[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Objective: We investigated the effect of a combination of vaginal ultra-low-dose estriol with lactobacilli on the sexual functioning domain of quality of life (QOL) during the treatment of breast cancer (BC) survivors on an aromatase inhibitor (AI) with vaginal atrophy. Subjects and Methods: This was an open label bicentric exploratory clinical study, in 16 postmenopausal BC survivors on AI suffering from vaginal atrophy-induced sexual disorders. Atrophy symptoms were assessed by scoring with an 11-point estimation scale (0 = not at all, 10 = worst imaginable feeling). Sexuality parameters of QOL and medication adherence were recorded in patient's diary and in 'Female Somatic Sexual Experience Instrument (FSSEI) questionnaire. Patients underwent an initial treatment for 4 weeks (1 vaginal tablet of Gynoflor(®) containing 0.03 mg estriol daily), followed by maintenance therapy (3 vaginal Gynoflor(®) tablets weekly) for 8 weeks. Results: Vaginal dryness continuously improved from a median score 8 at entry to score 4 at the end of initial therapy, and median score 2 at the end of maintenance therapy. Normal sexual activity before BC diagnosis was reported by 14 women (88%). At study entry only 3 women (19 %) were sexually active. At the end of the Gynoflor(®) regimen, 10 women (63%) reported sexual activity, of which 7 (44%) sexual intercourse. The FSSEI demonstrated a non-significant trend of improvement of parameters related to sexuality Conclusions: Local vaginal therapy with Gynoflor(®) in BC survivors on AIs reporting atrophic vaginitis could be considered as a useful treatment the quality of the sexual life.
[Show abstract][Hide abstract] ABSTRACT: Triple negative breast cancer (TNBC) is a distinct subtype of breast cancer burdened with a dismal prognosis due to the lack of effective therapeutic agents. Receptors for LHRH (luteinizing hormone-releasing hormone) can be successfully targeted with AEZS-108 [AN-152], an analog of LHRH conjugated to doxorubicin. Our study evaluates the presence of this target LHRH receptor in human specimens of TNBC and investigates the efficacy and toxicity of AEZS-108 in vivo. We also studied in vitro activity of AEZS-125, a new LHRH analog conjugated with the highly potent natural compound, Disorazol Z.
69 human surgical specimens of TNBC were investigated for LHRH-R expression by immunohistochemistry. Expression of LHRH-R in two TNBC cell lines was evaluated by real time RT-PCR. Cytotoxicity of AEZS-125 was evaluated by Cell Titer Blue cytoxicity assay. LHRH- receptor expression was silenced with an siRNA in both cell lines. For the in vivo experiments an athymic nude mice model xenotransplanted with the cell lines, MDA-MB-231 and HCC 1806, was used. The animals were randomised to three groups receiving solvent only (d 1, 7, 14, i.v.) for control, AEZS-108 (d 1, 7, 14, i.v.) or doxorubicin at an equimolar dose (d 1, 7, 14, i.v.).
In human clinical specimens of TNBC, expression of the LHRH-receptor was present in 49% (n = 69).HCC 1806 and MDA-MB-231 TNBC cells expressed mRNA for the LHRH-receptor. Silencing of the LHRH-receptor significantly decreased the cytotoxic effect of AEZS-108. MDA-MB-231 and HCC 1806 tumors xenografted into nude mice were significantly inhibited by treatment with AEZS-108; doxorubicin at equimolar doses was ineffective.As compared to AEZS 108, the Disorazol Z - LHRH conjugate, AEZS-125, demonstrated an increased cytotoxicity in vitro in HCC 1806 and MDA-MB-231 TNBC; this was diminished by receptor blockade with synthetic LHRH agonist (triptorelin) pretreatment.
The current study confirms that LHRH-receptors are expressed by a significant proportion of TNBC and can be successfully used as homing sites for cytotoxic analogs of LHRH, such as AEZS-108 and AEZS-125.
BMC Cancer 11/2014; 14(1):847. · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vascular disease is the leading cause of death in women. One-third of acute events affect women below age 60, when the prevalence of menopausal symptoms is high. This raises the question if hormone replacement therapy (HRT) may be an appropriate treatment for individual women although vascular disease is generally considered a contraindication.
Archives of Gynecology and Obstetrics 10/2014; · 1.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Triple negative breast cancers express receptors for gonadotropin-releasing hormone (GnRH) in more than 50 % of the cases, which can be targeted with peptidic analogs of GnRH, such as triptorelin. The current study investigates cytotoxic activity of triptorelin as a monotherapy and in treatment combinations with chemotherapeutic agents and inhibitors of the PI3K and the ERK pathways in in vitro models of triple negative breast cancers (TNBC). GnRH receptor expression of TNBC cell lines MDA-MB-231 and HCC1806 was investigated. Cells were treated with triptorelin, chemotherapeutic agents (cisplatin, docetaxel, AEZS-112), PI3K/AKT inhibitors (perifosine, AEZS-129), an ERK inhibitor (AEZS-134), and dual PI3K/ERK inhibitor AEZS-136 applied as single agent therapies and in combinations. MDA-MB-231 and HCC1806 TNBC cells both expressed receptors for GnRH on messenger (m)RNA and protein level and were found sensitive to triptorelin with a respective median effective concentration (EC50) of 31.21 ± 0.21 and 58.50 ± 19.50. Synergistic effects occurred when triptorelin was combined with cisplatin. In HCC1806 cells, synergy occurred when triptorelin was applied with PI3K/AKT inhibitors perifosine and AEZS-129. In MDA-MB-231 cells, synergy was observed after co-treatment with triptorelin and ERK inhibitor AEZS-134 and dual PI3K/ERK inhibitor AEZS-136. GnRH receptors on TNBC cells can be used for targeted therapy of these cancers with GnRH agonist triptorelin. Treatment combinations based on triptorelin and PI3K and ERK inhibitors and chemotherapeutic agent cisplatin have synergistic effects in in vitro models of TNBC. If confirmed in vivo, clinical trials based on triptorelin and cisplatin could be quickly carried out, as triptorelin is FDA approved for other indications and known to be well tolerated.
[Show abstract][Hide abstract] ABSTRACT: Introduction: Since 2000 all service providers in the German healthcare system are legally obliged to take part in quality assurance (QA) procedures as stipulated in Book Five of the German Social Code. Clinical cancer registries provide methodological tools to assess the quality of structures, processes and outcomes. The aim of this study was to analyze the consequences of guideline-concordant treatment using two examples of quality indicators: endocrine therapy (adjuvant hormonal therapy, AHT) to treat patients with steroid hormone receptor (SHR)-positive breast cancer and trastuzumab therapy to treat patients with HER2-positive breast cancer. Material and Methods: Data from the Tumor Center Regensburg (Bavaria, Germany) included all female patients listed in the registry with primary, non-metastatic invasive breast cancer diagnosed between 2000 and 2012. Results: A total of 6164 patients with invasive breast cancer and known HER2 status were analyzed. 1134 patients (18.4 %) had HER2-positive and 5346 patients (86.7 %) had SHR-positive breast cancer. Premenopausal patients with HER2-positive breast cancer receiving trastuzumab had a 7-year OS rate of 93.8 % compared to 86.8 % of patients who did not receive trastuzumab (p = 0.079). Similarly, postmenopausal patients with HER2-positive breast cancer treated with trastuzumab had better 7-year OS rates (87.3 %) than patients who did not receive the antibody (76.7 %) (p < 0.001). Premenopausal patients with SHR-positive breast cancer receiving AHT had a 7-year OS rate of 95.2 % compared to 75.9 % of patients who did not receive AHT (p < 0.001). Equally, postmenopausal patients treated with AHT had a 7-year OS rate of 83.8 % compared to 64.1 % without AHT (p < 0.001). Conclusion: Clinical cancer registries depend on the cooperation of the various health service providers to generate data that are essential for QA for breast cancer patients.
Geburtshilfe und Frauenheilkunde 09/2014; 74(9):868-874. · 0.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Susceptibility to ovarian cancer might be affected by genetic variations in genes involved in estrogen biosynthesis, metabolism or signal transduction. In this study we tested the hypothesis that single nucleotide polymorphisms (SNPs) in the promoter of human ESR2 gene, coding for estrogen receptor β, may be associated with increased risk for ovarian cancer. Three SNPs in the promoter region of human ESR2 gene were genotyped by means of allele-specific tetra-primer PCR. A total of 184 ovarian cancer cases and the same numbers of controls were included in the study. With regard to homozygous analysis, the AA genotype of SNP rs3020449 was found to be significantly more frequent in ovarian cancer cases staged as FIGO III+IV than in cases staged as I+II (OR 2.717, p=0.027). With regard to allele frequency, the G allele of this SNP was less frequent in FIGO I+II cases than in cases with higher FIGO stages (OR 1.739, p=0.018). With regard to genotype frequency, allele frequency, allele positivity or haplotype frequency of SNPs rs2987983, rs3020449 and rs3020450 we did not observe a significant difference between the cancer and the control group. Our data suggest that SNPs in the promoter region of ESR2 gene do not affect susceptibility to ovarian cancer, but SNP rs3020449 might affect progression of this disease.
[Show abstract][Hide abstract] ABSTRACT: Humanized tumor mice (HTM) were generated by the co-transplantation of human hematopoietic stem cells and human breast cancer cells overexpressing HER2 into neonatal NOD-scid IL2Rγ(null) (NSG) mice. These mice are characterized by the development of a human immune system in combination with human breast cancer growth. Due to concurrent transplantation into newborn mice, transfer of MHC-mismatched tumor cells resulted in solid coexistence and immune cell activation (CD4(+) T cells, natural killer cells, and myeloid cells), but without evidence for rejection. Histological staining of the spleen of HTM revealed co-localization of human antigen-presenting cells together with human T and B cells allowing MHC-dependent interaction, and thereby the generation of T cell-dependent antibody production. Here, we investigated the capability of these mice to generate human tumor-specific antibodies and correlated immunoglobulin titers with tumor outgrowth. We found detectable IgM and also IgG amounts in the serum of HTM, which apparently controlled tumor development when IgG serum concentrations were above 10 µg/ml. Western blot analyses revealed that the tumor-specific antibodies generated in HTM did not recognize HER2/neu antigens, but different, possibly relevant antigens for breast cancer therapy. In conclusion, HTM offer a novel approach to generate complete human monoclonal antibodies that do not require further genetic manipulation (e. g., humanization) for a potential application in humans. In addition, efficacy and safety of the generated antibodies can be tested in the same mouse model under human-like conditions. This might be of particular interest for cancer subtypes with no currently available antibody therapy.
[Show abstract][Hide abstract] ABSTRACT: Phase I pharmacokinetic (PK) study assessed circulating estrogens in breast cancer (BC) patients on a non-steroidal aromatase inhibitor (NSAI) with vaginal atrophy using vaginal ultra-low-dose 0.03 mg estriol (E3) and Lactobacillus combination vaginal tablets (Gynoflor(®)). 16 women on NSAI with severe vaginal atrophy applied a daily vaginal tablet of Gynoflor(®) for 28 days followed by a maintenance therapy of 3 tablets weekly for 8 weeks. Primary outcomes were serum concentrations and PK of E3, estradiol (E2), and estrone (E1) using highly sensitive gas chromatography-mass spectrometry. Secondary outcomes were clinical measures for efficacy and side effects; microscopic changes in vaginal epithelium and microflora; and changes in serum FSH, LH, and sex hormone-binding globulin. Compared with baseline, serum E1 and E2 did not increase in any of the women at any time following vaginal application. Serum E3 transiently increased after the first application in 15 of 16 women, with a maximum of 168 pg/ml 2-3 h post-insertion. After 4 weeks, serum E3 was slightly increased in 8 women with a maximum of 44 pg/ml. The vaginal atrophy resolved or improved in all women. The product was well tolerated, and discontinuation of therapy was not observed. The low-dose 0.03 mg E3 and Lactobacillus acidophilus vaginal tablets application in postmenopausal BC patients during AI treatment suffering from vaginal atrophy lead to small and transient increases in serum E3, but not E1 or E2, and therefore can be considered as safe and efficacious for treatment of atrophic vaginitis in BC patients taking NSAIs.
Breast Cancer Research and Treatment 04/2014; · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Local application of estradiol (E2) to treat vulvovaginal atrophy in postmenopausal breast cancer patients receiving aromatase inhibitors is known to elevate serum estradiol levels and thereby might counteract breast cancer therapy. Thus, vaginal application of estriol (E3) has been recommended for these patients. However, it is unclear to what extent E3 stimulates breast cancer cell growth. In this study, we examined the effect of E3 on growth and gene expression of two human breast cancer cell lines.
We used an established in vitro cell culture assay and compared the effect of E2 and E3 on growth of the estrogen receptor alpha-positive breast cancer cell lines MCF-7 and T-47D testing a wide range of hormone concentrations of 10−12 to 10−7 M. E3 effects on gene expression were examined by means of reporter gene assays, RT-qPCR and Western blot analysis.
E3 acted as a potent estrogen and exerted a mitogenic effect on T-47D and MCF-7 cells at concentrations of 10−9 M (288 pg/ml) and higher. With regard to activation of an estrogen response element (ERE) in breast cancer cells, effects of E3 were visible at 10−10 M. The same concentrations of E3 activated expression of the estrogen-responsive gene PR and of the proliferation genes cyclin A2, cyclin B1, Ki-67, c-myc and b-myb, providing molecular mechanisms underlying the observed growth increase.
Like E2, low levels of E3 were able to trigger a robust estrogenic response in breast cancer cells. Thus, our data suggest caution regarding use of E3 by breast cancer survivors.
[Show abstract][Hide abstract] ABSTRACT: Uterusmyome können ein Konzeptionshindernis darstellen und auch in einer bestehenden Schwangerschaft zu Komplikationen führen. Die Arbeit gibt eine Übersicht des aktuellen Kenntnisstandes zu Ätiologie und Therapiemöglichkeiten. Das Evidenzniveau, auf dessen Basis Therapieempfehlungen gegeben werden können, ist aufgrund der unzureichenden Datenlage niedrig. Patientinnen mit unerfülltem Kinderwunsch und submukösen oder intramural/submukösen Myomen scheinen von einer Myomenukleation hinsichtlich der Schwangerschaftsrate zu profitieren. Allerdings sollte diese erst nach Durchführung einer generellen Sterilitätsdiagnostik des Paares erfolgen. Offene und laparoskopische Myomenukleationen scheinen hinsichtlich der Schwangerschaftsrate gleichwertige Verfahren darzustellen. Ein laparoskopisches Vorgehen ist mit weniger perioperativem Blutverlust und Schmerzen sowie schnellerer Rekonvaleszenz assoziiert. Ob sich eine Patientin mit Kinderwunsch, jedoch ohne Sterilitätsanamnese und bekanntem Uterusmyom vor Anstreben der Schwangerschaft einer operativen Therapie unterziehen sollte oder nicht ist unklar. Aufgrund der insgesamt unzureichenden Datenlage scheint sowohl nach hysteroskopischer Myomenukleation als auch nach offener oder laparoskopischer Myomentfernung unter entsprechender Überwachung ein vaginaler Entbindungsversuch möglich.
[Show abstract][Hide abstract] ABSTRACT: Even though randomized controlled clinical trials demonstrated improved survival by adjuvant trastuzumab treatment of HER2-positive breast cancer patients, data on its effect in clinical routine are scarce. This study evaluated the use and efficacy of trastuzumab in routine treatment of HER2-positive breast cancer patients. Data from the clinical cancer registry Regensburg (Germany) were analyzed. The present study investigated 6,991 female patients with primary invasive breast cancer. In premenopausal HER2-positive patients a considerable increase of trastuzumab therapy was observed from 58.1% in 2006 to 90.9% in 2011, whereas in postmenopausal patients trastuzumab was rather used on a constant rate of 49.1%. Best overall survival (OS) was found in HER2/steroid hormone receptor-positive patients receiving guideline concordant treatment with trastuzumab plus chemotherapy (CHT) plus antihormone therapy (AHT) with a 7-year OS rate of 96% compared to the non-trastuzumab group with a 7-year OS rate of 92%. In multivariable analysis, HER2-positive patients treated with CHT or AHT who did not get trastuzumab, had a worse 7-year OS (65%, P = 0.006 versus 79%, P = 0.017) than the control groups. This population-based study demonstrated that guideline concordant use of adjuvant trastuzumab improves OS for HER2-positive breast cancer patients treated in routine clinical care.
BioMed research international. 01/2014; 2014:137304.
[Show abstract][Hide abstract] ABSTRACT: In this study, we tested the hypothesis that single nucleotide polymorphisms (SNPs) of differentiation-associated human gene icb-1 (C1orf38) may be associated with ovarian cancer susceptibility. For this purpose, we compared the genotype and allele frequencies of the SNPs rs1467465 and rs12048235 in a group of 184 ovarian cancer patients with a control group of 184 age- and gender-matched women without any malignancy. Genotype-phenotype association revealed that A allele of SNP rs1467465 was more frequent in ovarian cancer patients than in the control group (0.40 vs. 0.33, OR 1.37, 95% CI 1.013-1.853, p = 0.04). After analysis of allele positivity we observed that A-positive genotypes were more frequent in the ovarian cancer group (0.65 vs. 0.53, OR 1.63, 95% CI 1.072-2.483, p = 0.02). Furthermore, the heterozygous genotype of rs1467465 was found to be more frequent in the patients group (0.50 vs. 0.41, OR 1.63, 95% CI 1.045-2.045, p = 0.03). No significant results were obtained with regard to SNP rs1204823. Our data suggest, that SNP rs1467465 of human gene icb-1 might affect susceptibility to ovarian cancer.
Journal of Ovarian Research 01/2014; 7:42. · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Uterusmyome sind gutartige, hormonsensitive Tumoren. Sie sind die häufigsten pelvinen Tumoren der Frau und in der Regel asymptomatisch. Die wichtigsten Symptome bei einem Uterus myomatosus sind Blutungsstörungen, Drucksymptomatik und reproduktive Dysfunktion. Sie treten meist bei prämenopausalen Frauen auf. Nach der Menopause beobachtet man bei den meisten Frauen eine Schrumpfung der Myome. Nur Frauen mit symptomatischen Myomen sollten behandelt werden. Interventionen sollten in Abhängigkeit des Patientinnenalters, des Kinderwunsches, Lage bzw. Größe der Myome und symptomorientiert durchgeführt werden. Am häufigsten eingesetzt werden orale Kontrazeptiva, Levonorgestrel-haltige intrauterine Spiralen, Gonadotropin-releasing-Hormon-Agonisten und Progesteronrezeptormodulatoren. Es ist zu beachten, dass zwei Drittel aller konservativ Behandelten innerhalb von 2 Jahren operiert werden.