RESUMEN
We hypothesized that exemestane (EXE) would reduce mammographic breast density and have unique effects on biomarkers of bone and lipid metabolism. Healthy postmenopausal women were randomized to EXE (25 mg daily) or placebo (PLAC) for 12 months and followed for a total of 24 months. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms and secondary endpoints were changes in serum lipid levels, bone biomarkers, and bone mineral density (BMD). Ninety-eight women were randomized (49 to EXE; 49 to PLAC) and 65 had PD data at baseline and 12 months. Among women treated with EXE, PD was not significantly changed from baseline at 6, 12, or 24 months and was not different from PLAC. EXE was associated with significant percentage increase from baseline in N-telopeptide at 12 months compared with PLAC. No differences in percent change from baseline in BMD (lumbar spine and femoral neck) were observed between EXE and PLAC at either 12 or 24 months. Patients on EXE had a significantly larger percent decrease in total cholesterol than in the PLAC arm at 6 months and in HDL cholesterol at 3, 6, and 12 months. No significant differences in percent change in LDL or triglycerides were noted at any time point between the two treatment arms. EXE administered for 1 year to healthy postmenopausal women did not result in significant changes in mammographic density. A reversible increase in the bone resorption marker N-telopeptide without significant change in bone specific alkaline phosphatase or BMD during the 12 months treatment period and 1 year later was noted. Changes in lipid parameters on this trial were modest and reversible.
Asunto(s)
Androstadienos/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Densidad Ósea/efectos de los fármacos , Huesos/metabolismo , Mama/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Posmenopausia/metabolismo , Fosfatasa Alcalina/sangre , Neoplasias de la Mama/prevención & control , Colágeno Tipo I/orina , Método Doble Ciego , Femenino , Humanos , Mamografía , Persona de Mediana Edad , Péptidos/orinaRESUMEN
The third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole have largely replaced tamoxifen as the preferred treatment for hormone receptor - positive breast cancer in postmenopausal women. Approximately 185,000 new cases of invasive breast cancer are diagnosed yearly, and at least half of these women are both postmenopausal and eligible for adjuvant therapy with AIs. In addition, AIs are currently being tested as primary prevention therapy in large randomised trials involving tens of thousands of women at increased risk for breast cancer. Given the volume of use, internists will increasingly see postmenopausal women who are taking or considering treatment with AIs. Physicians need to be able to: (i) briefly discuss the pros and cons of using a selective estrogen receptor modulator such as tamoxifen or raloxifene vs. an AI for risk reduction and (ii) recognise and manage AI-associated adverse events. The primary purpose of this review is to help internists with these two tasks.
Asunto(s)
Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Anastrozol , Androstadienos/uso terapéutico , Neoplasias de la Mama/prevención & control , Enfermedades Cardiovasculares/inducido químicamente , Quimioterapia Adyuvante , Resistencia a Medicamentos , Femenino , Humanos , Letrozol , Enfermedades Musculoesqueléticas/inducido químicamente , Nitrilos/uso terapéutico , Posmenopausia , Premenopausia , Tamoxifeno/uso terapéutico , Tromboembolia/inducido químicamente , Triazoles/uso terapéuticoRESUMEN
AIMS: Immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) are both commonly used assays for evaluation of HER-2/neu status in breast cancer. However, there is still no consensus on which method is most predictive of patient response to Herceptin. Recently, the automated cellular imaging system (ACIS) has been shown to improve the accuracy and reproducibility in scoring IHC. Our aim was to compare the results of HER-2/neu expression and gene amplification in the same patients by IHC using the ACIS system and by FISH. METHODS AND RESULTS: Two hundred and forty-seven breast cancer cases were studied. The concordance rate between IHC-ACIS (> or = 2.2) and FISH (> or = 2.0) was 94%. Fifteen patients were discordant; three had borderline FISH values and three had borderline IHC values. The other nine discordant cases consisted of five IHC-ACIS+, FISH- and six IHC-ACIS-, FISH+. HER-2/neu overexpression was more common in tumours that were high-grade, aneuploid, progesterone receptor and bcl-2 negative, with MIB-1 > 10%. CONCLUSION: HER-2/neu assessment by the ACIS is reliable, rapid and inexpensive, and correlates highly with results obtained by FISH.
Asunto(s)
Neoplasias de la Mama/química , Procesamiento de Imagen Asistido por Computador/métodos , Inmunohistoquímica/métodos , Hibridación Fluorescente in Situ , Receptor ErbB-2/análisis , Receptor ErbB-2/genética , Adenocarcinoma/química , Adenocarcinoma/genética , Adenocarcinoma Mucinoso/química , Adenocarcinoma Mucinoso/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/química , Carcinoma Lobular/genética , Carcinoma Medular/química , Carcinoma Medular/genética , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Receptor ErbB-2/biosíntesisRESUMEN
Breast tissue and duct fluid provide a rich source of biomarkers to both aid in the assessment of short-term risk of developing breast cancer and predict and assess responses to prevention interventions. There are three methods currently being utilized to sample breast tissue in asymptomatic women for risk assessment: nipple-aspirate fluid (NAF), random periareolar fine-needle aspiration (RPFNA) and ductal lavage. Prospective single-institution trials have shown that the presence of atypical cells in NAF fluid or RPFNA specimens is associated with an increased risk of breast cancer. Furthermore, RPFNA-detected atypia has been observed to further stratify risk based on the commonly used Gail risk-assessment model. A prospective trial evaluating risk prediction on the basis of atypical cells in ductal-lavage fluid is ongoing. The ability of other established non-genetic biomarkers (mammographic breast density; serum levels of bioavailable estradiol, testosterone, insulin-like growth factor-1 and its insulin like growth factor binding protein-3) to stratify risk based on the Gail model is as yet incompletely defined. Modulation of breast intra-epithelial neoplasia (i.e. hyperplasia with or without atypia) with or without associated breast-tissue molecular markers, such as proliferation, is currently being used to evaluate response in Phase II chemoprevention trials. RPFNA has been the method most frequently used for Phase II studies of 6-12 months duration. However, ductal lavage, RPFNA and random and directed core needle biopsies are all being utilized in ongoing multi-institutional Phase II studies. The strengths and weaknesses of each method are reviewed.
Asunto(s)
Biomarcadores de Tumor/análisis , Biopsia/métodos , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/prevención & control , Mama/patología , Ensayos Clínicos como Asunto , Femenino , Humanos , Medición de RiesgoRESUMEN
A large number of new potential chemoprevention agents are available that target molecular abnormalities found in estrogen receptor (ER)-negative and/or ER-positive precancerous breast tissue and have side effect profiles that differ from tamoxifen. Classes of agents currently undergoing evaluation in clinical prevention trials or those for which testing is planned in the near future include new selective ER modulators, aromatase inactivators/inhibitors, gonadotrophin-releasing hormone agonists, monoterpenes, isoflavones, retinoids, rexinoids, vitamin D derivatives, and inhibitors of tyrosine kinase, cyclooxygenase-2, and polyamine synthesis. New clinical testing models will use morphological and molecular biomarkers to select candidates at highest short-term risk, to predict the response to a particular class of agent, and to assess the response in phase II prevention trials. If validated, morphological and molecular markers could eventually replace cancer incidence as an indicator of efficacy in future phase III trials.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Inhibidores de la Aromatasa , Ensayos Clínicos como Asunto , Femenino , Humanos , Clorhidrato de Raloxifeno/uso terapéutico , Retinoides , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/uso terapéuticoRESUMEN
The demonstration by the National Surgical Adjuvant Breast Project (NSABP) that 5 years of tamoxifen therapy is associated with an approximate 50% reduction in breast cancer incidence in high-risk women was a milestone in breast cancer prevention. Because tamoxifen is associated with increased risk of side-effects such as hot flashes, menstrual abnormalities, uterine cancer, and thromboembolic phenomena, its use will not be advisable or acceptable for all high-risk women. Women over 50 years of age appear to be at highest risk for serious adverse events, such as uterine cancer and thromboembolic phenomena. Individuals in whom tamoxifen-associated breast cancer risk reduction appears to outweigh risk of serious side-effects include women with prior in situ or estrogen receptor (ER)-positive invasive cancer, atypical hyperplasia, and/or women ages 35-49 with a calculated Gail 5-year risk of > or =1.7%, hysterectomized women aged 50 and older with a 5-year Gail risk of > or =2.5%, and nonhysterectomized women aged 50 and older with a 5-year Gail risk of >5.0%. It is not yet clear whether tamoxifen can reduce breast cancer incidence in women with BRCA1 and BRCA2 mutations, although preliminary evidence favors benefit for at least those with a BRCA2 mutation. Raloxifene is a selective ER modulator with less uterine estrogen agonist activity than tamoxifen, and it is hoped that it will result in fewer uterine cancers but will be equally efficacious in reducing the risk of breast cancer. The NSABP is currently conducting a randomized study of tamoxifen versus raloxifene in high-risk postmenopausal women. Approximately one third of invasive cancers are ER negative. Tamoxifen does not reduce the incidence of ER-negative cancers, nor does it appear to be effective in preventing the appearance of one third of ER-positive cancers. Priorities in prevention research are to develop (a) biomarkers to refine short-term risk assessments based on epidemiologic models, (b) biomarkers predictive of response to specific classes of preventive agents, (c) drugs with fewer side-effects and/or effective in ER-negative or ER-positive tamoxifen-resistant precancerous disease, and (d) efficient clinical trial models to assess new agent efficacy. Breast intraepithelial neoplasia (IEN) may be sampled by minimally invasive techniques and is an attractive short-term risk biomarker. Molecular abnormalities observed in IEN may be used to select potential agents for testing/therapy, and modulation of these abnormalities may be used in phase I trials to select appropriate doses and in phase II trials to assess response. Breast density volume and certain serum markers such as insulin-like growth factor-1 are also being studied as potential risk and response biomarkers. Reversal or prevention of advanced IEN as well as modulation of other risk biomarkers in randomized phase II and phase III trials is being evaluated as a means of more efficiently evaluating prevention drugs in the future. A number of agents are being developed that target molecular abnormalities in IEN, have fewer or different side effects than tamoxifen, and may be effective in ER-negative or tamoxifen-resistant disease.
Asunto(s)
Neoplasias de la Mama/prevención & control , Carcinoma in Situ/prevención & control , Ensayos Clínicos como Asunto/tendencias , Recurrencia Local de Neoplasia/prevención & control , Femenino , Humanos , Clorhidrato de Raloxifeno/uso terapéutico , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/uso terapéuticoRESUMEN
Although tamoxifen appears to markedly reduce breast cancer risk in women with a prior diagnosis of atypical hyperplasia or in situ carcinoma, it is not clear what other groups of women receive substantial benefit. Major breast chemoprevention priorities are to (1) develop new agents that (a) have fewer side effects, (b) are effective in ER--as well as tamoxifen-resistant precancerous tissue, and (c) are compatible with hormone therapy; and (2) develop efficient clinical strategies including prognostic and predictive morphologic and molecular biomarkers. Breast tissue may be repeatedly sampled for evidence of intraepithelial neoplasia by fine needle aspiration, ductal lavage, or needle biopsy to select candidates at highest short-term risk as well as to monitor response in small proof of principle studies prior to a large cancer incidence trial. Molecular marker expression may also be used to select a cohort most likely to respond to a particular agent. A large number of new agents are attractive as potential prevention agents and some are already in clinical prevention testing. Compounds which should be effective in ER + precancerous tissue but may have a better side-effect profile include new selective estrogen receptor modulators which lack uterine estrogen agonist activity, isoflavones, aromatase inactivators/inhibitors for postmenopausal women, and gonadotropin-releasing hormone regimens for premenopausal women. Retinoids, rexinoids, and deltanoids may be efficacious in ER+ tissue resistant to tamoxifen. Agents which should theoretically have activity in ER- or ER+ precancerous tissue include polyamine synthesis inhibitors, tyrosine kinase inhibitors, combined demethylating agents and histone deacetylase inhibitors, as well as metalloprotease and angiogenesis inhibitors. Sample Phase I and Phase II clinical trial designs are reviewed using modulation of molecular markers and breast intraepithelial neoplasia as the major endpoints.
Asunto(s)
Anticarcinógenos/uso terapéutico , Neoplasias de la Mama/prevención & control , Aneuploidia , Inhibidores de la Angiogénesis/uso terapéutico , Apoptosis/efectos de los fármacos , Inhibidores de la Aromatasa , Neoplasias de la Mama/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma in Situ/tratamiento farmacológico , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patología , Ensayos Clínicos Fase II como Asunto , Inhibidores de la Ciclooxigenasa/uso terapéutico , Progresión de la Enfermedad , Eflornitina/uso terapéutico , Determinación de Punto Final , Inhibidores Enzimáticos/uso terapéutico , Estrógenos , Femenino , Fenretinida/uso terapéutico , Hormona Liberadora de Gonadotropina/agonistas , Humanos , Hiperplasia , Isoflavonas/uso terapéutico , Proteínas de Neoplasias/análisis , Neoplasias Hormono-Dependientes/prevención & control , Fenotipo , Piperidinas/uso terapéutico , Poliaminas/antagonistas & inhibidores , Lesiones Precancerosas/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptores de Estrógenos/análisis , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/efectos adversos , Tamoxifeno/uso terapéutico , Tiofenos/uso terapéutico , Neoplasias Uterinas/inducido químicamenteRESUMEN
BACKGROUND: : Biomarkers are needed to refine short-term breast cancer risk estimates from epidemiologic models and to measure response to prevention interventions. The purpose of our study was to determine whether the cytologic appearance of epithelial cells obtained from breast random periareolar fine-needle aspirates or molecular marker expression in these cells was associated with later breast cancer development. METHODS: : Four hundred eighty women who were eligible on the basis of a family history of breast cancer, prior precancerous biopsy, and/or prior invasive cancer were enrolled in a single-institution, prospective trial. Their risk of breast cancer according to the Gail model was calculated, and random periareolar fine-needle aspiration was performed at study entry. Cells were characterized morphologically and analyzed for DNA aneuploidy by image analysis and for the expression of epidermal growth factor receptor, estrogen receptor, p53 protein, and HER2/NEU protein by immunocytochemistry. All statistical tests are two-sided. RESULTS: : At a median follow-up time of 45 months after initial aspiration, 20 women have developed breast cancer (invasive disease in 13 and ductal carcinoma in situ in seven). With the use of multiple logistic regression and Cox proportional hazards analysis, subsequent cancer was predicted by evidence of hyperplasia with atypia in the initial fine-needle aspirate and a 10-year Gail projected probability of developing breast cancer. Although expression of epidermal growth factor receptor, estrogen receptor, p53, and HER2/NEU was statistically significantly associated with hyperplasia with atypia, it did not predict the development of breast cancer in multivariable analysis. CONCLUSION: : Cytomorphology from breast random periareolar fine-needle aspirates can be used with the Gail risk model to identify a cohort of women at very high short-term risk for developing breast cancer. We recommend that cytomorphology be studied for use as a potential surrogate end point in prevention trials.
Asunto(s)
Biomarcadores de Tumor/análisis , Biopsia con Aguja/métodos , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/prevención & control , Mama/patología , Tamizaje Masivo/métodos , Adulto , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Transformación Celular Neoplásica/química , Transformación Celular Neoplásica/patología , Femenino , Humanos , Hiperplasia/patología , Modelos Logísticos , Persona de Mediana Edad , Modelos Biológicos , Modelos Estadísticos , Pezones/química , Pezones/patología , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Riesgo , Factores de TiempoRESUMEN
It is unknown what proportion of women at high risk for breast cancer, entering phase II chemoprevention trials, have BRCA1/2 alterations, and whether their initial biomarker patterns or response to preventive interventions will differ between carriers and non-carriers. As part of a 6-month phase II chemoprevention trial of diflouromethlyornithine (DFMO), high-risk subjects (family history, prior precancerous breast disease or prior breast cancer), who had random peri-areolar fine needle evidence of epithelial hyperplasia with or without atypia, were offered genetic counselling and testing at the completion of their study participation. 97% of the 119 women eligible for testing underwent BRCA1/2 gene sequencing, 3 declined. 26 (22%) of the 116 women had an alteration in BRCA1/2. Known deleterious mutations were present in 3 (3%), uncertain significance mutations in 19 (16%), and probable polymorphisms in 6 (5%). There does not appear to be a difference in initial biomarker distribution between participants with and without germ line alterations.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/genética , Eflornitina/uso terapéutico , Genes BRCA1/genética , Mutación de Línea Germinal/genética , Proteínas de Neoplasias/genética , Factores de Transcripción/genética , Adulto , Proteína BRCA2 , Neoplasias de la Mama/prevención & control , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Linaje , Factores de RiesgoRESUMEN
Selection of surrogate endpoint biomarkers (SEBs) and appropriate study design are two of the main challenges in evaluating potential chemopreventive agents. In a prospective random fine-needle aspiration (FNA) study of women at high risk of development of breast cancer, we previously demonstrated that cytologic evidence of epithelial hyperplasia with or without atypia, as well as abnormalities of several cellular biomarkers (DNA ploidy; immunocytochemical expression of p53, EGFR, ER, and/or Her-2/neu), were more prevalent in high-risk women than in low-risk controls. We also demonstrated that the subsequent development of breast cancer was best predicted by an initial presentation of hyperplasia with atypia, as well as by multiple biomarker abnormalities. These findings indicate that FNA cytology and biomarkers can be used to identify women who are appropriate subjects for chemoprevention trials, and can then be used as surrogate endpoint biomarkers to monitor efficacy of potential agents. An example of this use in an ongoing single-agent phase II trial is provided. Several options for study design of possible multi-agent breast cancer chemoprevention trials are discussed, depending upon the existing preclinical and clinical data, the questions being asked, and the number of eligible subjects available.
Asunto(s)
Biopsia con Aguja/métodos , Neoplasias de la Mama/prevención & control , Mama/patología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/análisis , Mama/metabolismo , Neoplasias de la Mama/metabolismo , Protocolos Clínicos , Ensayos Clínicos como Asunto , Eflornitina/uso terapéutico , Receptores ErbB/metabolismo , Femenino , Humanos , Hiperplasia , Placebos , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Several models are being explored for use in the phase I and phase II evaluation of breast cancer chemoprevention agents. The short-term DCIS/small invasive cancer model is probably best used in late phase I trials in conjunction with agents likely to have activity in the progression phase of neoplastic development in addition to activity in earlier phases. The core biopsy or FNA hyperplasia models may be best used with drugs that are likely to have activity primarily in the promotion phase of neoplastic development and that are suitable for longer duration trials lasting several months to years. Morphology currently is the key surrogate endpoint biomarker for assessing efficacy in phase II trials. Other biomarkers that may undergo modulation will have to be validated, in that modulation will have to be shown to be directly related to decreased cancer risk in subsequent phase III trials. Only then can they be considered as validated surrogate endpoint biomarkers and used as stand-alone efficacy markers in phase II trials. Despite accrual challenges and technologic hurdles, interest in phase I and phase II chemoprevention trials is high.
Asunto(s)
Neoplasias de la Mama/prevención & control , Quimioprevención , Ensayos Clínicos Fase I como Asunto/métodos , Ensayos Clínicos Fase II como Asunto/métodos , Femenino , HumanosRESUMEN
In a prospective pilot study, we performed breast fine needle aspirations (FNAs) on 224 high-risk and 30 low-risk women and analyzed these aspirates for cytologic changes and biomarker abnormalities of aneuploidy and overexpressed estrogen receptor (ER), epidermal growth factor receptor (EGFR), p53 and HER-2/neu. High-risk women had a first-degree relative with breast cancer (74%), prior biopsy indicating premalignant breast disease (25%), a history of breast cancer (13%), or some multiple of these risk factors (12%). Median ages of the high- and low-risk groups were 44 and 42, respectively. Seventy percent of high-risk and 17% of low-risk women had cytologic evidence of hyperplasia with or without atypia (P < .0001). Aneuploidy and overexpression of EGFR and p53 occurred in 27, 37, and 29% of high-risk subjects but only 0, 3, and 3% of low-risk subjects (P < .0023). Overexpression of ER and HER-2/neu occurred in 7 and 20% of high-risk women but in none of the low-risk subjects. Biomarker abnormalities were more frequent with increasing cytologic abnormality. Restricting the analysis to those 3 biomarkers most frequently overexpressed in the high-risk group (ploidy, EGFR, p53), 13% of high-risk women with normal cytology, 19% of high-risk women with epithelial hyperplasia, and 49% of high-risk women with hyperplasia with atypia had abnormalities of 2 or more of these 3 biomarkers (P = .00004). At a median follow-up of 32 months, four women have been diagnosed with invasive cancer and two with ductal carcinoma in situ (DCIS). Later detection of these neoplastic conditions was associated (P < or = .016) by univariate analysis with prior FNA evidence of hyperplasia with atypia; overexpression of p53 and EGFR; the modified Gail risk of breast cancer development at 10 years; and multiple biomarker abnormalities. By multivariate analysis, later detection of cancer was primarily predicted by the number of biomarker abnormalities in the 3-test battery (P = .0005) and secondarily by the Gail risk at 10 years (P = .0049). In turn, hyperplasia with atypia was associated with multiple biomarker abnormalities, particularly p53 and EGFR overexpression. Thus, hyperplasia with atypia and cytologic markers in breast FNAs have promise as risk predictors and as surrogate endpoint biomarkers for breast cancer chemoprevention trials.
Asunto(s)
Neoplasias de la Mama/patología , Mama/patología , Adulto , Anciano , Biomarcadores de Tumor , Biopsia con Aguja , Neoplasias de la Mama/prevención & control , Quimioprevención , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Medición de RiesgoRESUMEN
In a prospective pilot study, we performed breast fine needle aspirations (FNAs) on 213 high-risk and 30 low-risk women and analyzed these aspirates for cytologic changes and biomarker abnormalities of aneuploidy and overexpressed estrogen receptor (ER), epidermal growth factor receptor (EGFR), p53 and HER-2/neu. High-risk women were those with a first degree relative with breast cancer (73%), prior biopsy indicating premalignant breast disease (26%), a history of breast cancer (13%), or some multiple of these risk factors (11%). Median ages of the high-risk and low-risk groups were 44 and 42, respectively. Sixty-three percent of the high-risk and 73% of the low-risk group were premenopausal. Sixty-eight percent of the high-risk and 17% of low-risk women had cytologic evidence of hyperplasia with or without atypia (P < .0001). Aneuploidy and overexpression of EGFR and p53 occurred in 25%, 36%, and 28% of high-risk subjects but in less than 4% of low-risk subjects (P < .0002). Overexpression of ER and HER-2/neu occurred in 8% and 19%, respectively of high-risk women; nc low-risk women had these abnormalities. Sixty-eight percent of high-risk women and 7% of low-risk women had abnormalities of one or more of these biomarkers exclusive of cytology. Thirty-one percent of high-risk women, but no low-risk women had abnormalities of two or more biomarkers (P = .0004). Biomarker abnormalities were more frequent with increasing cytologic abnormality. Eighteen percent of women with normal cytology, 29% of women with epithelial hyperplasia and 60% of women with hyperplasia with atypia had abnormalities of two or more biomarkers (P = .048 and < .0001, respectively). Restricting the analysis to those three biomarkers most frequently overexpressed in the high-risk group (ploidy, EGFR, p53), 13% of high-risk women with normal cytology, 20% of high-risk women with epithelial hyperplasia and 51% of high-risk women with atypical hyperplasia had abnormalities of 2 or more of these 3 biomarkers. At a median follow up of two years, 8 of 213 women have been diagnosed with in situ (n = 5) or invasive (n = 3) cancer. Later detection of neoplasia was associated with prior FNA evidence of atypical hyperplasia (P < .0001) and multiple biomarker abnormalities in the 5 test battery (P = .006) by univariate analysis. By multivariate analysis, development and/or detection of cancer was primarily predicted by atypical hyperplasia (P = .0047) and secondarily by multiple biomarker abnormalities (P = 0.021). Atypical hyperplasia, EGFR, and p53 in breast FNAs have promise as risk markers and as surrogate endpoint biomarkers for breast cancer chemoprevention trials.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/prevención & control , Adulto , Aneuploidia , Biopsia con Aguja , Mama/química , Mama/patología , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Quimioprevención , Estudios de Cohortes , Receptores ErbB/análisis , Femenino , Humanos , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Receptor ErbB-2/análisis , Receptores de Estrógenos/análisis , Factores de Riesgo , Proteína p53 Supresora de Tumor/análisisRESUMEN
One theoretical method of increasing chemotherapeutic efficacy in breast cancer is to temporarily increase the number of tumor cells in cycle through hormonal recruitment prior to initiation of chemotherapy. In an effort to determine when and if this could be reliably accomplished, 50 women with locally advanced and/or metastatic breast cancer with known estrogen receptor (ER) status were entered into a serial breast biopsy study designed to measure increases in S-phase fraction (SPF) and proliferative index (PI; S + G2 + M) following administration of a high physiological dose of estrogen via estradiol vaginal suppositories prior to chemotherapy. Blood levels of estradiol were maintained in a range (0.5-5 nM) known to increase SPF in vitro. Compliance with suppository administration was monitored by serial blood sampling. Tumors were sampled at 0, 24, 48, 72, and/or 96 h. Thirty-one ER-positive and 9 ER-negative women had evaluable baseline biopsies and at least 1 subsequent biopsy. An increase was seen for SPF in 20 (69%) and for PI in 23 (79%) of 29 ER-positive patients at 48 h after estrogen initiation (95% confidence intervals, 49-85% for SPF and 60-92% for PI); similar increases were seen at 72 h. Median baseline SPF and PI values in ER-positive patients for whom increases were noted at 48 h were 6.2 and 8.5%, respectively. The median relative increases in these patients were 170 and 100%, respectively, at 48 h. The increases observed at 24 h in 4 (SPF) and 6 (PI) of the 9 ER-negative patients could have occurred by chance alone. Twenty-five of the 28 locally advanced (T4 and/or N2-3) patients achieved a complete response during combined modality treatment (estradiol-chemotherapy, mastectomy, and radiation). At a minimum follow-up time of 42 months, estimated 5-year progression-free and overall survivals are 30 and 49%, respectively, with a median time to progression of 35 months. Twenty-two women had metastatic disease (19 also had locally advanced disease). Thirteen had a complete or partial response, with a median duration of 12 months. Median progression-free and over-all survival times for all metastatic patients are 4 and 17 months, respectively. Estimated 5-year survival for metastatic disease patients is 27%. A high physiological dose of estrogen administered to patients with locally advanced ER-positive tumors can reliably increase the tumor SPF and PI within 48 h.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Neoplasias de la Mama/patología , Estradiol/sangre , Hormona Folículo Estimulante/sangre , Fase S/efectos de los fármacos , Neoplasias de la Mama/sangre , Neoplasias de la Mama/química , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , División Celular , Terapia Combinada , Estradiol/administración & dosificación , Estradiol/farmacología , Femenino , Citometría de Flujo , Humanos , Estadificación de Neoplasias , Receptores de Estrógenos/análisis , SupositoriosRESUMEN
OBJECTIVE: To determine if low-dose involved field radiation after complete remission induction with chemotherapy is effective in preventing relapse and improving survival in patients with stage III or IV Hodgkin disease. DESIGN: A randomized controlled trial with a median follow-up time of 8.1 years. SETTING: A Southwest Oncology Group multi-institutional study. Patients were entered from university- and community-based practices. PATIENTS: 278 adults with clinical or pathologic stage III or IV Hodgkin disease, who achieved complete responses after 6 cycles of MOP-BAP (nitrogen mustard, vincristine, prednisone, bleomycin, doxorubicin, and procarbazine) and who agreed to be randomly assigned to either radiation or no further treatment. INTERVENTION: Patients were assigned to either no further treatment or low-dose radiation to all initially involved sites (radiation dose, 2000 cGy to lymph node areas and 1000 to 1500 cGy to other involved organ sites). MEASUREMENTS: Differences in remission duration, relapse-free survival, and survival. RESULTS: Remission duration, relapse-free survival, and overall survival were similar for the two groups (P = 0.09, P > 0.2, and P = 0.14, respectively). Factors that predicted shorter remission duration in a multivariate analysis were nodular sclerosis histology, bulky disease, and receipt of less than 85% of planned chemotherapy. Low-dose radiation improved remission duration in the subgroups of patients with nodular sclerosis and bulky disease. For the 169 patients with nodular sclerosis, the 5-year remission-duration estimate was 82% for the low-dose radiation group and 60% for the no further treatment group (P = 0.002). For all patients with bulky disease, the 5-year remission-duration estimate was 75% for the low-dose radiation group and 57% for the no further treatment group (P = 0.05). No difference in overall survival was noted between low-dose radiation and no further treatment in all patients or major subgroups. The 5-year survival was 86% for all patients who had a complete response as well as for patients in the nodular sclerosis subgroup. CONCLUSIONS: Low-dose involved field radiation after MOP-BAP chemotherapy in patients with stage III or IV Hodgkin disease did not prolong remission duration or overall survival in randomized patients. However, remission duration was prolonged in several subgroups of patients, most prominently in those with nodular sclerosis histology.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/radioterapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/etiología , Pronóstico , Modelos de Riesgos Proporcionales , Radioterapia/efectos adversos , Dosificación Radioterapéutica , Recurrencia , Inducción de Remisión , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Breast tissue biomarkers which accurately predict breast cancer development within a 10 year period in high risk women are needed but currently not available. We initiated this study to determine 1) the prevalence of one or more breast tissue abnormalities in a group of women at high risk for breast cancer, and 2) if the prevalence of biomarker abnormalities is greater in high risk than in low risk women. Eligible high risk women were those with a first degree relative with breast cancer, prior breast cancer, or precancerous mastopathy. Low risk women were those without these or other major identifiable risk factors. Ductal cells were obtained via random fine needle aspirations and cytologically classified. Biomarkers included DNA ploidy, estrogen receptor (ER), and epidermal growth factor receptor (EGFR). The prevalence of DNA aneuploidy was 30%, overexpression of ER 10%, and overexpression of EGFR 35%, in the 206 high risk women whose median 10 year Gail risk (projected probability) of developing breast cancer was 4.5%. The prevalence of aneuploidy and overexpressed EGFR was significantly higher in the high risk women than in the 25 low risk controls (p < 0.002), whose median 10 year Gail risk was 0.7%. The difference in the prevalence of ER overexpression between high and low risk groups was not statistically significant (p = 0.095). This may be due to the low prevalence of overexpressed ER and the small number of controls. A significant difference was noted in the prevalence of one or more abnormal biomarkers between the high risk and low risk women (p < 0.001). A large prospective trial is needed to determine if one or more of these biomarkers, is predictive of breast cancer development.
Asunto(s)
Aneuploidia , Neoplasias de la Mama/epidemiología , Mama/metabolismo , Receptores ErbB/biosíntesis , Receptores de Estrógenos/biosíntesis , Adulto , Factores de Edad , Biomarcadores/análisis , Biopsia con Aguja , Mama/citología , ADN/análisis , Receptores ErbB/análisis , Eritrocitos/citología , Eritrocitos/metabolismo , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Premenopausia , Prevalencia , Distribución Aleatoria , Receptores de Estrógenos/análisis , Análisis de Regresión , Medición de Riesgo , Factores de RiesgoRESUMEN
Fine needle aspirates (FNA) from 106 high-risk women and 25 low-risk women were evaluated for overexpression of estrogen receptor (ER), epidermal growth factor receptor (EGFR), mutant p53, and HER-2/neu by immunocytochemistry, and for aneuploidy by image analysis. Aspirates were also classified cytologically as normal, apocrine metaplasia, epithelial hyperplasia (EH), or dysplasia. High-risk women were those with a first-degree relative with breast cancer (76%), precancerous breast disease (26%), prior cancer of the contralateral breast (9%), or multiple abnormalities (11%). Low-risk women had none of the above risk factors, nor a prior breast biopsy or clinical evidence of fibrocystic disease. The median 10-year Gail risk for the high-risk group was 4%, compared to 0.7% for the low-risk group. There were significant differences (p < 0.01) between high- and low-risk women in the prevalences of hyperplasia (55% versus 12%), dysplasia (19% versus 0%), aneuploidy (32% versus 0%), overexpressed EGFR (32% versus 4%), and overexpressed p53 (29% versus 4%). The prevalence of multiple biomarker abnormalities was also greater in high-risk than in low-risk women (28% versus 0%; p < 0.01). Four percent (4%) of FNAs from high-risk women with normal cytology, 29% of aspirates with hyperplastic cytology, and 60% of those with dysplasia were associated with two or more biomarker abnormalities. The differences in the prevalence of multiple biomarker abnormalities among various cytologic categories were statistically significant (p = 0.02, normal versus EH; p = 0.02, EH versus dysplasia; p < 0.01, normal versus dysplasia).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Biopsia con Aguja , Neoplasias de la Mama/metabolismo , Receptores ErbB/genética , Femenino , Genes p53 , Humanos , Procesamiento de Imagen Asistido por Computador , Persona de Mediana Edad , Proyectos Piloto , Ploidias , Proteínas Proto-Oncogénicas/genética , Receptor ErbB-2 , Receptores de Estrógenos/metabolismo , Factores de RiesgoRESUMEN
The limiting toxicity of low dose continuous infusion 5-fluorouracil (200-300 mg/m2/day) is often palmar-plantar erythrodysesthesia (PPE). PPE developed in 16/25 patients (exact 95% confidence interval of 42%-82%) with metastatic colon cancer enrolled in a phase II trial. In this trial, 5-FU was given continuously at a dose of 200 mg/m2/day until toxicity or progressive disease forced discontinuation. The first signs of the syndrome developed at a median of 2 months following infusion initiation and, unless treatment was interrupted, became progressively worse. The incidence of moderate to severe PPE was 71% in the 14 previously untreated patients (exact 95% confidence intervals of 42-92%). Seventy-eight percent of the responders in the no prior treatment group developed PPE. The incidence of moderate to severe PPE was only 27% in the 11 previously treated patients (exact 95% confidence intervals of 6-61%). The higher incidence of PPE in the previously untreated patients probably resulted from a longer total infusion time (median = 7.3 months) than the previously treated (median = 4.5 months). The longer infusion time in turn was a result of the higher response rates (64 vs 18%) in the previously untreated versus treated groups. Five previously untreated patients who developed PPE received 50 or 150 mg of pyridoxine/day when moderate PPE changes were noted. Reversal of PPE without interruption of the 5-FU was seen in 4/5 patients. Four of these patients who received pyridoxine had responded to 5-FU treatment. No adverse affect of pyridoxine on clinical response was noted.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Eritema/tratamiento farmacológico , Fluorouracilo/efectos adversos , Dermatosis del Pie/tratamiento farmacológico , Dermatosis de la Mano/tratamiento farmacológico , Parestesia/tratamiento farmacológico , Piridoxina/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Edema/inducido químicamente , Edema/tratamiento farmacológico , Eritema/inducido químicamente , Estudios de Seguimiento , Dermatosis del Pie/inducido químicamente , Dermatosis de la Mano/inducido químicamente , Humanos , Infusiones Intraarteriales , Persona de Mediana Edad , Parestesia/inducido químicamenteRESUMEN
Thirty-eight patients with Stage B2, C1 or C2 colon cancer (Astler-Coller Modification of Dukes) received 3000 rads whole abdominal radiation and concomitant intermittent bolus 5-FU as part of a phase I-II adjuvant trial. Patients whose tumor penetrated the serosa (B2 or C2) in addition received a 1600 rad boost to the tumor bed. 5-FU was administered only during radiation. It was given at a dose of 300 mg/m2 days 1-5 and 28-32 in 21 patients (Group A) and day 1-3 and 28-31 in 17 patients (Group B). Median follow-up time for Group A is 44 months. Group A patients have a disease-free survival of 66% and overall survival of 73% at 44 months. The 16 C2 patients in Group A have a disease-free survival of 54% and overall survival of 65% at 44 months. There was a 26% incidence of moderate to severe acute toxicity in Group A but no long term bowel, liver, or hematologic toxicity. One patient developed acute myelogenous leukemia 2 years after treatment. Group B patients had only a 6% incidence of moderate to severe toxicity, but had a disease-free survival of 60% and overall survival of 100% at median follow-up of 23 months. Group B Stage C2 patients had a disease-free survival of 53% and overall survival of 100% at this same follow-up period. Disease-free and overall survival in Group A Stage C2 patients is superior to that in several published trials. Given the manageable toxicity, adjuvant whole abdominal radiation with concomitant 5-FU and tumor bed boost should be tested in a randomized fashion for possible therapeutic benefits.