ABSTRACT
Non-invasive methods to assess mutational status, as well as novel prognostic biomarkers, are warranted to foster therapy personalization of patients with advanced non-small cell lung cancer (NSCLC). This study investigated the association of contrast-enhanced Computed Tomography (CT) radiomic features of lung adenocarcinoma lesions, alone or integrated with clinical parameters, with tumor mutational status (EGFR, KRAS, ALK alterations) and Overall Survival (OS). In total, 261 retrospective and 48 prospective patients were enrolled. A Radiomic Score (RS) was created with LASSO-Logistic regression models to predict mutational status. Radiomic, clinical and clinical-radiomic models were trained on retrospective data and tested (Area Under the Curve, AUC) on prospective data. OS prediction models were trained and tested on retrospective data with internal cross-validation (C-index). RS significantly predicted each alteration at training (radiomic and clinical-radiomic AUC 0.95-0.98); validation performance was good for EGFR (AUC 0.86), moderate for KRAS and ALK (AUC 0.61-0.65). RS was also associated with OS at univariate and multivariable analysis, in the latter with stage and type of treatment. The validation C-index was 0.63, 0.79, and 0.80 for clinical, radiomic, and clinical-radiomic models. The study supports the potential role of CT radiomics for non-invasive identification of gene alterations and prognosis prediction in patients with advanced lung adenocarcinoma, to be confirmed with independent studies.
ABSTRACT
Epidemiologic data support an inverse association between green tea intake and breast cancer risk. Greenselect Phytosome (GSP) is a lecithin formulation of a caffeine-free green tea catechin extract. The purpose of the study was to determine the tissue distribution of epigallocatechin-3-O-gallate (EGCG) and its effect on cell proliferation and circulating biomarkers in breast cancer patients. Twelve early breast cancer patients received GSP 300 mg, equivalent to 44.9 mg of EGCG, daily for 4 weeks prior to surgery. The EGCG levels were measured before (free) and after (total) enzymatic hydrolysis by HPLC-MS/MS in plasma, urine, breast cancer tissue, and surrounding normal breast tissue. Fasting blood samples were taken at baseline, before the last administration, and 2 hours later. Repeated administration of GSP achieved levels of total EGCG ranging from 17 to 121 ng/mL in plasma. Despite a high between-subject variability, total EGCG was detectable in all tumor tissue samples collected up to 8 ng/g. Median total EGCG concentration was higher in the tumor as compared with the adjacent normal tissue (3.18 ng/g vs. 0 ng/g, P = 0.02). Free EGCG concentrations ranged from 8 to 65.8 ng/mL in plasma (P between last administration and 2 hours after <0.001). Free EGCG plasma levels showed a significant positive correlation with the Ki-67 decrease in tumor tissue (P = 0.02). No change in any other biomarkers was noted, except for a slight increase in testosterone levels after treatment. Oral GSP increases bioavailability of EGCG, which is detectable in breast tumor tissue and is associated with antiproliferative effects on breast cancer tissue. Cancer Prev Res; 10(6); 363-9. ©2017 AACR.
Subject(s)
Anticarcinogenic Agents/pharmacokinetics , Breast Neoplasms/therapy , Camellia sinensis/chemistry , Catechin/analogs & derivatives , Plant Extracts/pharmacokinetics , Administration, Oral , Anticarcinogenic Agents/therapeutic use , Biological Availability , Biomarkers, Tumor/blood , Biopsy , Breast/pathology , Breast/surgery , Breast Neoplasms/blood , Catechin/pharmacokinetics , Catechin/therapeutic use , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Female , Humans , Hydrolysis , Lecithins/chemistry , Mastectomy , Middle Aged , Pilot Projects , Plant Extracts/therapeutic use , Tandem Mass Spectrometry , Testosterone/blood , Tissue DistributionABSTRACT
Silybin-phosphatidylcholine is an orally bioavailable complex of silybin, a polyphenolic flavonolignan derived from milk thistle, endowed with potential anticancer activity in preclinical models. The purpose of this window of opportunity trial was to determine, for the first time in early breast cancer patients, the breast tissue distribution of silybin. Twelve breast cancer patients received silybin-phosphatidylcholine, 2.8 g daily for 4 weeks prior to surgery. Silybin levels were measured before (SIL) and after (TOT-SIL) enzymatic hydrolysis by high-performance liquid chromatography (HPLC)-MS/MS in biologic samples (plasma, urine, breast cancer, and surrounding normal tissue). Fasting blood samples were taken at baseline, before the last administration, and 2 hours later. All patients were fully compliant and completed the treatment program. No toxicity was observed. SIL and TOT-SIL were undetectable in baseline samples. Despite a high between-subject variability, repeated administration of Siliphos achieved levels of TOT-SIL of 31,121 to 7,654 ng/mL in the plasma and up to 1,375 ng/g in breast cancer tissue. SIL concentrations ranged from 10,861 to 1,818 ng/mL in plasma and up to 177 ng/g in breast cancer tissue. Median TOT-SIL concentration was higher in the tumor as compared with the adjacent normal tissue (P = 0.018). No significant change in either blood levels of IGF-I and nitric oxide or Ki-67 in tumors was noted. Silybin-phosphatidylcholine, taken orally, can deliver high blood concentrations of silybin, which selectively accumulates in breast tumor tissue. These findings provide the basis for a future phase II biomarker trial in breast cancer prevention.
Subject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/drug therapy , Phosphatidylcholines/administration & dosage , Silymarin/administration & dosage , Administration, Oral , Antineoplastic Agents/pharmacokinetics , Biological Availability , Biomarkers, Tumor , Breast Neoplasms/immunology , Chromatography, High Pressure Liquid , Enzyme-Linked Immunosorbent Assay , Female , Humans , Hydrolysis , Middle Aged , Phosphatidylcholines/pharmacokinetics , Reproducibility of Results , Silybin , Silymarin/pharmacokinetics , Tandem Mass SpectrometryABSTRACT
Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin. Two-hundred non-diabetic women were randomly allocated to metformin (850 mg/bid) or placebo for 4 weeks prior to breast cancer surgery. The ki-67 response to metformin was assessed comparing data obtained from baseline biopsy (ki-67 and tumor subtype) and serum markers (HOMA index, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, hs-CRP, adiponectin) with the same measurements at definitive surgery. For patients with a blood sample taken within 24 h from last drug intake, metformin level was measured. Compared with placebo, metformin significantly decreased ki-67 in women with HOMA > 2.8, those in the lowest IGFBP-1 quintile, those in the highest IGFBP-3 quartile, those with low free IGF-I, those in the top hs-CRP tertile, and those with HER2-positive tumors. In women with HOMA index > 2.8, drug levels were positively correlated with the ki-67 decrease, whereas no trend was noted in women with HOMA < 2.8 (p-interaction = 0.07). At conventional antidiabetic doses, the effect of metformin on tumor ki-67 of non-diabetic breast cancer patients varies with host and tumor characteristics. These findings are relevant to design breast cancer prevention and treatment trials with metformin.
Subject(s)
Biomarkers, Tumor/blood , Breast Neoplasms/pathology , Hypoglycemic Agents/therapeutic use , Insulin Resistance , Metformin/therapeutic use , Adult , Breast Neoplasms/blood , Cell Proliferation/drug effects , Double-Blind Method , Female , HumansABSTRACT
BACKGROUND: Despite positive results from large phase III clinical trials proved that it is possible to prevent estrogen-responsive breast cancers with selective estrogen receptor modulators and aromatase inhibitors, no significant results have been reached so far to prevent hormone non-responsive tumors. The Ductal Lavage (DL) procedure offers a minimally invasive method to obtain breast epithelial cells from the ductal system for cytopathologic analysis. Several studies with long-term follow-up have shown that women with atypical hyperplasia have an elevated risk of developing breast cancer. The objective of the proposed trial is to assess the efficacy and safety of a daily administration of nimesulide or simvastatin in women at higher risk for breast cancer, focused particularly on hormone non-responsive tumor risk. The primary endpoint is the change in prevalence of atypical cells and cell proliferation (measured by Ki67) in DL or fine needle aspirate samples, after 12 months of treatment and 12 months after treatment cessation. METHODS-DESIGN: From 2005 to 2011, 150 women with a history of estrogen receptor negative ductal intraepithelial neoplasia or lobular intraepithelial neoplasia or atypical hyperplasia, or unaffected subjects carrying a mutation of BRCA1 or with a probability of mutation >10% (according to BRCAPRO) were randomized to receive nimesulide 100mg/day versus simvastatin 20mg/day versus placebo for one year followed by a second year of follow-up. DISCUSSION: This is the first randomized placebo controlled trial to evaluate the role of DL to study surrogate endpoints biomarkers and the effects of these drugs on breast carcinogenesis. In 2007 the European Medicines Agency limited the use of systemic formulations of nimesulide to 15 days. According to the European Institute of Oncology Ethics Committee communication, we are now performing an even more careful monitoring of the study participants. Preliminary results showed that DL is a feasible procedure, the treatment is well tolerated and the safety blood tests do not show any significant liver toxicity. There is an urgent need to confirm in the clinical setting the potential efficacy of other compounds in contrasting hormone non-responsive breast cancer. This paper is focused on the methodology and operational aspects of the clinical trial. TRIAL REGISTRATION: (ClinicalTrials.gov Identifier: NCT01500577).
Subject(s)
Breast Neoplasms/prevention & control , Simvastatin/administration & dosage , Sulfonamides/administration & dosage , Adolescent , Adult , Aged , Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Double-Blind Method , Female , Follow-Up Studies , Humans , Middle Aged , Risk Factors , Simvastatin/adverse effects , Sulfonamides/adverse effects , Therapeutic Irrigation/methods , Young AdultABSTRACT
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.
Subject(s)
Adiponectin/blood , Anticarcinogenic Agents/therapeutic use , Breast Neoplasms/blood , Breast Neoplasms/prevention & control , Fenretinide/therapeutic use , Premenopause/blood , Tamoxifen/therapeutic use , Double-Blind Method , Female , Fenretinide/administration & dosage , Humans , Leptin/blood , Middle Aged , Prognosis , Risk Factors , Tamoxifen/administration & dosageABSTRACT
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.
Subject(s)
Anticarcinogenic Agents/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Biomarkers, Tumor/blood , Breast Neoplasms/pathology , Breast Neoplasms/prevention & control , Fenretinide/therapeutic use , Insulin-Like Growth Factor I/metabolism , Mammography , Premenopause , Tamoxifen/therapeutic use , Adult , Anticarcinogenic Agents/administration & dosage , Anticarcinogenic Agents/adverse effects , Anticarcinogenic Agents/blood , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/adverse effects , Antineoplastic Agents, Hormonal/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/blood , Breast Neoplasms/diagnostic imaging , Carcinoma, Intraductal, Noninfiltrating/prevention & control , Carcinoma, Lobular/prevention & control , Double-Blind Method , Drug Administration Schedule , Drug Synergism , Female , Fenretinide/administration & dosage , Fenretinide/adverse effects , Fenretinide/blood , Humans , Incidence , Insulin-Like Growth Factor Binding Protein 3/blood , Middle Aged , Multivariate Analysis , Odds Ratio , Premenopause/blood , Proportional Hazards Models , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/administration & dosage , Tamoxifen/adverse effects , Tamoxifen/analogs & derivatives , Tamoxifen/blood , Treatment Outcome , Vitamin A/bloodABSTRACT
BACKGROUND: Oral conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) relief menopause symptoms, but may increase breast cancer risk, while the effects of transdermal estradiol (E2) and MPA are less known. In previous studies, fenretinide decreased second breast malignancies in premenopausal but not in postmenopausal women, suggesting a hormone-sensitizing effect. We have evaluated the quality of life through a self-administered questionnaire during a randomized study of oral CEE or transdermal E2 and fenretinide or placebo. METHODS: A total of 226 postmenopausal women were randomly assigned to either CEE 0.625mg/day and placebo (n=55), or CEE and fenretinide 100mg/bid (n=56), or E2, 50microg/day and placebo (n=59), or E2 and fenretinide (n=56) for 12 months. Sequential MPA 10mg/day was added in all groups. Treatment effects were investigated using a validated questionnaire, the Menopause Quality of Life questionnaire (MENQOL). RESULTS: Oral CEE and transdermal E2 have a comparable activity in reducing menopausal symptoms (p=ns). Both routes ameliorate significantly the symptoms after 1 year of treatment (p<0.0001). Fenretinide does not modify the effects of hormonal replacement therapy. CONCLUSIONS: Oral CEE and transdermal E2 have similar effect on menopausal symptoms relief. The choice of the best estrogen replacement therapy (ERT) route should be decided based on a careful analysis of all the clinical aspects of every subject, considering that transdermal therapy may have a safer effect on the cardiovascular system.
Subject(s)
Estradiol/administration & dosage , Estrogen Replacement Therapy , Estrogens, Conjugated (USP)/administration & dosage , Fenretinide/administration & dosage , Hot Flashes/prevention & control , Quality of Life , Administration, Cutaneous , Administration, Oral , Drug Administration Schedule , Drug Therapy, Combination , Female , Hot Flashes/pathology , Hot Flashes/psychology , Humans , Medroxyprogesterone Acetate/administration & dosage , Menopause , Middle Aged , Surveys and Questionnaires , Treatment OutcomeABSTRACT
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.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/prevention & control , Adult , Double-Blind Method , Endometrium/drug effects , Endometrium/pathology , Female , Fenretinide/administration & dosage , Fenretinide/adverse effects , Humans , Insulin-Like Growth Factor I/analysis , Middle Aged , Premenopause , Tamoxifen/administration & dosage , Tamoxifen/adverse effects , Vitamin A/bloodABSTRACT
BACKGROUND: Tamoxifen reduces the risk of breast cancer in women at high risk for the disease but increases the risk for endometrial tumors and venous thromboembolisms, possibly in a dose-dependent fashion. We compared the effects of tamoxifen at 1 mg/day and 5 mg/day with those of the standard dose of 20 mg/day on breast cancer proliferation using a surrogate endpoint marker (Ki-67 expression) and blood biomarkers associated with breast cancer, cardiovascular disease, and bone fracture risk. METHODS: We randomly assigned 120 women with estrogen receptor (ER)-positive breast cancer to tamoxifen at 1, 5, or 20 mg/day for 4 weeks. Expression of the tumor proliferation marker Ki-67 and of biomarkers of breast cancer (insulin-like growth factor-I, sex hormone-binding globulin), cardiovascular disease (cholesterol, triglycerides, ultrasensitive C-reactive protein, fibrinogen, antithrombin-III), and bone fracture (type I collagen C-telopeptide) risk were determined before (baseline) and after treatment. All levels were compared with those in two nonrandomized control groups (34 women with ER-negative breast cancer and 29 additional women with ER-positive breast cancer). Data were analyzed by analysis of covariance. All statistical tests were two-sided. RESULTS: Expression of Ki-67 decreased in all three tamoxifen groups, with no difference in the magnitude of reduction among groups (P =.81). Relative to baseline, Ki-67 expression decreased by a median of 15.0% (95% confidence interval = 0.0% to 24.1%) among the tamoxifen groups but increased by 12.8% (95% confidence interval = 0.0% to 19.6%) among the nonrandomized control groups. Several blood biomarkers showed dose-response relationships with tamoxifen, including decreased insulin-like growth factor-I, increased sex hormone-binding globulin, and decreased low-density lipoprotein-cholesterol, ultrasensitive C-reactive protein, fibrinogen, and antithrombin-III levels. CONCLUSIONS: The effects on Ki-67 expression of lower doses of tamoxifen were comparable to those achieved with the standard dose, although the effects on blood biomarkers were variable. The effects of lower doses of tamoxifen should be assessed further in randomized trials.
Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Biomarkers, Tumor/blood , Breast Neoplasms/drug therapy , Estrogen Receptor Modulators/therapeutic use , Estrogens/blood , Tamoxifen/therapeutic use , Adult , Aged , Antineoplastic Agents, Hormonal/administration & dosage , Breast Neoplasms/blood , Breast Neoplasms/chemistry , Dose-Response Relationship, Drug , Drug Administration Schedule , Estrogen Receptor Modulators/administration & dosage , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Immunohistochemistry , Ki-67 Antigen/blood , Middle Aged , Research Design , Tamoxifen/administration & dosageABSTRACT
BACKGROUND: The increase in C-reactive protein (CRP) during oral conjugated equine estrogen (CEE) may explain the initial excess of cardiovascular disease observed in clinical studies. Because the effect of transdermal estradiol (E2) on CRP is unclear, we compared CRP changes after 6 and 12 months of transdermal E2 and oral CEE in a randomized 2x2 retinoid-placebo trial. METHODS AND RESULTS: A total of 189 postmenopausal women were randomized to 50 microg/d transdermal E2 and 100 mg BID of the retinoid fenretinide (n=45), 50 microg/d transdermal E2 and placebo (n=49), 0.625 mg/d oral CEE and 100 mg BID fenretinide (n=46), or 0.625 mg/d oral CEE and placebo (n=49) for 1 year. Sequential medroxyprogesterone acetate was added in each group. Relative to baseline, CRP increased by 10% (95% CI -9% to 33%) and by 48% (95% CI 22% to 78%) after 6 months of transdermal E2 and oral CEE, respectively. The corresponding figures at 12 months were 3% (95% CI -14% to 23%) for transdermal E2 and 64% (95% CI 38% to 96%) for oral CEE. Fenretinide did not change CRP levels at 6 and 12 months relative to placebo. Relative to oral CEE, the mean change in CRP after 12 months of transdermal E2 was -48% (95% CI -85% to -7%, P=0.012), whereas fenretinide was associated with a mean change of -1% (95% CI -34% to 40%, P=0.79) compared with placebo. CONCLUSIONS: In contrast to oral CEE, transdermal E2 does not elevate CRP levels up to 12 months of treatment. The implications for early risk of coronary heart disease require further studies.
Subject(s)
Antineoplastic Agents/therapeutic use , C-Reactive Protein/analysis , Estradiol/pharmacology , Estrogens, Conjugated (USP)/pharmacology , Fenretinide/therapeutic use , Administration, Oral , Biomarkers/blood , Breast Neoplasms/etiology , Breast Neoplasms/prevention & control , Coronary Disease/etiology , Coronary Disease/prevention & control , Dermis , Estradiol/administration & dosage , Estrogen Replacement Therapy , Estrogens, Conjugated (USP)/administration & dosage , Female , Humans , Kinetics , Middle Aged , Postmenopause , Risk FactorsABSTRACT
Hormone replacement therapy (HRT) can increase the quality as well as the length of life, but a prolonged use can also increase the risk of breast cancer. The combination of HRT and a selective estrogen receptor modulator (SERM) such as tamoxifen may retain the benefits while reducing the risks of either agent. A post hoc analysis of the Italian Tamoxifen Prevention Study showed a borderline significant reduction of breast cancer among women who were on HRT continuously and tamoxifen as compared with continuous HRT users who received placebo. Recent studies suggest that the standard dose of tamoxifen may be reduced to one-quarter (i.e., 10 mg every other day) without loss of its beneficial biological effects. Since the endometrial effect of tamoxifen seems to be both dose and time dependent, a dose reduction could substantially reduce the risk of endometrial cancer while retaining its preventive efficacy. On the other hand, the addition of HRT containing progestins could also minimize the risk of endometrial cancer associated with tamoxifen. Moreover, estrogen should reduce the incidence of vasomotor and urogenital symptoms, which are a major reason for tamoxifen withdrawal in prevention studies. Notably, in the National Surgical Adjuvant Breast Project (NSABP) P-1 trial, women ages 50 or younger had no increased incidence of adverse events, including endometrial cancer and venous thromboembolic events. One possible explanation for the lack of toxicity in premenopause is the presence of adequate circulating estrogen levels which prevent tamoxifen to act as an estrogen agonist at these target tissues. Moreover, data from the current Italian tamoxifen prevention trial indicate that the compliance was substantially higher for de novo and current HRT users as compared to women who never received HRT during the study. The combination of HRT and tamoxifen at low doses could thus reduce the risks and side effects while retaining the benefits of either agent.