Breast Cancer Abstracts 7

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Effect of ultra-low-dose estriol and lactobacilli vaginal tablets (Gynoflor®) on inflammatory and infectious markers of the vaginal ecosystem in postmenopausal women with breast cancer on aromatase inhibitors.
            (Donders et al., 2015) Download
This study was a detailed microscopic analysis of the changes of vaginal microflora characteristics after application of 0.03 mg estriol-lactobacilli combination on the vaginal ecosystem in postmenopausal breast cancer (BC) survivors on aromatase inhibitors (AI) with severe atrophic vaginitis. A total of 16 BC women on AI applied daily one vaginal tablet of Gynoflor® for 28 days followed by a maintenance therapy of three tablets weekly for 8 weeks. During four follow up visits a smear from the upper lateral vaginal wall was analysed by phase contrast microscopy at 400 times magnification in order to classify the lactobacillary grades(LBG), bacterial vaginosis (BV), aerobic vaginitis (AV), vulvovaginal candidosis (VVC), proportional number of leukocytes and evidence of parabasal cells and epitheliolysis. LBG improved from 81% LBG-III at entry to 88% LBG-I&IIa after 2 weeks of initial therapy, which further improved upon follow up (p < 0.001). Whereas BV was a rare event, AV was frequent and substantially improved during treatment (p < 0.01). While at entry most patients had moderate or severe AV, after maintenance therapy no patient except one had AV. The number of leukocytes dropped dramatically from a score of 1.78 ± 0.70 to 1.06 ± 0.25 which was consistent till the end of the study (p < 0.01). Parabasal cells dropped from a score of 3.4 ± 0.64 at entry to 1.3 ± 0.60 at the final visit (p trend < 0.01). Starting from a low rate of Candida colonisation of 2/14 (14%), a sudden rise to 7/16 (44%) occurred after 2 weeks, to return back to base levels at subsequent visits. The vaginal use of ultra-low dose estriol and lactobacilli results in rapid and enduring improvement of all markers of the vaginal microflora and epithelial vaginal cell quality in women with breast cancer on AI with dyspareunia. Candida may develop soon after its use, but rapidly disappears again upon their prolonged use. Due to its excellent safety profiles and clinical efficacy we recommend this product as first choice in women on AI with severe dyspareunia.


 

Urinary estrogens and estrogen metabolites and subsequent risk of breast cancer among premenopausal women.
            (Eliassen et al., 2012) Download
Endogenous estrogens and estrogen metabolism are hypothesized to be associated with premenopausal breast cancer risk but evidence is limited. We examined 15 urinary estrogens/estrogen metabolites and breast cancer risk among premenopausal women in a case-control study nested within the Nurses' Health Study II (NHSII). From 1996 to 1999, urine was collected from 18,521 women during the mid-luteal menstrual phase. Breast cancer cases (N = 247) diagnosed between collection and June 2005 were matched to two controls each (N = 485). Urinary estrogen metabolites were measured by liquid chromatography-tandem mass spectrometry and adjusted for creatinine level. Relative risks (RR) and 95% confidence intervals (CI) were estimated by multivariate conditional logistic regression. Higher urinary estrone and estradiol levels were strongly significantly associated with lower risk (top vs. bottom quartile RR: estrone = 0.52; 95% CI, 0.30-0.88; estradiol = 0.51; 95% CI, 0.30-0.86). Generally inverse, although nonsignificant, patterns also were observed with 2- and 4-hydroxylation pathway estrogen metabolites. Inverse associations generally were not observed with 16-pathway estrogen metabolites and a significant positive association was observed with 17-epiestriol (top vs. bottom quartile RR = 1.74; 95% CI, 1.08-2.81; P(trend) = 0.01). In addition, there was a significant increased risk with higher 16-pathway/parent estrogen metabolite ratio (comparable RR = 1.61; 95% CI, 0.99-2.62; P(trend) = 0.04). Other pathway ratios were not significantly associated with risk except parent estrogen metabolites/non-parent estrogen metabolites (comparable RR = 0.58; 95% CI, 0.35-0.96; P(trend) = 0.03). These data suggest that most mid-luteal urinary estrogen metabolite concentrations are not positively associated with breast cancer risk among premenopausal women. The inverse associations with parent estrogen metabolites and the parent estrogen metabolite/non-parent estrogen metabolite ratio suggest that women with higher urinary excretion of parent estrogens are at lower risk.

Estrone - a partial estradiol antagonist in the normal breast.
            (Lundström et al., 2015) Download
Oral hormone replacement therapy (HRT) based on estradiol-17β (E2) greatly increases circulating estrone (E1) levels. E1 is an estrogen receptor agonist but may also be a partial E2 antagonist. We investigated the effects of circulating E1 on the association between circulating E2 and the increase in mammographic density (∂MD) in 46 healthy post-menopausal women treated with E2 2 mg and norethisterone acetate 1 mg daily. MD and serum E1 and E2 were measured before and after 6 months of treatment. At high E1 levels, ∂MD showed significant positive correlations leading to increase (∂-values) in both E1 and E2. Lowering the upper serum E1 limit strengthened the correlations to ∂E2 while the significant correlations to ∂E1 disappeared. E1 at high concentrations may act as a partial E2 antagonist also in the normal breast in vivo and disturb relationships between circulating E2 and biological estrogen effects. When investigating the relations between circulating steroids and their effects, structurally related compounds, which may act as partial antagonists, have to be considered, at least when they are present in higher concentrations.

Vaginal Estrogen Therapy for Patients with Breast Cancer.
            (Moegele et al., 2013) Download
On account of the good prognosis for patients with breast cancer, improving or maintaining the quality of life in the aftercare period is becoming more and more important. In particular, the increasing usage of aromatase inhibitors in the past few years has led to an increased incidence of vaginal atrophy with symptoms such as vaginal dryness, petechial bleeding, dyspareunia and recurrent cystitis. And just these symptoms have a detrimental impact on the quality of life of breast cancer patients. Application of a topical estrogen therapy represents the most effective means to treat vaginal atrophy. The use of a systemic or, respectively, topical hormone therapy is, however, contraindicated for breast cancer patients. Further clinical trials are needed in order to assess the safety of vaginal estrogen therapy. ZUSAMMENFASSUNG:  Aufgrund der guten Prognose von Mammakarzinompatientinnen nimmt die Verbesserung bzw. Erhaltung der Lebensqualität in der Nachsorge einen zunehmenden Stellenwert ein. Gerade der vermehrte Einsatz von Aromatasehemmern hat in den vergangenen Jahren zu einer Zunahme der vaginalen Atrophie mit Symptomen wie Scheidentrockenheit, petechialen Blutungen, Dyspareunie und rezidivierenden Zystitiden geführt. Gerade diese Symptome beeinflussen in gravierender Weise die Lebensqualität von Mammakarzinompatientinnen. Die Anwendung einer lokalen Östrogentherapie stellt die effektivste Behandlungsform der Vaginalatrophie dar. Die Anwendung einer systemischen bzw. einer lokalen Hormontherapie bei Brustkrebspatientinnen ist jedoch kontraindiziert. Zur Beurteilung der Sicherheit einer vaginalen ET sind weitere klinische Studien erforderlich.

Vaginal estriol to overcome side-effects of aromatase inhibitors in breast cancer patients.
            (Pfeiler et al., 2011) Download
OBJECTIVE:  Aromatase inhibitors are essential as endocrine treatment for hormone receptor-positive postmenopausal breast cancer patients. Menopausal symptoms are often aggravated during endocrine treatment. We investigated whether vaginal estriol is a safe therapeutic option to overcome the urogenital side-effects of aromatase inhibitors. Serum hormone levels were used as the surrogate parameter for safety. METHODS:  Fasting serum hormone levels of ten postmenopausal breast cancer patients receiving aromatase inhibitors were prospectively measured by electro-chemiluminescence immunoassays and gas chromatography/mass spectrometry before and 2 weeks after daily application of 0.5 mg vaginal estriol (Ovestin® ovula), respectively. RESULTS:  Two weeks of daily vaginal estriol treatment did not change serum estradiol or estriol levels. However, significant decreases in levels of serum follicle stimulating hormone (p = 0.01) and luteinizing hormone (p = 0.02) were observed. Five out of six breast cancer patients noticed an improvement in vaginal dryness and/or dyspareunia. CONCLUSIONS:  The significant decline in gonadotropin levels, indicating systemic effects, has to be kept in mind when offering vaginal estriol to breast cancer patients receiving an aromatase inhibitor.

Primary prevention of breast cancer by hormone-induced differentiation.
            (Russo and Russo, 2007) Download
Breast cancer is a fatal disease whose incidence is gradually increasing in most industrialized countries and in all ethnic groups. Primary prevention is the ultimate goal for the control of this disease. The knowledge that breast cancer risk is reduced by early full-term pregnancy and that additional pregnancies increase the rate of protection has provided novel tools for designing cancer prevention strategies. The protective effect of pregnancy has been experimentally reproduced in virgin rats by treatment with the placental hormone human chorionic gonadotropin (hCG). HCG prevents the initiation and inhibits the progression of chemically induced mammary carcinomas by inducing differentiation of the mammary gland, inhibiting cell proliferation, and increasing apoptosis. It also induces the synthesis of inhibin, a tumor suppressor factor, downregulates the level of expression of the estrogen receptor alpha (ER-alpha) by methylation of CpG islands, imprinting a permanent genomic signature that characterizes the refractory condition of the mammary gland to undergo malignant transformation. The genomic signature induced by hCG is identical to that induced by pregnancy and is specific for this hormone. Comparison of the mammary gland's genomic profile of virgin Sprague-Dawley rats treated daily with hCG for 21 days with that of rats receiving 17beta-estradiol (E2) and progesterone (Pg) (E2 + Pg) revealed that in hCG-treated rats 194 genes were significantly up-modulated (> 2.5 log2-folds) (p < 0.01) and commonly expressed, whereas these genes were not expressed in the E2 + Pg group. The genomic signature induced by hCG and pregnancy included activators or repressors of transcription genes, apoptosis, growth factors, cell division control, DNA repair, tumor suppressor, and cell-surface antigen genes. Our data indicate that hCG, like pregnancy, induces permanent genomic changes that are not reproduced by steroid hormones and in addition regulates gene expression through epigenetic mechanisms that are differentiation-dependent processes, leading us to conclude that hormonally induced differentiation offers enormous promise for the primary prevention of breast cancer.


 

Free β-human chorionic gonadotropin, total human chorionic gonadotropin and maternal risk of breast cancer.
            (Toriola et al., 2014) Download
BACKGROUND:  We investigated whether the free β-human chorionic gonadotropin (free β-hCG) would provide additional information to that provided by total hCG alone and thus be useful in future epidemiological studies relating hCG to maternal breast cancer risk. MATERIALS & METHODS:  Cases (n = 159) and controls (n = 286) were a subset of our previous study within the Northern Sweden Maternity Cohort on total hCG during primiparous pregnancy and breast cancer risk. RESULTS:  The associations between total hCG (hazard ratio: 0.79; 95% CI: 0.49-1.27), free β-hCG (hazard ratio: 0.85; 95% CI: 0.33-2.18) and maternal risk of breast cancer were very similar in all analyses and mutual adjustment for either one had minor effects on the risk estimates. CONCLUSION:  In the absence of a reliable assay on intact hCG, total hCG alone can be used in epidemiological studies investigating hCG and breast cancer risk, as free β-hCG does not appear to provide any additional information.

Human alpha-fetoprotein peptides bind estrogen receptor and estradiol, and suppress breast cancer.
            (Vakharia and Mizejewski, 2000) Download
Alpha-fetoprotein (AFP) is a transporter of various serum ligands and regulator of cellular growth during pregnancy. Estrogens modify AFP to exhibit growth suppressive properties. We recently synthesized a peptide (P149) from human AFP that suppresses the growth of mouse uterus and MCF-7 breast cancer cells. Here it is shown that molar excess treatment of native AFP with estradiol-17 beta (E2) exposes the P149 site on AFP. The anti-estrogenic and anti-tumor activities of AFP-peptides were tested in vivo in the immature mouse uterine assay and mammary tumor (6WI-101)-induced ascites assay, and in vitro in a cytostatic assay using five different human breast tumor cell lines. AFP-peptide P149, and fragments of P149, P149A and P149C but not P149B, suppressed the growth in both in vivo assays. P149 also suppressed the in vitro growth of MCF-7, MDA-MB-231, MDA-MB435 breast cancer cells by more than 75%. P149 and P149A bound the estrogen receptor-alpha (ER) with low affinities compared to E2 and tamoxifen, while P149B bound 3H-E2 with 10(5) fold less affinity compared to ER. The recent epidemiologic observation that high AFP levels in young pregnant women reduce their subsequent risk of postmenopausal breast cancer may be related to the growth suppressive property of AFP with the exposed P149 epitope.

 


References

Donders, G, et al. (2015), ‘Effect of ultra-low-dose estriol and lactobacilli vaginal tablets (Gynoflor®) on inflammatory and infectious markers of the vaginal ecosystem in postmenopausal women with breast cancer on aromatase inhibitors.’, Eur J Clin Microbiol Infect Dis, 34 (10), 2023-28. PubMed: 26223323
Eliassen, AH, et al. (2012), ‘Urinary estrogens and estrogen metabolites and subsequent risk of breast cancer among premenopausal women.’, Cancer Res, 72 (3), 696-706. PubMed: 22144471
Lundström, E, et al. (2015), ‘Estrone - a partial estradiol antagonist in the normal breast.’, Gynecol Endocrinol, 31 (9), 747-49. PubMed: 26190536
Moegele, M, et al. (2013), ‘Vaginal Estrogen Therapy for Patients with Breast Cancer.’, Geburtshilfe Frauenheilkd, 73 (10), 1017-22. PubMed: 24771890
Pfeiler, G, et al. (2011), ‘Vaginal estriol to overcome side-effects of aromatase inhibitors in breast cancer patients.’, Climacteric, 14 (3), 339-44. PubMed: 21226657
Russo, IH and J Russo (2007), ‘Primary prevention of breast cancer by hormone-induced differentiation.’, Recent Results Cancer Res, 174 111-30. PubMed: 17302191
Toriola, AT, et al. (2014), ‘Free β-human chorionic gonadotropin, total human chorionic gonadotropin and maternal risk of breast cancer.’, Future Oncol, 10 (3), 377-84. PubMed: 24559445
Vakharia, D and GJ Mizejewski (2000), ‘Human alpha-fetoprotein peptides bind estrogen receptor and estradiol, and suppress breast cancer.’, Breast Cancer Res Treat, 63 (1), 41-52. PubMed: 11079158