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1.
Cancers (Basel) ; 16(7)2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38611089

RESUMO

BACKGROUND AND AIM: The involvement of cholesterol in cancer development remains a topic of debate, and its association with breast cancer has yet to be consistently demonstrated. Considering that circulating cholesterol levels depend on several concomitant processes, we tested the liability of plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in the context of breast neoplastic events. METHODS: Within a prospective randomized breast cancer prevention trial we measured baseline plasma levels of PCSK9. A total of 235 at-risk premenopausal women were randomized and followed up for 17 years. Participants enrolled in this placebo-controlled, phase II, double-blind trial were randomly assigned to receive either tamoxifen 5 mg/d or fenretinide 200 mg/d, both agents, or placebo for 2 years. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models, adjusted for randomization strata (5-year Gail risk ≥ 1.3% vs. intraepithelial neoplasia or small invasive breast cancer of favorable prognosis), age, and treatment allocation. PCSK9 associations with biomarkers linked to breast cancer risk were assessed on blood samples collected at baseline. RESULTS: The plasmatic PCSK9 median and interquartile range were 207 ng/mL and 170-252 ng/mL, respectively. Over a median follow-up period of 17 years and 89 breast neoplastic events, disease-free survival curves showed a hazard ratio of 1.002 (95% CI: 0.999-1.005, p = 0.22) for women with PCSK9 plasma levels ≥ 207 ng/mL compared to women with levels below 207 ng/mL. No differences between randomization strata were observed. We found a negative correlation between PCSK9 and estradiol (r = -0.305), maintained even after partial adjustment for BMI and age (r = -0.287). Cholesterol (r = 0.266), LDL-C (r = 0.207), non-HDL-C (r = 0.246), remnant cholesterol (r = 0.233), and triglycerides (r = 0.233) also correlated with PCSK9. CONCLUSIONS: In premenopausal women at risk of early-stage breast cancer, PCSK9 did not appear to have a role as a prognostic biomarker of breast neoplastic events. Larger studies are warranted investigating patients in different settings.

2.
Cancer Prev Res (Phila) ; 17(6): 255-263, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38530139

RESUMO

Fenretinide, a retinoid with a low-toxicity profile that accumulates in the breast, has been shown to prevent second breast cancer in young women. Fenretinide exhibits apoptotic and antiinvasive properties and it improves insulin sensitivity in overweight premenopausal women with insulin resistance. This study aimed to further characterize its role in cancer prevention by measuring circulating biomarkers related to insulin sensitivity and breast cancer risk.Sixty-two women, ages 20 to 46 years, healthy or who had already undergone breast cancer surgery, with a known BRCA1/2 mutation or a likelihood of mutation ≥20% according to the BRCAPRO model, were randomly assigned to receive fenretinide (200 mg/day) or placebo for 5 years (trial registration: EudraCT No. 2009-010260-41). Fasting blood samples were drawn at baseline, 12 and 36 months, and the following biomarkers were analyzed: retinol, leptin, adiponectin, retinol-binding protein 4 (RBP-4), total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, glucose, insulin, insulin-like growth factor (IGF-1), IGF-binding protein 3, sex hormone binding globulin (SHBG), testosterone, and vascular endothelial growth factor (VEGF).After 12 months of treatment, we observed a favorable effect of fenretinide on glucose (decrease; P = 0.005), insulin (decrease; P = 0.03), homeostatic model assessment index (decrease; P = 0.004), HDL cholesterol (increase; P = 0.002), even though these effects were less prominent after 36 months. Retinol and retinol-binding protein 4 markedly decreased (P < 0.0001) throughout the study. None of the other measured biomarkers changed. PREVENTION RELEVANCE: Fenretinide exhibits beneficial effects on the metabolic profile, supporting its clinical use in breast cancer prevention especially in premenopausal women with a positive family history and pathogenic variants in BRCA1/2 genes. This finding requires further investigations in larger trials to confirm its role in breast cancer prevention.


Assuntos
Proteína BRCA1 , Proteína BRCA2 , Neoplasias da Mama , Fenretinida , Humanos , Fenretinida/uso terapêutico , Fenretinida/administração & dosagem , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Proteína BRCA2/genética , Proteína BRCA1/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Predisposição Genética para Doença , Mutação , Resistência à Insulina , Método Duplo-Cego
3.
Breast Cancer Res Treat ; 142(3): 569-78, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24241787

RESUMO

Tamoxifen and fenretinide have been extensively studied and exhibit breast cancer-preventing activity. We aimed to assess their effect on sex hormones, sex hormone binding globulin (SHBG) and retinol, and their association with mammographic density (MD) and breast cancer events. In a double-blind, placebo-controlled trial, premenopausal women at risk for breast cancer were randomized to tamoxifen 5 mg/day, fenretinide, both agents, or placebo for 2 years. We measured MD and circulating concentrations of follicle-stimulating hormone, luteinizing hormone (LH), estradiol, progesterone, testosterone, androstenedione, dehydro-epiandrosteronesulfate, prolactin, SHBG, and retinol at baseline and on yearly intervals. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models. Low-dose tamoxifen markedly and enduringly increased SHBG, whereas the increases in testosterone, estradiol, and prolactin and reduction in LH weakened after 1 year. Fenretinide increased testosterone and androstenedione and decreased retinol. MD correlated directly with SHBG and inversely with retinol. After a median follow-up of 12 years, the 10-year cumulative incidence of breast cancer events was 37 % in women with SHBG ≤ 59.3 nmol/L, 22 % in women with SHBG between 59.3 and 101 nmol/L, and 19 % in women with SHBG > 101 nmol/L (P = 0.018). The difference among SHBG tertiles remained statistically significant at multivariable analysis: HR = 2.26 (95 % CI 1.04, 4.89) for the lowest versus the highest tertile. We conclude that low-dose tamoxifen or fenretinide exhibits favorable hormonal profiles as single agents, further supporting their administration for prevention of breast cancer in premenopause. Notably, SHBG levels were inversely associated with breast neoplastic events.


Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/prevenção & controle , Fenretinida/administração & dosagem , Hormônios/sangue , Pré-Menopausa , Tamoxifeno/administração & dosagem , Adulto , Densidade da Mama , Neoplasias da Mama/epidemiologia , Feminino , Seguimentos , Hormônios Esteroides Gonadais/sangue , Humanos , Incidência , Glândulas Mamárias Humanas/anormalidades , Pessoa de Meia-Idade , Risco , Fatores de Risco , Globulina de Ligação a Hormônio Sexual/metabolismo , Vitamina A/sangue
4.
Clin Cancer Res ; 27(13): 3576-3583, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33608319

RESUMO

PURPOSE: Low-dose tamoxifen halved recurrence after surgery in a phase III trial in breast noninvasive disease without increasing adverse events. We explored the effect of low-dose tamoxifen in clinically relevant subgroups, including menopausal status, estradiol levels, smoking, body mass index, and proliferation of baseline lesion. PATIENTS AND METHODS: Incidence of invasive breast cancer or ductal carcinoma in situ was the primary endpoint. HRs and interaction terms were estimated using Cox models. RESULTS: A favorable HR and 95% confidence interval (CI) could be demonstrated for postmenopausal status (HR = 0.30; 95% CI, 0.11-0.82 vs. HR = 0.73; 95% CI, 0.30-1.76 in premenopausal women; P interaction = 0.13), women with estradiol less than 15.8 pg/mL, presence of menopausal symptoms at baseline, and never smoking (P interaction = 0.07), although the interaction P value was >0.05 for all characteristics. Efficacy was similar in all body mass index categories. Tumors with Ki-67 above the median level of 10% had a greater benefit (HR = 0.27; 95% CI, 0.09-0.81) than those with Ki-67 ≤10% (HR = 1.58; 95% CI, 0.45-5.60; P interaction = 0.04). CONCLUSIONS: The efficacy of low-dose tamoxifen seems to be greater in postmenopausal women and in women with lower estradiol levels. Benefits appear to be larger also in women with menopausal symptoms, never smokers, and tumors with Ki-67 >10%. Our results by menopausal status provide important insight into low-dose tamoxifen personalized treatment, although caution is necessary given their exploratory nature. Observation of an improved response in tumors with Ki-67 >10% is consistent but the use of the marker in this setting is investigational.See related commentary by Fabian, p. 3510.


Assuntos
Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Feminino , Humanos , Pré-Menopausa , Tamoxifeno/efeitos adversos
5.
J Clin Oncol ; 37(19): 1629-1637, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30973790

RESUMO

PURPOSE: Tamoxifen administered for 5 years at 20 mg/d is effective in breast cancer treatment and prevention, but toxicity has limited its broad use. Biomarker trials showed that 5 mg/d is not inferior to 20 mg/d in decreasing breast cancer proliferation. We hypothesized that a lower dose given for a shorter period could be as effective in preventing recurrence from breast intraepithelial neoplasia but have a lower toxicity than the standard dose. PATIENTS AND METHODS: We conducted a multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ. RESULTS: Five hundred women 75 years of age or younger were included. After a median follow-up of 5.1 years (interquartile range, 3.9-6.3 years), there were 14 neoplastic events with tamoxifen and 28 with placebo (11.6 v 23.9 per 1,000 person-years; hazard ratio, 0.48; 95% CI, 0.26 to 0.92; P = .02), which resulted in a 5-year number needed to treat of 22 (95% CI, 20 to 27). Tamoxifen decreased contralateral breast events by 75% (three v 12 events; hazard ratio, 0.25; 95% CI, 0.07 to 0.88; P = .02). Patient-reported outcomes were not different between arms except for a slight increase in frequency of daily hot flashes with tamoxifen (P = .02). There were 12 serious adverse events with tamoxifen and 16 with placebo, including one deep vein thrombosis and one stage I endometrial cancer with tamoxifen and one pulmonary embolism with placebo. CONCLUSION: Tamoxifen at 5 mg/d for 3 years can halve the recurrence of breast intraepithelial neoplasia with a limited toxicity, which provides a new treatment option in these disorders.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Intraductal não Infiltrante/tratamento farmacológico , Recidiva Local de Neoplasia , Tamoxifeno/administração & dosagem , Idoso , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Biomarcadores Tumorais/metabolismo , Esquema de Medicação , Feminino , Seguimentos , Humanos , Incidência , Pessoa de Meia-Idade , Placebos/efeitos adversos , Projetos de Pesquisa , Tamoxifeno/efeitos adversos , Resultado do Tratamento
6.
Circulation ; 111(5): 650-6, 2005 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-15699284

RESUMO

BACKGROUND: Tamoxifen, a selective estrogen-receptor modulator, increases venous thromboembolic events (VTE), but the factors explaining this risk are unclear. Atherosclerosis may induce VTE, or the 2 conditions may share common risk factors. We assessed the effect of tamoxifen on VTE in a breast cancer prevention trial and studied its association with risk factors for VTE. METHODS AND RESULTS: The incidence of VTE was studied in 5408 hysterectomized women randomly assigned to tamoxifen 20 mg/d or placebo for 5 years. There were 28 VTEs on placebo and 44 on tamoxifen therapy (hazard ratio [HR]=1.63; 95% confidence interval [CI], 1.02 to 2.63), 80% of which were superficial phlebitis, accounting for all of the excess due to tamoxifen within 18 months from randomization. Compared with placebo, the risk of VTE on tamoxifen was higher in women aged 55 years or older, women with a body mass index > or =25 kg/m2, elevated blood pressure, total cholesterol > or =250 mg/dL, current smoking, and a family history of coronary heart disease (CHD). Of the 685 women with a CHD risk score > or =5 who entered the trial, 1 in the placebo arm and 13 in the tamoxifen arm developed VTE (log-rank P=0.0013). In multivariate regression analysis, age > or =60 years, height > or =165 cm, and diastolic blood pressure > or =90 mm Hg had independent detrimental effects on VTE risk during tamoxifen therapy, whereas transdermal estrogen therapy concomitant with tamoxifen was not associated with any excess of VTE (HR=0.64; 95% CI, 0.23 to 1.82). CONCLUSIONS: Women with conventional risk factors for atherosclerosis have a higher risk of VTE during tamoxifen therapy. This information should be incorporated into counseling women on its risk-benefit ratio, particularly in the prevention setting.


Assuntos
Anticarcinógenos/efeitos adversos , Neoplasias da Mama/prevenção & controle , Embolia Pulmonar/epidemiologia , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Tamoxifeno/efeitos adversos , Trombose Venosa/epidemiologia , Adulto , Idoso , Anticarcinógenos/uso terapêutico , Neoplasias da Mama/complicações , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Embolia Pulmonar/complicações , Fatores de Risco , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Trombose Venosa/complicações
7.
PLoS One ; 10(9): e0136731, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26340098

RESUMO

BACKGROUND: The management of pT1a-b pN0 HER2-positive breast cancer is controversial and no data about the efficacy of trastuzumab in this setting are available from randomized clinical trials. The aims of this retrospective study were to assess how patients are managed in clinical practice in Italy, which clinical or biological characteristics influenced the choice of adjuvant systemic therapy and the outcome of patients. METHODS: Data of consecutive patients who underwent surgery from January 2007 to December 2012 for HER2-positive, pT1a-b pN0 M0 breast cancer were retrospectively collected from 28 Italian centres. Analysis of contingency tables and multivariate generalized logit models were used to investigate the association between the baseline clinical and biological features and the treatment strategy adopted. RESULTS: Among 303 enrolled patients, 204 received adjuvant systemic therapy with trastuzumab, 65 adjuvant systemic therapy without trastuzumab and 34 did not receive adjuvant systemic therapy. At the multivariate analysis age, tumor size, proliferation index and hormone receptor status were significantly associated with the treatment choice. Five-year disease-free survival (DFS) probability was 95%, 94.3% and 69.6% for patients treated with adjuvant systemic therapy and trastuzumab, with adjuvant systemic therapy without trastuzumab and for patients who did not receive adjuvant systemic therapy, respectively (p<0.001). CONCLUSIONS: The majority of patients (66%) with pT1a-b pN0 HER2-positive breast cancer enrolled in this retrospective study received adjuvant systemic therapy with trastuzumab, whereas only 11% patients did not receive any adjuvant systemic therapy. It should be emphasized, however, that in the adjuvant systemic therapy without trastuzumab group 94% of tumors were hormone receptor positive and 89% of patients were treated with endocrine therapy only [corrected]. The 5-year DFS probability was significantly higher for patients receiving adjuvant systemic therapy with trastuzumab compared with patients not receiving adjuvant systemic therapy or receiving adjuvant systemic therapy without trastuzumab.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Receptor ErbB-2/genética , Trastuzumab/uso terapêutico , Adjuvantes Farmacêuticos/uso terapêutico , Adulto , Fatores Etários , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/cirurgia , Quimioterapia Adjuvante , Gerenciamento Clínico , Feminino , Expressão Gênica , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Prognóstico , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Carga Tumoral
8.
J Clin Oncol ; 30(2): 151-7, 2012 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-22162577

RESUMO

PURPOSE: Adipokines are linked to obesity and insulin sensitivity and have recently been related to breast cancer risk and prognosis. We investigated the associations of plasma leptin and adiponectin with mammographic density and disease status and assessed their prognostic effect on recurrence-free survival in premenopausal women at risk for breast cancer. PATIENTS AND METHODS: We measured circulating lipids, insulin-like growth factor 1, glucose, insulin and insulin sensitivity (calculated by homeostasis model assessment [HOMA] index), leptin, adiponectin, and leptin-to-adiponectin ratio in 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), intraepithelial neoplasia (n = 160), or 5-year Gail risk of 1.3% or greater (n = 54) who participated in a 2 × 2 trial of low-dose tamoxifen, fenretinide, both agents, or placebo over a 2-year period. RESULTS: At baseline, adiponectin levels were directly associated with mammographic density and HDL cholesterol and negatively associated with leptin, leptin-to-adiponectin ratio, body mass index (BMI), and HOMA index. Median adiponectin levels were lower in affected than in unaffected women (P = .006). After a median of 7.2 years and total of 57 breast neoplastic events, there was a 12% reduction in the risk of breast neoplastic events per unit increase of adiponectin (adjusted hazard ratio, 0.88; 95% CI, 0.81 to 0.96; P = .03). There was no interaction between treatment and adiponectin levels. CONCLUSION: Low adiponectin levels are associated with a history of prior intraepithelial neoplasia or pT1mic/pT1a breast cancer and higher risk of second breast neoplastic events in premenopausal women. The associations are independent of BMI, mammographic density, and treatment. Our findings support the role of adiponectin as a potential target for premenopausal breast cancer prevention and treatment.


Assuntos
Adiponectina/sangue , Anticarcinógenos/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/prevenção & controle , Fenretinida/uso terapêutico , Pré-Menopausa/sangue , Tamoxifeno/uso terapêutico , Método Duplo-Cego , Feminino , Fenretinida/administração & dosagem , Humanos , Leptina/sangue , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Tamoxifeno/administração & dosagem
10.
J Clin Oncol ; 27(23): 3749-56, 2009 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-19597031

RESUMO

PURPOSE: Tamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial. PATIENTS AND METHODS: A total of 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), or intraepithelial neoplasia (IEN, n = 160), or 5-year Gail risk > or = 1.3% (n = 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years. RESULTS: During the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n = 48) was 3.5% +/- 1.0%, 2.1% +/- 0.8%, 4.7% +/- 1.3%, and 5.2% +/- 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen x fenretinide adverse interaction P = .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density. CONCLUSION: Despite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated.


Assuntos
Anticarcinógenos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias da Mama/patologia , Neoplasias da Mama/prevenção & controle , Fenretinida/uso terapêutico , Fator de Crescimento Insulin-Like I/metabolismo , Mamografia , Pré-Menopausa , Tamoxifeno/uso terapêutico , Adulto , Anticarcinógenos/administração & dosagem , Anticarcinógenos/efeitos adversos , Anticarcinógenos/sangue , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/prevenção & controle , Carcinoma Lobular/prevenção & controle , Método Duplo-Cego , Esquema de Medicação , Sinergismo Farmacológico , Feminino , Fenretinida/administração & dosagem , Fenretinida/efeitos adversos , Fenretinida/sangue , Humanos , Incidência , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Pré-Menopausa/sangue , Modelos de Riscos Proporcionais , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Tamoxifeno/análogos & derivados , Tamoxifeno/sangue , Resultado do Tratamento , Vitamina A/sangue
11.
Cancer Res ; 68(22): 9512-8, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19010927

RESUMO

The prevalence of metabolic syndrome is increasing along with breast cancer incidence worldwide. Because fenretinide improves insulin action and glucose tolerance in insulin-resistant obese mice and because tamoxifen has shown to regulate several markers involved in metabolic syndrome, we sought to investigate the effect of fenretinide or tamoxifen at low dose on features linked to insulin resistance in premenopausal women at risk for breast cancer. We randomized 235 women to low-dose tamoxifen (5 mg/daily), fenretinide (200 mg/daily), or their combination or placebo for 2 years. We used the homeostasis model assessment (HOMA; fasting insulin x glucose/22.5) to estimate insulin sensitivity. Women were considered to improve insulin sensitivity when they shifted from a HOMA >/=2.8 to <2.8. There was no effect of fenretinide or tamoxifen on HOMA overall, but overweight women (body mass index, >or=25 kg/m(2)) had a 7-fold greater probability to normalize HOMA after 2 years of fenretinide treatment [odds ratio (OR), 7.0; 95% confidence interval (95% CI), 1.2-40.5], with 25% of women improving their insulin sensitivity, whereas tamoxifen decreased insulin sensitivity by almost 7 times compared with subjects not taking tamoxifen (OR, 0.15; 95% CI, 0.03-0.88). In this group only, 5% improved their insulin sensitivity. Interestingly, women with intraepithelial or microinvasive neoplasia had higher HOMA (3.0) than unaffected subjects (2.8; P = 0.07). Fenretinide can positively balance the metabolic profile in overweight premenopausal women and this may favorably affect breast cancer risk. Furthermore, features of the metabolic syndrome should be taken into consideration before proposing tamoxifen for breast cancer prevention. The clinical implications of these results require further investigations.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Fenretinida/farmacologia , Resistência à Insulina , Tamoxifeno/farmacologia , Índice de Massa Corporal , Neoplasias da Mama/metabolismo , HDL-Colesterol/sangue , Método Duplo-Cego , Feminino , Humanos , Fator de Crescimento Insulin-Like I/análise , Leptina/sangue , Pré-Menopausa , Proteínas Plasmáticas de Ligação ao Retinol/análise
12.
J Clin Oncol ; 24(1): 129-35, 2006 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-16382122

RESUMO

PURPOSE: To determine whether low-dose tamoxifen and fenretinide have a synergistic effect on surrogate biomarkers, including circulating insulin-like growth factor I (IGF-I) and mammographic density, in premenopausal women at risk for breast cancer and to study drug safety. PATIENTS AND METHODS: Premenopausal women (n = 235) were randomly assigned in a double-blind four-arm trial to receive tamoxifen 5 mg/d, fenretinide 200 mg/d, both agents, or placebo for 2 years. The present analysis refers to preliminary data on safety, IGF-I, and breast cancer events. RESULTS: Patients were included if they had an excised ductal carcinoma-in-situ (57%), lobular carcinoma-in-situ (13%), minimal invasive breast cancer (7%), or a 5-year Gail risk > or = 1.3% (23%). After a median follow-up of 40 months, there was a reduction of 13%, 2%, 20%, and 1% in IGF-I levels for patients on tamoxifen, fenretinide, tamoxifen plus fenretinide, and placebo, respectively. Recruitment was stopped based on the lack of an interaction on IGF-I levels, which was a primary end point for the study. Thirty-six patients have dropped out of the study, 17 because of adverse events and 19 for various other reasons. One stage I endometrial cancer occurred in a patient on fenretinide, and one optic nerve ischemia and one deep venous thrombosis occurred on tamoxifen. There was no difference in menopausal symptoms, endometrial thickness, polyps, or ovarian cysts among treatment arms. To date, 24 breast cancers have been observed, without differences among arms. CONCLUSION: The combination of low-dose tamoxifen and fenretinide is safe but not synergistic in lowering IGF-I levels in premenopausal women. The clinical implications require further follow-up.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/prevenção & controle , Adulto , Método Duplo-Cego , Endométrio/efeitos dos fármacos , Endométrio/patologia , Feminino , Fenretinida/administração & dosagem , Fenretinida/efeitos adversos , Humanos , Fator de Crescimento Insulin-Like I/análise , Pessoa de Meia-Idade , Pré-Menopausa , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Vitamina A/sangue
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