03). This convened ten years after surgery to an inferior survival with OA, and the adjusted hazard ratio was 2.37 (95% CI 1.43 to 3.91; p<0.01). DISCUSSION: This prospective cohort study indicates that eligible patients not participating in the DBCG 89B trial had a similar disease-free and overall survival as participants. Survival was similar after OA and CMF in the first ten years, but became inferior in the OA group 10 or more years after surgery.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/terapia , Ovario/fisiología , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Estudios de Seguimiento , Humanos , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Ovariectomía , Ovario/efectos de la radiación , Ovario/cirugía , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE AND PATIENTS: During the period from January 1990 to January 1996 a total of 953 patients with lymph node negative primary breast cancer were randomised to oral pamidronate (n=460) 150 mg twice daily for 4 years or no adjuvant pamidronate (n=493) in order to investigate whether oral pamidronate can prevent the occurrence of bone metastases and fractures. The patients received adjuvant chemotherapy, loco-regional radiation therapy, but no endocrine treatment. RESULTS: During the follow-up period the number of patients with pure bone metastases was 35 in the control group and 31 in the pamidronate group. The number of patients with a combination of bone and other distant metastases were 22 in the control group and 20 in the pamidronate group. The hazard rate ratio for recurrence in bone in the pamidronate group compared to the control group was 1.03 (95% confidence interval 0.75-1.40) and p=0.86. No effect was observed on overall survival. In a small subgroup of 27 patients from the study, 12 of whom were treated with pamidronate a significant bone preserving effect was observed on bone mineral density in the lumbar spine, but not in the proximal femur. CONCLUSION: The results from the trial do not support a beneficial effect of oral pamidronate on the occurrence of bone metastases or fractures in patients with primary breast cancer receiving adjuvant chemotherapy.