During the last two decades, considerable experimental evidence has been collected indicating that epithelial ovarian cancer might be gonadotropin dependent. LH and FSH receptors have been described in some of these tumors. The proliferation of ovarian cancer cells could be stimulated in vitro by gonadotropins. Suppression of endogenous LH and FSH secretion by GnRH-agonist treatment inhibited the growth of experimental or heterotransplanted ovarian cancers in various animal models. A number of recent phase II clinical trials have shown that the application of GnRH-agonists can lead to remission or stable disease in patients with relapsed advanced ovarian cancer. At present, prospective controlled clinical studies are being performed to assess the efficacy of GnRH-agonist treatment in addition to conventional surgical and cytostatic therapy in ovarian cancer in FIGO stages III and IV. Also, direct effects of GnRH analogues on ovarian cancer seem possible: a GnRH-like protein has been found in the human ovary. Our group discovered and partially characterized a specific GnRH-binding site (mol. wt 63.2 kDa) in ovarian cancer which is very similar to other human extrapituitary GnRH-binding sites of the low affinity, high capacity type, e.g. in breast cancer or the placenta. Recently, other groups have described also high affinity GnRH-agonist binding sites in ovarian cancer as well as in other extrapituitary tissues. First results from our laboratory indicate that the proliferation of certain ovarian cancer cell lines in vitro is reduced by both agonistic and antagonistic analogues of GnRH. Other authors were able to inhibit gonadotropin-induced in vitro proliferation of ovarian cancer cell lines by co-incubation with a GnRH-agonist. Thus GnRH - or a related compound - might act as an autocrine regulator of ovarian cancer proliferation, a finding which might be useful for the development of new therapeutic approaches.

582 Background: Trastuzumab (T) and Lapatinib (L) containing neoadjuvant chemotherapy (NACT) increases pathological complete response (pCR) (vs. T or nihil) in HER2+ early breast cancer (EBC). Early clinical response markers (e.g. Ki67) in a 3-week biopsy or in residual tumor correlate with therapy efficacy and risk of relapse. This WSG Neo-Predict trial aimed to define early predictive markers for therapy response in a dual blockade (T+L) NACT setting. Methods: Patients with cT1c-cT4c HER2+ EBC were treated by paclitaxel (P) (80 mg/m2weekly) with L (750 mg p.o. daily) + T (2 mg/kg) weekly for 12 weeks. Adjuvant treatment with 4 cycles of Epirubicin/Cyclophosphamide (omission allowed in patients with pCR) and T for an additional 40 weeks was recommended. Primary objectives were pCR (ypT0/is/ypN0) and identification of a dynamic predictive test for pCR using a re-biopsy after three weeks of NACT (early response defined as central Ki67 decrease >30% (vs. baseline) and/or low cellularity (<500 invasive tumor cells)). Results: From 2013-2015, 64 patients (n=80 planned) were recruited. Overall pCR was 41% (41% for HER2+/HR+ (n=34) and 45.5% for HER2+//HR- (n=22)). A 0% pCR in the “non-responder” (n=7) group (vs. 50% in the “responder” (n=34) and 42% in the “missing response” (n=20) groups) is intriguing despite methodological limitations. Missing data for early response assessment in a substantial number of patients and negative DFS data from the ALTTO trial did not justify trial continuation. 27% of patients experienced severe adverse events (AE). 11.5% had > grade 3 AEs (including diarrhea, septic shock, leukopenia, and pneumonia). Conclusions: We observed a clinically meaningful pCR with moderate toxicity with only 12 weeks of paclitaxel weekly with dual HER2 blockade (T+L). Effect of additional chemotherapy in patients with pCR after 12 weeks of monochemotherapy remains questionable due to a strong prognostic effect of pCR in HER2+ EBC. In view of 0% pCR (by hypothesis-generating explorative analysis), a different treatment approach should be investigated in patients without “early response” by further prospective trials. Clinical trial information: 2012-003679-21.

Prostanoids, especially prostaglandin (PG) E2, are important mediators of uterine relaxation and contractions during gestation and parturition. Inhibitors of PG formation as well as PG analogues are used to modulate uterine tonus. So far, only limited data are available regarding the expression of prostanoid receptors in human pregnant myometrium. In the present study, the expression of the receptors for PGE2 (EP1, EP2, EP3, EP4), PGF2α (FP), prostacyclin (IP), and thromboxane A2 (TP) in human pregnant myometrium was studied by RT-PCR, in situ hybridization and immunohistochemistry. Myometrial tissue was obtained from five women at term and not in labour and from two women who delivered preterm. Tissue specimens were excised from the upper edge of the transverse lower uterine segment incision. In all tissues analysed, EP1, EP2, EP3, EP4, FP, TP and IP receptor mRNA and protein was detected. mRNA expression for PGD2 (DP) receptor was not detected in the majority of tissue specimens. EP1, EP2, EP4, IP, TP and FP receptor protein was detected on myometrial smooth muscle cells, whereas EP3 receptor protein was only expressed by stromal and endothelial cells. In situ hybridization experiments yielded similar results. The expression of the EP2 receptor mRNA was inversely related to gestational age. We suggest that the contractile effect of PGE2 at term is probably mediated directly by the EP1 receptor expressed in myometrial smooth muscle cells and indirectly by the EP3 receptor expressed in stromal cells and a decrease in EP2 receptor expression.

Fast auf den Tag genau vor 10 Jahren hatte ich bereits einmal den Auftrag, vor diesem Forum zur gleichen Thematik zu referieren [14]. 10 Jahre sind auf dem Gebiet der medizinischen Forschung und Entwicklung ein sehr langer Zeitraum, in dem sich in zahlreichen Bereichen geradezu revolutionäre Veränderungen vollzogen haben. Obwohl das Mammakarzinom, nicht zuletzt wegen der ständig ansteigenden Morbidität, inzwischen zu einem besonderen gesundheitspolitischen Problem geworden ist, konnten nur geringe Fortschritte auf dem Gebiet der medikamentösen Behandlung metastasierter Formen erreicht werden. Damals und heute ist immer noch gültig, daß bei klinisch manifesten Fernmetastasen keine definitive Heilung der Mammatumorerkrankung erreichbar ist. Mit den verfügbaren Therapieverfahren ist es nicht einmal möglich, das Überleben der betroffenen Frauen mit hinreichender Sicherheit zu verlängern. Es ist unverkennbar, daß Fortschritte erzielt werden konnten, mit denen es gelingt, nicht nur eine zeitlich limitierte Tumorremissionen zu erreichen, sondern diese auch mit einer Verbesserung der Lebensqualität zu verbinden. Jedoch bedarf jede Therapieentscheidung einer sorgfältigen Abwägung zwischen Wirksamkeit und Nutzen für die betroffene Patientin. Trotz fehlender Heilungschance macht gerade die Unheilbarkeit der Erkrankung eine intensive ärztliche Zuwendung erforderlich, die nur durch eine besondere onkologische Sachkompetenz realisierbar ist. Zwischen der Erstdiagnose einer klinisch-manifesten Fernmetastasierung und dem letalen Ausgang des Tumorleidens liegen häufig mehrere Jahre, in denen sich die Patientinnen niemals allein überlassen werden dürfen.

Cells of the human ovarian carcinoma lines EFO-21, EFO-27, MFO-35 and MFO-36 secrete binding proteins for insulin-like growth factors (IGFBPs) into their culture media. By sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS-PAGE) and ligand blotting, seven groups of IGFBPs with molecular masses of 25, 30 (doublet), 34, 37, 40, 45, and 50 kDa were observed, depending on the cell line under investigation. By Northern blot analyses using cDNAs or oligonucleotides specific for the six types of IGFBP (IGFBP-1 to IGFBP-6), mRNA for all IGFBPs tested except for IGFBP-1 could be detected in the ovarian carcinoma cell extracts. In detail, analysis of EFO-21 protein products by SDS-PAGE yielded IGFBPs of 25, 34, and 50 kDa; extracts of EFO-21 cells contained mRNAs for IGFBP-2, -3, -4, and -6. EFO-27 cells produced IGFBPs of 40 kDa and 45 kDa as determined by SDS-PAGE, and mRNAs for IGFBP-3, -4, and -6 were detected. In the conditioned medium of MFO-35 cells, IGFBPs of 25, 30 (doublet), 34, 37, 40, and 45 kDa were observed by SDS-PAGE, while mRNAs for the five proteins IGFBP-2 to IGFBP-6 were found. MFO-36 cells produced IGFBPs of 34 kDa and 50 kDa as determined by SDS-PAGE, and the cells expressed mRNAs for IGFBP-2, -3, -4, and -6. In relation to published molecular mass data of the known IGFBPs, the size of the secreted proteins could be correlated to the mRNA patterns expressed by the ovarian carcinoma cells. It is concluded that ovarian carcinoma cells frequently express IGFBP-3, -4, and -6 and, to a lesser extent, IGFBP-2; the expression of IGFBP-5 appears as a rather rare event, while IGFBP-1 was not found to be expressed in ovarian carcinoma cells.

This study demonstrates for the first time, that medroxyprogesterone acetate (MPA) inhibits the proliferation of the estrogen and progesterone receptor negative mammary cancer cell line MFM-223 via the androgen receptor. MPA is a progestin, which is used in the hormonal treatment of disseminated breast cancer. It binds to the progesterone, androgen, and glucocorticoid receptor and may exert its antiproliferative effects via different receptors. MFM-223 human mammary cancer cells contain a very high level of androgen receptors (160 fmol/mg protein) and low levels of estrogen, progesterone, and glucocorticoid receptors (< 20 fmol/mg protein). This cell line provides therefore a good model system to analyze the possible role of the androgen receptor in the action of MPA avoiding interference with other steroid hormone receptors. Effective inhibition of proliferation is achieved by 10 nM MPA or 1 nM of the androgen dihydrotestosterone, corresponding well to the binding affinities of both compounds (3.6 and 0.18 nM, respectively). The involvement of the androgen receptor was confirmed by competition experiments with antiandrogens. Furthermore, MFM-DHT cells, which are an androgen resistant subline of MFM-223 cells, are also resistant to MPA. This data supports the involvement of the androgen receptor in the action of MPA and additionally rules out direct hormone-independent cytotoxic effects of MPA.

Das Ziel einer adjuvanten medikamentösen Therapie ist die Verbesserung kurativer Möglichkeiten, wie sie durch die alleinige operative und/oder radiotherapeutische lokale Tumorsanierung nicht zu erreichen sind. Derartige Behandlungskonzepte finden beim Endometriumkarzinom seit Jahrzehnten Anwendung. Um so erstaunlicher mag es erscheinen, daß bis heute eine definitive Aussage zum Sinn und Unsinn dieser Therapieform nicht möglich ist. Die aktuellen Diskussionen werden sehr kontrovers und sehr heftig geführt.

The regulatory influence of medroxyprogesterone acetate (MPA) on estrogen and androgen receptors of the human breast cancer cell lines MCF-7 and EFM-19 was explored in conjunction with the growth-promoting properties of these steroids. In the absence of steroidal stimulation, up to 1 μM MPA had no effect on the proliferation of the MCF-7 cell strain used and of EFM-19 cells. Under stimulation with 10 nM 17β-estradiol or 1 μM dihydrotestosterone, dose-dependent inhibition of the cell proliferation rates by 0.1–1 μM MPA was observed. Binding of MPA to the androgen receptor (Kd=2.1 nM) but not to the estrogen receptor was demonstrable. During incubation of MCF-7 or EFM-19 cells with 1 μM MPA for 7 days, the estrogen and androgen receptor contents were down-regulated by approximately 50% and 60%, respectively. Likewise, the number of androgen-binding sites was reduced to 35% of the untreated controls after incubation of MCF-7 cells with 1 μM synthetic progestin R5020 for 7 days. The results indicate down-regulation of estrogen and androgen receptors by progestins in the absence of stimulatory effects on the proliferation of mammary carcinoma cells.

The proliferation of three mammary carcinoma cell lines was explored for the effectiveness of dihydrotestosterone (DHT) and the antiandrogenic substances cyproterone acetate (CPA) or hydroxyflutamide. The cell growth, determined in multiple experimental cultures of the estrogen-sensitive lines MCF-7 and EFM-19, was stimulated by 10-9M to 10-6M DHT, whereas estrogen-resistant MFM-21 cells were unresponsive to the hormonal factors applied. Growth-promoting effects of 10-8M to 10-6M CPA were detected in cultures of those cell lines which were sensitive to estrogen and androgen. Competition experiments with DHT and the antiandrogens suggested involvement of the androgen receptor in the stimulation of cell growth by CPA. Participation of the estrogen receptor was excluded by lack of competition between CPA and the enhancement of proliferation by estradiol-17β. At the receptor level the anti-androgens were able to compete with androgen binding. The results of the study demonstrate androgenic properties of CPA in regard to the growth of human mammary carcinoma cells.

Mammakarzinome mit klinisch manifester Fernmetastasierung sind, trotz Verbesserung der Behandlungsmöglichkeiten, immer noch unheilbar. Durch eine geeignete Auswahl medikamentöser Therapieverfahren können allenfalls langdauernde Remissionen mit hoher Lebensqualität induziert werden. Zytostatische und endokrine Maßnahmen sind gleichberechtigte Partner der gegenwärtigen Behandlungskonzepte. Die Indikationsstellung für den Einsatz der einen oder anderen Methode erfolgt auf der Basis inzwischen etablierter Risiko- und Prognosefaktoren.