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Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Manejo de Datos , Humanos , Homólogo 1 de la Proteína MutL/genética , Estudios ProspectivosRESUMEN
Background: Tumor-infiltrating lymphocytes (TILs) are a robust prognostic adjunct in invasive breast cancer, but their clinical role in ductal carcinoma in situ (DCIS) has not been ascertained. Patients and methods: We evaluated the prevalence and clinical relevance of TILs in a well annotated series of 1488 consecutive DCIS women with a median follow-up of 8.2 years. Detailed criteria for TILs evaluation were pre-defined involving the International Immuno-Oncology Biomarker Working Group. TILs percentage was considered both as a continuous and categorical variable. Levels of TILs were examined for their associations with ipsilateral breast event (IBE), whether in situ or invasive. Results: Of the 1488 patients with DCIS under study, 35.1% had <1%, 58.3% 1-49% and 6.5% ≥50% peri-ductal stromal lymphocytes. The interobserver agreement in TILs evaluation, measured by the intraclass correlation coefficient (ICC) was 0.96 (95% CI 0.95-0.97). At univariable analysis, clinical factors significantly associated with TILs (P ≤0.001) were intrinsic subtype, grade, necrosis, type of surgery. Her-2 positive DCIS were more frequently associated with TILs (24% of patients with TILs ≥50%), followed by the triple negative (11%), Luminal B/Her-2 positive (9%) and Luminal A/B subtypes (1%) (P < 0.0001). We did not find any association between TILs as a continuous variable and the risk of IBEs. Likewise, when patients were stratified by TILs percentage (<1%, between 1% and 49.9%, and ≥50%), no statistically significant association was observed (10-year cumulative incidence of IBEs: 19%, 17.3%, and 18.7% respectively, P = 0.767). Conclusion: TILs occur more frequently in the Her-2 positive DCIS. Although we did not find a significant association between TILs and the 10-year risk of IBE, our data suggest that immunotherapies might be considered in subsets of DCIS patients.
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Linfocitos Infiltrantes de Tumor/patología , Recurrencia Local de Neoplasia/inmunología , Adulto , Anciano , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/terapia , Carcinoma Intraductal no Infiltrante/epidemiología , Carcinoma Intraductal no Infiltrante/inmunología , Carcinoma Intraductal no Infiltrante/terapia , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/prevención & control , Prevalencia , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
While aggressive tobacco control and help to stop smoking are essential weapons in the fight against lung cancer, screening with low-dose computed tomography (LDCT) in high-risk populations and chemoprevention may also contribute to reducing lung cancer deaths. Persons undergoing LDCT screening are an ideal population to be tested for agents potentially able to prevent the development of lung cancer by the regression of precancerous lesions, which are routinely monitored as part of the screening process. Peripheral subsolid nodules appear as particularly suitable targets, since many are adenocarcinoma precursors. A study on inhaled budesonide (a potential chemopreventive drug) for 1 year found that the mean size of non-solid lung nodules was significantly reduced over 5 years of follow-up, compared to inhaled placebo, in a population of high-risk individuals with indeterminate lung nodules not requiring immediate specific investigation for lung cancer and detected as part of a lung cancer screening program with LDCT. A new randomised placebo-controlled phase-II trial to test the ability of aspirin to induce the regression of non-solid and partially solid nodules detected by LDCT screening has been started. The effect of aspirin on a miRNA signature able to predict the presence of both cancer and precancerous lesions in high-risk asymptomatic individuals is also being monitored in the trial. This signature was previously shown to predict the presence of both lung cancer and non-solid lung nodules in asymptomatic individuals.
RESUMEN
BACKGROUND: A previously carried out randomized phase IIb, placebo-controlled trial of 1 year of inhaled budesonide, which was nested in a lung cancer screening study, showed that non-solid and partially solid lung nodules detected by low-dose computed tomography (LDCT), and not immediately suspicious for lung cancer, tended to regress. Because some of these nodules may be slow-growing adenocarcinoma precursors, we evaluated long-term outcomes (after stopping the 1-year intervention) by annual LDCT. PATIENTS AND METHODS: We analyzed the evolution of target and non-target trial nodules detected by LDCT in the budesonide and placebo arms up to 5 years after randomization. The numbers and characteristics of lung cancers diagnosed during follow-up were also analyzed. RESULTS: The mean maximum diameter of non-solid nodules reduced significantly (from 5.03 mm at baseline to 2.61 mm after 5 years) in the budesonide arm; there was no significant size change in the placebo arm. The mean diameter of partially solid lesions also decreased significantly, but only by 0.69 mm. The size of solid nodules did not change. Neither the number of new lesions nor the number of lung cancers differed in the two arms. CONCLUSIONS: Inhaled budesonide given for 1 year significantly decreased the size of non-solid nodules detected by screening LDCT after 5 years. This is of potential importance since some of these nodules may progress slowly to adenocarcinoma. However, further studies are required to assess clinical implications. CLINICAL TRIAL NUMBER: NCT01540552.
Asunto(s)
Adenocarcinoma/prevención & control , Antineoplásicos/administración & dosificación , Budesonida/administración & dosificación , Neoplasias Pulmonares/prevención & control , Nódulos Pulmonares Múltiples/tratamiento farmacológico , Lesiones Precancerosas/tratamiento farmacológico , Nódulo Pulmonar Solitario/tratamiento farmacológico , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma del Pulmón , Administración por Inhalación , Antineoplásicos/efectos adversos , Budesonida/efectos adversos , Ensayos Clínicos Fase II como Asunto , Detección Precoz del Cáncer/métodos , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Tomografía Computarizada Multidetector , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Lesiones Precancerosas/diagnóstico por imagen , Valor Predictivo de las Pruebas , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Factores de Riesgo , Nódulo Pulmonar Solitario/diagnóstico por imagen , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: To assess the prognostic role of human epidermal growth factor receptor 2 (HER2) overexpression in patients with ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: We identified patients with HER2-positive DCIS among a population of 1667 cases, prospectively diagnosed and surgically treated at the European Institute of Oncology from 1996 to 2008. Rates of subsequent DCIS or invasive cancer in HER2-positive disease were estimated. We evaluated Cumulative Incidence of In Situ Breast Cancer Recurrence (isBCR), INvasive Breast Cancer Recurrence (IBCR) and any Breast Cancer Recurrence (BCR). isBCR, IBCR and BCR were defined as the time from surgery to breast cancer recurrence as first event (in situ, invasive or both, respectively) or last visit in case of no events. RESULTS: We identified 560 (33.5%) patients with HER2-positive DCIS. The median follow-up was 7.6 years (interquartile range 5.9-9.5). We observed 422 events out of 1667 patients, with 141 in situ recurrences, 201 invasive recurrences and 80 other events (64 second primaries and 16 deaths). The 10-year isBCR proportions were 11.8% [95% confidence interval (CI) 9.0% to 15.4%] in the HER2-positive group and 8.8% (95% CI 6.9% to 11.0%) in the HER2-negative group (Gray test, P = 0.010). At multivariable analysis, the adjusted risk of isBCR was higher in the HER2-positive group than in the HER2-negative group [hazard ratio (HR) HER2 positive versus negative: 1.59 (95% CI 1.06-2.39)]. We observed significant differences both in BCR and isBCR for patients treated by quadrantectomy without radiotherapy versus patients treated with radiotherapy [adjusted HR HER2 positive versus negative: 1.53 (95% CI 1.07-2.18) and adjusted HR HER2 positive versus negative: 2.18 (95% CI 2.18-3.69), respectively]. CONCLUSION: HER2 overexpression predicts an increased risk of isBCR. Radiotherapy reduces local failure rates in HER2-positive DCIS.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Recurrencia Local de Neoplasia/epidemiología , Receptor ErbB-2/metabolismo , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/terapia , Carcinoma Intraductal no Infiltrante/metabolismo , Carcinoma Intraductal no Infiltrante/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Incidencia , Italia/epidemiología , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/metabolismo , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Ki-67 is increasingly being used as a response biomarker in window of opportunity, pre-surgical trials for breast cancer patients. Since Ki-67 is often higher at surgery than at baseline core biopsy in subjects allocated to placebo, we investigated which factors affected this change. PATIENTS AND METHODS: We retrieved data from 274 patients who received no active treatment in three consecutive pre-surgical trials from a single institution. We assessed the association between changes in Ki-67 from diagnostic biopsy to surgical specimen and the following factors: age, body mass index, tumor prognostic and predictive factors, including immunohistochemical molecular subtype, number and size of biopsy specimens, time from biopsy to surgery, circulating insulin-like growth factor-I, sex hormone-binding globulin and hsCRP. RESULTS: A total of 269 patients with paired measures of Ki-67 at biopsy and surgery were analyzed. Overall, the mean (±SD) change was 2.2 ± 9.2% after a median interval of 41 days (inter-quartile range 33-48). Molecular subtype was the only factor associated with a significant change of Ki-67 (P = 0.004), with a mean absolute increase of 5.3% [95% confidence interval (CI): 2.3-8.3, P = 0.0005] in estrogen receptor-negative HER2-positive tumors (n = 36) and 5.4% (95% CI: 2.9-7.9, P < 0.0001) in triple-negative tumors (n = 78). No significant change in luminal-A (n = 46), luminal-B (n = 85) and luminal-B HER2-positive (n = 24) tumors was observed. CONCLUSIONS: A significant increase in Ki-67 from baseline biopsy to end point surgery in untreated subjects was ascertained in HER2-positive and triple-negative tumors. This biological association suggests a real increase in cancer proliferation, possibly as a result of a biopsy-driven wound healing effect, and should be considered in the design and interpretation of pre-surgical studies. REGISTERED CLINICAL TRIAL NUMBERS: ISRCTN86894592; ISRCTN16493703.
Asunto(s)
Antígeno Ki-67/genética , Tipificación Molecular , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/cirugía , Biomarcadores de Tumor/genética , Biopsia , Índice de Masa Corporal , Proliferación Celular , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina , Terapia Neoadyuvante , Placebos/uso terapéutico , Pronóstico , Receptor ErbB-2/biosíntesis , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Globulina de Unión a Hormona Sexual , Neoplasias de la Mama Triple Negativas/mortalidadRESUMEN
BACKGROUND: Metformin has been associated with antitumour activity in breast cancer (BC) but its mechanism remains unclear. We determined whether metformin induced a modulation of apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) overall and by insulin resistance status in a presurgical trial. METHODS: Apoptosis was analysed in core biopsies and in surgical samples from 100 non-diabetic BC patients participating in a randomised trial of metformin vs placebo given for 4 weeks before surgery. RESULTS: Eighty-seven subjects (45 on metformin and 42 on placebo) were assessable for TUNEL measurement at both time points. TUNEL levels at surgery were higher than that at baseline core biopsy (P<0.0001), although no difference between arms was noted (metformin arm: median difference surgery-biopsy levels +4%, interquartile range (IQR): 2-12; placebo arm: +2%, IQR: 0-8, P=0.2). Ki67 labelling index and TUNEL levels were directly correlated both at baseline and surgery (Spearman's r=0.51, P<0.0001). In the 59 women without insulin resistance (HOMA index<2.8) ,there was a higher level of TUNEL at surgery on metformin vs placebo (median difference on metformin +4%, IQR: 2-14 vs +2%, IQR: 0-7 on placebo), whereas an opposite trend was found in the 28 women with insulin resistance (median difference on metformin +2%, IQR: 0-6, vs +5%, IQR: 0-15 on placebo, P-interaction=0.1). CONCLUSION: Overall, we found no significant modulation of apoptosis by metformin, although there was a trend to a different effect according to insulin resistance status, with a pattern resembling Ki67 changes. Apoptosis was significantly higher in the surgical specimens compared with baseline biopsy and was directly correlated with Ki67. Our findings provide additional evidence for a dual effect of metformin on BC growth according to insulin resistance status.
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Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Periodo Preoperatorio , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugía , Terapia Combinada , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Antígeno Ki-67/análisis , Persona de Mediana Edad , Terapia Neoadyuvante , PlacebosRESUMEN
BACKGROUND: The post-surgical management of ductal intraepithelial neoplasia (DIN) of the breast is still a dilemma. Ki-67 labelling index (LI) has been proposed as an independent predictive and prognostic factor in early breast cancer. METHODS: The prognostic and predictive roles of Ki-67 LI were evaluated with a multivariable Cox regression model in a cohort of 1171 consecutive patients operated for DIN in a single institution from 1997 to 2007. RESULTS: Radiotherapy (RT) was protective in subjects with DIN with Ki-67 LI ≥ 14%, whereas no evidence of benefit was seen for Ki-67 LI <14%, irrespective of nuclear grade and presence of necrosis. Notably, the higher the Ki-67 LI, the stronger the effect of RT (P-interaction <0.01). Hormonal therapy (HT) was effective in both Luminal A (adjusted hazard ratio (HR)=0.56 (95% CI, 0.33-0.97)) and Luminal B/Her2neg DIN (HR 0.51 (95% CI, 0.27-0.95)). CONCLUSION: Our data suggest that Ki-67 LI may be a useful prognostic and predictive adjunct in DIN patients. The Ki-67 LI of 14% could be a potential cutoff for better categorising this population of women at increased risk for breast cancer and in which adjuvant treatment (RT, HT) should be differently addressed, independent of histological grade and presence of necrosis.
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Neoplasias de la Mama/terapia , Carcinoma in Situ/terapia , Carcinoma Ductal de Mama/terapia , Carcinoma Intraductal no Infiltrante/terapia , Antígeno Ki-67/metabolismo , Adulto , Anciano , Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Carcinoma in Situ/metabolismo , Carcinoma in Situ/radioterapia , Carcinoma in Situ/cirugía , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/radioterapia , Carcinoma Ductal de Mama/cirugía , Carcinoma Intraductal no Infiltrante/metabolismo , Carcinoma Intraductal no Infiltrante/radioterapia , Carcinoma Intraductal no Infiltrante/cirugía , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante , Estudios Retrospectivos , Tamoxifeno/administración & dosificaciónRESUMEN
BACKGROUND: Postsurgical treatment of ductal intraepithelial neoplasia (DIN) with standard doses of tamoxifen has not reached a consensus yet. Given positive results of low-dose tamoxifen on breast cancer biomarkers modulation, we analyzed a large cohort of DIN patients treated with low-dose tamoxifen or no treatment as per institutional guidelines. PATIENTS AND METHODS: All consecutive women operated on at the European Institute of Oncology for estrogen receptor (ER)-positive DIN (474 treated with low-dose tamoxifen and 509 untreated patients) were followed up for a median of 7 years. RESULTS: Compared with untreated patients, a significant 30% reduction in breast cancer risk was observed on low-dose tamoxifen with an adjusted hazard ratio (HR) = 0.70 [95% confidence interval (CI) 0.51-0.94], with a greater benefit in postmenopausal (HR = 0.57; 95% CI 0.34-0.94) than in premenopausal women (HR = 0.79; 95% CI 0.54-1.17). Treated patients with ER and progesterone receptor (PgR) >50% DIN had a lower incidence of breast events than untreated ones (HR = 0.61; 95% CI 0.40-0.94), whereas no protective effect has been observed in patients with ER or PgR <50% DIN. Drug discontinuation resulted in a doubled risk of recurrence in premenopausal women only (HR = 1.95; 95% CI 0.98-3.89). No excess of endometrial cancer occurred. CONCLUSIONS: Low-dose tamoxifen is a promising and safe strategy for highly endocrine responsive DIN. Treatment adherence is crucial in premenopausal women. A definitive trial is ongoing.
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Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma in Situ/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Tamoxifeno/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma in Situ/patología , Carcinoma in Situ/cirugía , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugía , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Mastectomía Segmentaria , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Studies have shown that Ki-67 response after short-term neoadjuvant aromatase inhibitors may predict recurrence in postmenopausal breast cancer, whereas its prognostic effect in premenopausal women is unknown. PATIENTS AND METHODS: We compared the prognostic and predictive value of baseline and post-treatment Ki-67 in 120 pre- and postmenopausal women with early-stage estrogen receptor-positive breast cancer who participated in a 4-week presurgical trial of tamoxifen. RESULTS: After 7.2 years of follow-up, women with post-treatment Ki-67 in the second (14%-19%), third (20%-29%) and top (≥30%) quartiles had a recurrence hazard ratio of 2.92 [95% confidence interval (CI) 0.95-8.96], 4.37 (1.56-12.25) and 6.05 (2.07-17.65), respectively, as compared with those in the bottom quartile (<14%) (P-trend = 0.001). The risk of invasive disease recurrence was 2.2% (95% CI 0.9-5.0) per point increase in baseline Ki-67 (P-trend = 0.076) and 5.0% (95% CI 2.3-7.7) per point increase in post-tamoxifen Ki-67 (P-trend < 0.001). The risk of death was 5.5 (95% CI 1.26-23.16) times higher in patients with post-drug Ki-67 ≥20% than in those with Ki-67 <20% (P-trend = 0.006). CONCLUSIONS: Ki-67 response after short-term neoadjuvant tamoxifen is a good predictor of recurrence-free survival and overall survival, further supporting its use as surrogate biomarker to personalize adjuvant treatment and to screen novel drugs cost-effectively.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/patología , Antígeno Ki-67/metabolismo , Neoplasias Hormono-Dependientes/patología , Receptores de Estrógenos/metabolismo , Tamoxifeno/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Terapia Neoadyuvante , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias Hormono-Dependientes/cirugía , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Coloración y Etiquetado , Carga Tumoral/efectos de los fármacosRESUMEN
The role of pharmacogenomics and tamoxifen was investigated by analyzing several polymorphisms of cytochrome P450 and SULT1A1 gene in a nested case control study from the Italian Tamoxifen Prevention Trial. This study included 182 Caucasian subjects, 47 breast cancer (BC) cases and 135 matched controls. We used the AmpliChip CYP450 Test to screen 33 alleles of CYP2D6 and 3 of CYP2C19. One more variant for CYP2C19*17 and two single-nucleotide polymorphisms for the gene SULT1A1 were also performed. By using the AmpliChip CYP450 Test, out of 182 subjects, we identified 8 poor metabolizer (PM), 17 intermediate metabolizer (IM), 151 extensive metabolizer (EM) and 3 ultrarapid metabolizer (UM). PM women allocated to the tamoxifen arm showed a higher risk of developing BC compared to the remaining phenotypes (P=0.035). In an exploratory analysis, among 58 women with a CYP2D6*2A allele, 9 BCs were diagnosed in the placebo arm and only 1 in the tamoxifen arm (P=0.0001). CYP2C19 and SULT1A1 polymorphisms did not show any correlation with tamoxifen efficacy. Tamoxifen showed reduced efficacy in CYP2D6 PMs in the chemoprevention setting. Conversely, the CYP2D6*2A allele may be associated with increased efficacy of tamoxifen. These findings support the relevance of pharmaco-genomics in tailoring tamoxifen treatment.
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Antineoplásicos Hormonales/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/genética , Neoplasias de la Mama/prevención & control , Citocromo P-450 CYP2D6/genética , Resistencia a Antineoplásicos/genética , Tamoxifeno/uso terapéutico , Arilsulfotransferasa/genética , Estudios de Casos y Controles , Ensayos Clínicos como Asunto , Citocromo P-450 CYP2C19 , Femenino , Humanos , Italia , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Resultado del TratamientoRESUMEN
BACKGROUND: Tamoxifen's cost-benefit ratio for breast ductal intraepithelial neoplasia (DIN) is unclear. Since low-dose tamoxifen showed a favorable modulation of breast cancer biomarkers in phase II trials, a monoinstitutional cohort of women with DIN treated with low-dose tamoxifen or no systemic treatment was analyzed. PATIENTS AND METHODS: A total of 309 patients with DIN received low-dose tamoxifen as part of institutional guidelines and were compared with 371 patients with DIN who received no systemic treatment after surgery. RESULTS: Women with estrogen receptor (ER)/progesterone receptor (PgR) >50% DIN who were not treated had a higher incidence of breast events than women on tamoxifen [hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.00-3.12] or women with ER/PgR <50% DIN (HR 1.72; 95% CI 1.14-2.58). Among untreated patients with ER >50% DIN, recurrence was higher in PgR > or =50% DIN than in PgR <50% DIN, whereas it was similar among low PgR (<50%) DIN against which tamoxifen had no effect. No difference in endometrial cancer incidence was noted. CONCLUSIONS: High ER and especially high PgR expression is a significant adverse prognostic indicator of DIN, and low-dose tamoxifen appears to be an active treatment. Women with low-expression ER or PgR DIN do not seem to benefit from tamoxifen. A definitive clinical trial is warranted.
Asunto(s)
Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma in Situ/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Tamoxifeno/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Posmenopausia , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: We have previously reported the favourable effect of transdermal estradiol (E2), relative to oral conjugated equine oestrogen (CEE), on ultrasensitive C-reactive protein after 12 months of treatment in a retinoid-placebo controlled two-by-two randomized breast cancer prevention trial (Decensi A et al (2002) Circulation106 10 1224-8). Here, we investigate the changes in lipids and clotting profile in patients of the same trial. METHODS AND RESULTS: Recent post-menopausal women were randomised to either oral CEE 0.625 mg/day and placebo (n = 55), CEE and fenretinide 200 mg/day (n = 56), transdermal E2 50 mg/day and placebo (n = 59) or E2 and fenretinide 200 mg/day (n = 56). Sequential medroxyprogesterone acetate 10 mg/day was given in each group. After 12 months, there was a statistically significant effect of the route of administration of hormone replacement therapy (HRT) on fibrinogen levels; the median percentage change being -5.7% with CEE and -1.1% with E2 (p = 0.012). Total cholesterol decreased in all arms (p < 0.0001). HDL-C decreased significantly with transdermal E2 (p = 0.006) compared to oral CEE and with fenretinide relative to placebo (p<0.001). Triglycerides exhibited an opposite modulation in the HRT route, with a 21.4% median increase with oral CEE and an 8.6% reduction with transdermal E2 (p < 0.0001). Antithrombin-III showed a 4% borderline significant reduction in the fenretinide arm relative to placebo, irrespective of the HRT administration route (p = 0.055). CONCLUSIONS: Our data indicate that transdermal E2 may be preferable to oral CEE based on its safer cardiovascular risk profile. Fenretinide modified some cardiovascular risk biomarkers and confirmed a safer profile compared to other retinoids.
RESUMEN
The use of tamoxifen as a breast cancer preventive agent may be contraindicated by an increased risk of endometrial cancer and venous thromboembolic events, particularly in postmenopausal women. Since these estrogenic effects may be dose-related, a dose reduction may reduce toxicity. We have recently shown a comparable activity of lower doses of tamoxifen on putative surrogate biomarkers of cardiovascular disease and breast cancer. To provide further insight into the effect of tamoxifen at low doses on the cardiovascular system, we compared the effect of three different doses on circulating levels of C-reactive protein (CRP), an independent risk marker for cardiovascular disease (CVD), which was lowered by tamoxifen at the standard dose of 20 mg day-1 in previous studies. We compared the changes in CRP after 2 months of either placebo (n = 24), or tamoxifen 10 mg alternate daily (n = 26), or 10 mg day-1 (n = 22), or 20 mg day-1 (n = 19) in healthy women aged 35-70 years. The median percent change was -2.2% (95% CI, -23.3 to 42.8) with placebo, -39.1 (95% CI, -59.9 to -28.7) with 10 mg alternate daily, -56.9% (95% CI, -68.6 to -38.4) with 10 mg day-1 and -42.9% (95% CI, -62.6 to 1.6) with 20 mg day-1 (P = 0.291 for the linear dose-response trend). Similar results were obtained when the data were classified according to blood tamoxifen concentrations, with a median reduction of 47% (95% CI, 65.5-36.3) for women with low tamoxifen concentrations (< 30 ng mL-1). We conclude that tamoxifen at low doses is able to lower ultrasensitive CRP and that this might be associated with a beneficial effect on CVD.
Asunto(s)
Proteína C-Reactiva/biosíntesis , Tamoxifeno/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/prevención & control , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Antagonistas de Estrógenos/uso terapéutico , Estrógenos/metabolismo , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Placebos , Factores de RiesgoRESUMEN
The effect on the IGF system of 60 mg and 600 mg daily of raloxifene administered for 2 weeks prior to surgery was investigated in 37 postmenopausal women with breast cancer. Raloxifene significantly decreased insulin-like growth factor (IGF-I) as compared to placebo (P < 0.05) with no dose-response relationship. No significant change was observed in IGFBP-3, while the IGF-I/IGFBP-3 molar ratio was decreased by treatment, with a statistically significant effect only for the higher dose. Given that high plasma levels of IGF-I have been suggested as a risk factor for breast cancer, these findings provide further support for the potential activity of raloxifene in breast cancer prevention.
Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Proteínas de Neoplasias/sangre , Clorhidrato de Raloxifeno/farmacología , Clorhidrato de Raloxifeno/uso terapéutico , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Depresión Química , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Mastectomía , Persona de Mediana Edad , Posmenopausia , Premedicación , Clorhidrato de Raloxifeno/administración & dosificación , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéuticoRESUMEN
We have shown previously that a reduction from the conventional dose of tamoxifen is associated with a comparable modulation of circulating biomarkers, including insulin-like growth factor-I and cholesterol. In the present study, we have correlated serum tamoxifen elimination with biomarker recovery in healthy subjects completing a 5-year intervention period. Tamoxifen, N-desmethyltamoxifen, and biomarker levels were measured at 0 (baseline), 2, 4, and 6 weeks after completion of treatment in 23 healthy postmenopausal women allocated to tamoxifen 20 mg/day and in 6 women allocated to placebo. Mean (+/-SD) serum tamoxifen and N-desmethyltamoxifen concentrations were, respectively, 141 +/- 50 and 226 +/- 77 ng/ml at baseline, 36 +/- 19 and 99 +/- 46 at 2 weeks, 20 +/- 15 and 61 +/- 37 at 4 weeks, and 12 +/- 9 and 36 +/- 26 at 6 weeks. Serum tamoxifen and N-desmethyltamoxifen half-lives were 9 and 13 days, respectively. Body mass index was associated positively with drug's serum half-life. Compared with baseline values, the percentage increase in total cholesterol, low-density lipoprotein cholesterol, and insulin-like growth factor-I 4 weeks after treatment completion was 5, 9, and 14%, respectively. No change during the 6-week period was observed in the placebo arm. Our findings indicate that the biomarker recovery is slower than serum tamoxifen elimination, suggesting that low tamoxifen concentrations may still exert a biological effect. In addition, the prolonged half-life of tamoxifen and metabolite provides the rationale for a weekly administration of the drug in a preventive context. However, the clinical implications of our findings remain to be defined.
Asunto(s)
Neoplasias de la Mama/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacocinética , Tamoxifeno/farmacocinética , Anciano , Biomarcadores/sangre , Índice de Masa Corporal , Colesterol/sangre , LDL-Colesterol/sangre , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Persona de Mediana Edad , Posmenopausia , Moduladores Selectivos de los Receptores de Estrógeno/sangre , Tamoxifeno/análogos & derivados , Tamoxifeno/sangreRESUMEN
The Italian Tamoxifen Prevention Study includes 5408 healthy hysterectomized women aged 35-70 years who have been randomized to 20 mg/day of tamoxifen or placebo for 5 years. After 46 months median follow-up, an increased risk of venous vascular events (38 women on tamoxifen vs. 18 women on placebo, P = 0.0053), mainly consisting of superficial phlebitis, has been observed and 41 breast cancers have occurred (19 on tamoxifen vs. 22 on placebo, P = 0.64). However, subgroup analyses indicated a borderline significant reduction of breast cancer among women continuously on estrogen replacement therapy (ERT, mostly transdermal) and receiving tamoxifen, with 8 cases of breast cancer among 390 ERT users on placebo versus 1 case among 362 ERT users on tamoxifen (RR = 0.13, 95% CI = 0.02-1.02). Withdrawal rate (mainly due to menopausal symptoms) differed according to ERT use, with compliance being 78% and 75% at 3 and 5 years, respectively, for women who never took ERT, and 92% and 88% at 3 and 5 years, respectively, for women not on ERT at baseline, but who took ERT at some time during the trial. Pharmacokinetic and pharmacodynamic (surrogate end point biomarkers) studies showed that a lower dose of tamoxifen (such as 5 mg/day) does not affect the drug's activity on several biomarkers of both cardiovascular and breast cancer risk. We are therefore planning a multicenter placebo-controlled phase III trial in postmenopausal healthy women on hormone replacement therapy (HRT) to test whether the combination of HRT and low-dose tamoxifen retains the benefits while reducing the risks of either agent maintaining a high compliance rate.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/prevención & control , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Tamoxifeno/uso terapéutico , Adulto , Anciano , Quimioprevención , Método Doble Ciego , Femenino , Humanos , Italia , Persona de Mediana EdadRESUMEN
The use of tamoxifen as a preventive agent may be limited by the increased risk of endometrial cancer and venous thromboembolic events observed in postmenopausal women. We have recently shown a comparable activity of lower doses of tamoxifen on several surrogate biomarkers of cardiovascular disease and breast cancer, including Insulin-like Growth Factor-I (IGF-I). To provide further insight into the effect of tamoxifen at low doses on the IGF system, we have correlated the drug serum levels attained after 2 months of either placebo (n = 32), tamoxifen 20 mg/day (n = 26), 10 mg/day (n = 23) or 10 mg/every other day (n = 29) with the changes in IGF-I, Insulin-like Growth Factor-II (IGF-II), Insulin-like Growth Factor Binding Protein-1 (IGFBP-1), Insulin-like Growth Factor Binding Protein-3 (IGFBP-3), and IGF-I/IGFBP-3 ratio. Compared with placebo, tamoxifen induced a mean +/- standard error (SE) reduction of IGF-I of 16.9 +/- 7.8%, p < 0.05, a non-significant increase of 22.9 +/- 12.2% in IGF-II, an increase in IGFBP-1 of 49.3 +/- 22.7%, p < 0.05, and a non-significant change of IGFBP-3 (-4.0% +/- 9.2). No significant concentration-response relationship was observed between serum tamoxifen concentrations and the biomarker changes except for the ratio of IGF-I/IGFBP-3, which decreased by 1.53 +/- 0.68% for any increase by 10 ng/ml of serum tamoxifen concentration (p = 0.02). Although low tamoxifen concentrations induce a comparable modulation of the IGF family relative to the conventional dose, the lower decrements in the IGF-I/IGFBP-3 ratio observed at low drug concentrations might be associated with a reduced preventive activity. Further studies on the search of the minimal active dose of tamoxifen are warranted.
Asunto(s)
Anticarcinógenos/farmacología , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/prevención & control , Factor I del Crecimiento Similar a la Insulina/análisis , Tamoxifeno/farmacología , Anticarcinógenos/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Persona de Mediana Edad , Placebos , Tamoxifeno/administración & dosificaciónRESUMEN
The activity of our group is focused on the conduction of chemoprevention clinical trials of breast cancer in at-risk subjects, among which we include women on hormone replacement therapy (HRT). The role of the insulin-like growth factor (IGF) system and of mammographic breast density as surrogate biomarkers for breast cancer prevention is also being investigated. The IGF system is involved in human carcinogenesis of several solid tumors. IGF-I is a potent mitogen for breast cancer cells; elevated circulating IGF-I levels have been associated with a higher risk of premenopausal breast cancer, prostate and colorectal cancer in prospective studies. Both tamoxifen and the synthetic retinoid fenretinide (4-HPR) have been shown to decrease plasma IGF-I levels. A trial of their combination is ongoing in premenopausal women with increased risk for breast cancer. Mammographic breast density has also been associated with an increased risk of breast cancer in several prospective studies. In this article, we discuss the rationale for selection of appropriate cohorts, candidate agents, and putative surrogate biomarkers in our breast cancer prevention trials. Moreover, updated results of the secondary prevention trial of 4-H PR and of the primary prevention trial of tamoxifen are presented. Finally, the rationale for a reduction of tamoxifen dose in future prevention trials is provided.