Fig 3 - uploaded by Aliana Guerrieri-Gonzaga
Content may be subject to copyright.
Relationship between baseline and post-treatment (12 months) sex-hormone binding protein (SHBG) levels. The solid black line corresponds to the regression line of the predicted values of SHBG on oral conjugated equine estrogen (CEE; F); the dotted line corresponds to the regression line of the predicted values of SHBG on transdermal estradiol (E2; ). All of the subjects received sequential medroxyprogesterone acetate, 10 mg/day for 12 days each cycle. Predicted SHBG values were obtained from analysis of covariance for post-treatment SHBG values for a woman with median body mass index of 24 kg/m 2 . Note the log scale on both axes.
Source publication
Oral conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) increase breast cancer risk, whereas the effect of transdermal estradiol (E2) and MPA is less known. Fenretinide may decrease second breast malignancies in premenopausal women but not in postmenopausal women, suggesting a hormone-sensitizing effect. We compared the 6 and 12...
Citations
... Sample concentrations were obtained by a four-parameter logistic curve fit, with a minimum detectable PCSK9 concentration of 0.219 ng/mL [20]. Percentage mammographic density was centrally measured on analogue screen films or digital scans by a single trained radiologist, using a computer-assisted method [21]. ...
Simple Summary
Breast cancer is recognized as the most common cancer within the female population. In this context, cholesterol is recognized as a vital component for the proliferation and survival of cancer cells. These cells primarily acquire cholesterol through the receptor-mediated uptake from external sources, including low-density lipoprotein (LDL), utilizing the endocytosis pathway. Thus, this observational study aimed to test the effectiveness of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in cancer onset. Although PCSK9 correlated with lipid parameters (e.g., cholesterol, LDL) and with 17 β-estradiol, our results do not portend PCSK9 is a prognostic biomarker, at least, in the context of breast neoplastic events.
Abstract
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.
... Moreover, Flyvbjerg et al., did not include data on BMI, diabetes mellitus (DM), and hormone replacement therapy (HRT) in their publication [25], which questions the reliability of the results, given the fact that both, BMI and DM have a proven effect on serum IGF-1 level [33,34]. Numerous studies have also indicated that oral HRT leads to a significant decrease in serum IGF-1 levels, which is probably due to direct inhibition of the synthesis of this factor in the liver by oral estrogen [35]. We observed no significant differences in either, BMI values or distribution of comorbidities in OC patients with IGF-1 and controls. ...
... IGF-1 is most likely involved in the etiology of OC. Unfortunately, the level of serum IGF-1 is influenced by numerous factors both, genetic and exogenous, such as diet, exercise, medication, BMI, chronic diseases (DM, cardiovascular and other), and age [14,15,29,[31][32][33][34][35]37]. In addition, not all factors which influence the regulation of serum IGF-1 have been fully elucidated. ...
... However, based on our results and the available literature, it seems safe to conclude that the level of IGF-1 in OC tissues is probably affected by endocrine and autocrine regulation, which is consistent with the results obtained by Brokow and Conover [6,38]. Studies conducted to clarify the role of IGF-1 (both, locally synthesized and peripherally circulating serum) in the biology of breast cancer, have confirmed the role of this factor in the oncogenesis of this tumor [35]. The carcinogenesis of OC may be analogous and the IGF-1 present in the serum is involved in the carcinogenesis of this tumor mainly in young, menstruating women. ...
Objectives:
The aim of the study was to investigate serum concentrations of the insulin-like growth factor-1 in women with ovarian cancer and healthy controls, and to compare free IGF-1 levels with selected clinical and pathological param-eters. Correlation analysis was used to measure the following: IGF-1 concentration and Ca125; IGF-1 level and the height of the OC patients.
Material and methods:
The study included 70 patients with OC and 50 healthy controls. Serum concentrations of free IGF-1 were measured in all subjects. Routine diagnostic tests (CBC and USG and Ca125) were performed.
Results:
Significantly higher serum concentrations of free IGF-1 were found in the study group as compared to controls. No statistically significant relationships between IGF-1 serum concentrations and tumor differentiation, histological type, and disease stage were detected. No statistically significant correlations between IGF-1 and Ca125 level or between IGF-1 and growth of OC patients were found.
Conclusions:
Serum IGF-1 participates in the etiopathogenesis of ovarian cancer in menstruating women, while local synthesis of this factor and other components of the autocrine loop of the IGF-1 system play a greater role in their post-menopausal peers.
... Importantly, serum IGF-1 is synthesized mainly in the liver, and its level is affected by numerous endogenous -genetic predispositions, and exogenous factors -diet, physical exercise, medication use, including HRT, BMI, chronic disease (DM, cardiovascular and other conditions), as well as age [37][38][39][40][41][42][43][44][45][46][47]. Authors of the abovementioned publications adjusted their results to the factors which might potentially affect the results of their analyses. ...
Insulin-like growth factor 1 (IGF-1) is a mitogen which plays a key role in regulating cell proliferation, differentiation, and apoptosis. It belongs to the family of proteins also composed of insulin-like growth factor 2 (IGF-2), two types of membrane receptors (IGF-1R and IGF-2R), 6 binding proteins (IGFBP 1-6), hydrolyzing proteases, and reactive molecules binding proteins, which regulate the activity of growth factors. Disturbances in the functioning of IGFBP/IGF/1GF1R can lead to induction of carcinogenesis, which has been demonstrated in breast, prostate or colon cancers. Findings evaluating the role of IGF-1 in endometrial cancer biology are ambiguous and contradictory. Therefore, in the present study, we analyzed the role of IGF-1 in the process of carcinogenesis of endometrial cancer, based on the available literature.
... Intake of ocs is reported to raise the expression level and bioactivity of circulating estradiol in diverse ways [17][18][19] . However, the effect of oc intake on serum igf-1and igfbp-3 expression has been evaluated only in population studies, which have produced inconsistent results [20][21][22][23] . ...
Background:
Previous studies suggest a combined effect of insulin-like growth factor 1 (igf-1) and igf binding protein 3 (igfbp-3) gene polymorphisms, xenoestrogen, and phytoestrogen on the igf-1 signalling pathway and serum concentrations in the igf system, which are associated with premenopausal breast cancer (bca) risk.
Methods:
Between 2010 and 2012, our study recruited 140 premenopausal bca patients and 160 community-based premenopausal control subjects. Participants were surveyed about oral contraceptive (oc) use, dietary habits, and other bca risk factors. TaqMan assays were used to determine igf-1 rs1520220 and igfbp-3 rs2854744 genotypes. Daily intakes of energy-adjusted soy isoflavones (easis) were calculated by the residual method. Multivariate logistic regression was applied to estimate the adjusted odds ratios (ors) and 95% confidence intervals (cis) of the igf-1 rs1520220 and igfbp-3 rs2854744 genotypes, oc use, and intake of easis. Stratified analyses were performed to detect the gene-environment combined effect, and multivariate logistic regression was used to estimate interaction coefficients (iors) by the multiplicative model, with 95% cis. The delta method was used to calculate interaction coefficients by the additive model [relative excess risk of interaction (reri), attributable proportions of interaction (apis)] and 95% cis.
Results:
The igf-1 and igfbp-3 genotypes, oc use, and easis were not found to be associated with bca risk (p > 0.05). Stratified analysis showed that the risk of bca was markedly increased in women carrying the igfbp-3C allele and using ocs compared with women either carrying the igfbp-3C allele or using ocs (or: 3.02; 95% ci: 1.04 to 8.79). The interaction coefficients ior, reri, and api were 4.89 (95% ci: 1.09 to 21.90), 2.42 (95% ci: -0.76 to 5.61), and 0.80 (95% ci: 0.46 to 1.67) respectively.
Conclusions:
The igfbp-3 rs2854744 polymorphism and oc use might synergistically increase premenopausal bca risk.
... Fenretinide (in combination with HRT) was also studied by our group in 226 postmenopausal healthy women, randomized in a two-by-two factorial design to either oral CEE 0.625 mg/day or transdermal E2, 50 microg/day and to fenretinide 100 mg/twice a day or placebo for 12 months [61]. Oral CEE showed more favorable changes than transdermal E2 on circulating breast cancer risk biomarkers, while fenretinide exerted little modulation on most biomarkers. ...
The incidence and mortality of breast cancer have been recently influenced by several new therapeutic strategies. In particular our knowledge on cancer precursors, risk biomarkers, and genetics has considerably increased, and prevention strategies are being successfully explored. Since their discovery, retinoids, the natural and synthetic derivatives of vitamin A, have been known to play a crucial role in cell and tissue differentiation and their ability to inhibit carcinogenesis has made them the ideal chemopreventive agents studied in several preclinical and clinical trials. Fenretinide (4-HPR) is the most studied retinoid in breast cancer chemoprevention clinical trials due to its selective accumulation in breast tissue and its favorable toxicological profile. This agent showed a significative reduction of the incidence of second breast tumors in premenopausal women confirmed after 15-year followups. Considering Fenretinide protective action, a similar trend on ovarian cancer, this drug warrants reevaluations as a preventive agent for high-risk young women, such as BRCA-1 and 2 mutation carriers or with a high familial risk. This favorable effect therefore provides a strong rationale for a primary prevention trial in these unaffected cohort of women.
... A critical aspect in the design of these trials has been the selection of appropriate surrogate end-points of treatment response. In addition to measuring objective tumor response, a few studies have incorporated serum measurement of IGFBP-3 as a biomarker of disease progression.1213141516 IGFBP-3, the most abundant IGFBP in circulation, is expressed in several cancers and was recently shown to exert IGF-independent inhibitory activity on angiogenesis in vivo.[17,18] ...
Different Insulin-like Growth Factor Binding Proteins (IGFBPs) have been investigated as potential biomarkers in several types of tumors. In this study, we examined both IGFBP-3 and -4 levels in tissues and sera of melanoma patients representing different stages of melanoma progression.
The study cohort consisted of 132 melanoma patients (primary, n = 72; metastatic, n = 60; 64 Male, 68 Female; Median Age = 56) prospectively enrolled in the New York University School of Medicine Interdisciplinary Melanoma Cooperative Group (NYU IMCG) between August 2002 and December 2006. We assessed tumor-expression and circulating sera levels of IGFBP-3 and -4 using immunohistochemistry and ELISA assays. Correlations with clinicopathologic parameters were examined using Wilcoxon rank-sum tests and Spearman-rank correlation coefficients.
Median IGFBP-4 tumor expression was significantly greater in primary versus metastatic patients (70% versus 10%, p = 0.01) A trend for greater median IGFBP-3 sera concentration was observed in metastatic versus primary patients (4.9 microg/ml vs. 3.4 microg/ml, respectively, p = 0.09). However, sera levels fell within a normal range for IGFBP-3. Neither IGFBP-3 nor -4 correlated with survival in this subset of patients.
Decreased IGFBP-4 tumor expression might be a step in the progression from primary to metastatic melanoma. Our data lend support to a recently-described novel tumor suppressor role of secreting IGFBPs in melanoma. However, data do not support the clinical utility of measuring levels of IGFBP-3 and -4 in sera of melanoma patients.
... Sex hormone replacement therapy in postmenopausal women has been shown to decrease colorectal cancer risk as well as the development of colorectal adenomas (2)(3)(4). Both sex hormone replacement therapy (5,6) and selective estrogen receptor modulators, e.g., tamoxifen (7,8), have been shown to reduce serum insulin-like growth factor-I (IGF-I) concentrations. ...
Increased insulin-like growth factor (IGF)-I and IGF-II concentrations are related to increased colorectal cancer risk. Isoflavones have been associated with reduced colorectal cancer risk, and may affect the IGF system because of their weak estrogenic activity. The aim of the study was to investigate the effect of isolated isoflavones on serum concentrations of IGF system components.
We conducted a randomized, placebo-controlled, double-blinded, crossover trial in four hospitals in the Netherlands to investigate the effect of an 8-week supplementation with red clover-derived isoflavones (84 mg/d) on serum IGF-I concentrations. In addition, serum concentrations of IGF-II and IGF binding proteins (IGFBP)-1, IGFBP-2, and IGFBP-3 were assessed. Normal colorectal tissue biopsies were obtained after the first intervention period and mRNA expression of IGF-I, IGF-II, IGFBP-3, and IGF-IR was evaluated. Our study population consisted of 34 postmenopausal women with a family history of colorectal cancer or a personal history of colorectal adenomas.
Isoflavone supplementation did not significantly affect serum concentrations of total IGF-I (mean relative within-person difference; IGF-I, -2.0%; 95% confidence interval, -8.0% to 3.9%). IGF-II and IGFBPs were also not significantly altered after isoflavone supplementation. Colorectal tissue mRNA expression of IGF system components did not significantly differ between individuals on isoflavone supplementation and those who received placebo.
The results of our trial, supported by a qualitative review of soy trials published to date, suggest that isoflavones do not significantly affect circulating levels of IGF system components. Increased levels of IGF-I, as observed in most of these trials, are likely due to simultaneous protein supplementation.
... This may explain the lower CHD risk associated with transdermal E2 [16]. In addition, we found that transdermal E2 has different effects to oral CEE on circulating IGF-I and SHBG, but is associated with a similar increase in mammographic density [17]. To provide insight into the effects of fenretinide and the different routes of HRT administration on biomarkers of CHD risk, we investigated in a randomized trial the changes in lipids and clotting profiles, including total cholesterol high-density lipoprotein cholesterol (HDL-C), lowdensity lipoprotein cholesterol (LDL-C), triglycerides antithrombin III (AT-III), fibrinogen platelets and PAI-1, after 12 months of transdermal E2, oral CEE and fenretinide or placebo. ...
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.
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).
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.
... It has been reported that oral conjugated equine estrogen has more favorable changes than transdermal estradiol on circulating breast cancer risk biomarkers, but gives similar effects on mammographic density [64]. The Million Women Study [4], reported that, compared with never users, the risk of breast cancer in transdermal HRT users was only moderately lower than that of oral HRT. ...
The effects of persistence with hormone replacement therapy (HRT) on the risk of hospitalization for cancer and of the route of HRT administration on the risk of breast and colorectal cancer were explored in a large cohort study.
The 73 505 women residing in Lombardia (Italy), aged 45-75 years, who received at least one HRT prescription during 1998-2000 were followed until 2005. Among these, 3687 experienced cancer hospitalization. Proportional hazards model was fitted to estimate the association between cumulative HRT persistence and cancer risk.
Compared with women who took HRT for <6 months, those exposed for >2 years showed hazard ratios (HR) of 0.78 (95% confidence interval 0.68-0.92) for colorectal cancer and 1.34 (1.13-1.58) for breast cancer. HR for breast cancer associated with long-term use of transdermal and oral HRT were, respectively, 1.27 (1.07-1.51) and 2.14 (1.43-3.21).
Evidence that long-term use of HRT is associated with increased risk of breast cancer and decreased risk of colorectal cancer is supplied from this study from a southern European population. Our findings indicate that transdermal therapy might have lower effect than oral therapy in increasing breast cancer risk.
... The percentage of breast density showed an absolute increase of 3.5% (95% CI, 2.5–4.6%) during hormone therapy, with no significant differences between groups (Decensi et al. 2004b). As for the effects of treatments on biomarkers of CVD risk, CRP increased by 3% (95% CI, x14 to 23%) and by 64% (95% CI, 38–96%) after 12 months of transdermal E 2 and oral CEE respectively, relative to baseline. ...
... Serious adverse events occurred in two subjects, who developed breast cancer (one on transdermal E 2 and placebo, and one on transdermal E 2 and fenretinide), while the vast majority of the remaining adverse events were grade 1 or 2. In conclusion, CEE produced more favourable changes than transdermal E 2 on circulating breast cancer risk biomarkers, but gave similar effects on mammographic density. The addition of fenretinide provided little modulation of circulating biomarkers, suggesting that it is not an active antidote for reducing breast cancer risk promoted by ERT use (Decensi et al. 2004b). In view of the effects observed on CRP levels, transdermal E 2 might be safer than oral CEE at cardiovascular level, especially in women with high CVD risk (Decensi et al. 2002). ...
... The Million Women Study has recently shown that, compared with never users, women on oestrogen replacement therapy (ERT) with transdermal E 2 have a similar breast cancer risk as women taking oral CEE (Beral & Million Women Study Collaborators 2003), although transdermal E 2 does not seem to be associated with increased venous thromboembolism and, consequently, might have a safer profile on CVD risk (Scarabin et al. 2003). To provide additional insights into the effects of transdermal E 2 on breast cancer risk, the changes induced by oral CEE or transdermal E 2 , administered in a continuous sequential regimen with MPA, on a panel of breast cancer risk biomarkers have been compared in a study recently conducted at the European Institute of Oncology (Decensi et al. 2004b). In addition, the effect of fenretinide during ERT was also investigated in this study, in an attempt to reduce breast cancer risk in ERT users. ...
Retinoids have been studied as chemopreventive agents in clinical trials due to their established role in regulating cell growth, differentiation and apoptosis in preclinical models. Experimental evidence suggests that retinoids affect gene expression both directly, by activating and/or repressing specific genes, and indirectly, by interfering with different signal transduction pathways. Induction of apoptosis is a unique feature of fenretinide, the most widely studied retinoid in clinical trials on breast cancer chemoprevention due to its selective accumulation in breast tissue and to its favourable toxicological profile. In a phase III breast cancer prevention trial, fenretinide showed a durable trend to a reduction of second breast malignancies in premenopausal women. This pattern was associated with a favourable modulation of circulating IGF-I and its main binding protein (IGF-binding protein-3, IGFBP-3), which have been associated with breast cancer risk in premenopausal women in different prospective studies. In a subsequent biomarker study on premenopausal women who had participated in the phase III trial, high IGF-I and low IGFBP-3 baseline levels were found to predict second breast cancer risk, although the magnitude of their changes during treatment did not fulfil the requirements for suitable surrogate end-point biomarkers. In postmenopausal women, fenretinide did not reduce second breast cancer incidence, nor did it induce significant modulation of the IGF system. Similarly, fenretinide was not found to affect risk biomarkers significantly in early postmenopausal women on hormone replacement therapy, who are at increased risk of developing breast cancer. Biomarker studies of fenretinide alone or in combination with different nuclear receptor ligands are being conducted. In particular, clinical trials of fenretinide and tamoxifen have proved to be feasible, and this combination appears to be safe and well tolerated in high-risk women, especially when low-dose tamoxifen is employed. Novel retinoid X receptor-selective retinoids, or rexinoids, have been shown to suppress the development of breast cancer in several animal models with minimal toxicity, and are being intensively studied either alone or in combination with selective oestrogen receptor modulators, both in vitro and in vivo. The rexinoid, bexarotene, has recently been approved for the treatment of patients with cutaneous T-cell lymphoma, and a biomarker trial with bexarotene in women with high breast cancer risk is currently underway.
