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Background: We previously showed that intense dose-dense (idd) epirubicin (E), paclitaxel (T), cyclophosphamide (C) results in a superior DFS and OS compared to conventionally dosed EC-T in pts with primary breast cancer (PBC) and ≥4 involved lymph nodes (LN) (Möbus et al JCO 2010). In the GAIN study, the intense dose-dense strategy has been further investigated as well as the adjuvant application of ibandronate (I). We here report on the planned interim efficacy analysis after 50% (N>401) of the required events have occurred. Methods: A prospective, multi-center, controlled, non-blinded, randomized phase III trial investigating ETC (E: 150 mg/m2, T:225 mg/m2, C:2500–2000 mg/m2, i.v. day 1, q15 for 3 cycles each: A1); or EC→TX (E: 112.5 mg/m2 + C: 600 mg/m2, i.v. day 1, q 15 for 4 cycles→T: 67.5 mg/m2 i.v. day 1, q 8 for 10 weeks + X: 2000 mg/m2 p. o. day 1–14, q 22 for 4 cycles: A2). Pts were further randomized in a 2:1 ratio to receive ibandronate: 50 mg/day p.o. for 2 years (B1) or observation (B2). Pts received a primary prophylaxis with either epoetin β or darbepoetin α and pegfilgrastim during ETC or EC. After recruitment of 1500 pts prophylactic ciprofloxacin was implemented and the dose of C was reduced to 2000 mg/m2. Eligibility: Females ≥18 and <65 years, histologically confirmed LN positive uni- or bilateral PBC; adequate surgery, ≥1 pos.LN; ECOG ≤2; written informed consent. Primary objective:compare DFS A1 vs. A2 and B1 vs.B2. Secondary objectives: OS, safety, incidence of secondary primaries, and EFS in subgroups of hormone sensitivity and number of pos. LN between arms; assessment of compliance; determine prognostic factors. 3000 pts with 801 events were needed to show an increase of 5-year DFS from 75% to 79% for pts receiving EC→TX and 728 events to show an increase of 5-year DFS from 75% to 79.5% for pts receiving I, assuming a drop-out rate of 5%, α=0.05 (two-sided)and 1-β =80%. An interim analysis for both primary objectives was planned after 50% of the expected events occurred. Safety results have been reported previously (Möbus et al. SABCS 2009). Results: 3023 patients were randomized between 06/2004 and 08/2008.1512 received ETC and 1511 EC→TX. 29pts never started therapy, 14 in ETC, 15 in EC→TX. Median follow-up is 38.7 months. Median age was 50 years; pN1 (37.7%), pN2 (35.4%); pN3 (26.9%); 77.4% had ductal invasive carcinoma, 46.6% were grade 3; 76.7% had hormone receptor-positive tumors, 22% were HER2−positive. 405 events have occurred by 12.05.2011.380pts relapsed and 25pts. died w/o relapse. The interim futility boundary for chemotherapy was not crossed. For the ibandronate question the futility boundary was reached. There was no difference in DFS and OS between the patients with and without ibandronate (DFS log-rank p=0.593; HR 1.059; 95%CI 0.861−1.301; OS log-rank p=0.801 HR 0.961; 95% CI 0.705−1.31). Conclusion: The GAIN study demonstrated that adjuvant ibandronate does neither improve DFS nor OS in primary node positive breast cancer after treatment with dose-intensified chemotherapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S2-4.

Background: Severe forms of genital endometriosis are known to be associated with infertility and its subsequent treatment failure. Both gonadotropin-releasing hormone analogs (a-GnRH) and dienogest have been suggested as additional hormone therapy for patients with endometriomas. However, the result of hormonal suppression before an in vitro fertilization (IVF) cycle remains undetermined. Materials and methods: A prospective cohort study of 144 infertile women planning IVF after laparoscopic surgery of ovarian endometriomas was conducted at our department in 2012-2015. Patients were divided into three groups: group I (N ¼ 38) with dienogest course, group II (N ¼ 70) with a-GnRH group III (N ¼ 70) without any hormonal therapy within 6 months preceding IVF. Results: The study groups did not differ by removed endometriomas size and ovarian reserve indicators. The gonadotropin dose per Cycle was higher, while the number of retrieved oocytes was lower in group III patients (p < .001). In women with dienogest pretreatment, clinical pregnancy rate was 2.5 times (44.7% versus 16.7%, p ¼ .012) and delivery rate -three times higher (36.8% versus 11.1%, p ¼ .013) as compared with those from group III. Conclusions: The present study confirms the necessity of pre-cycle medical interventions in women with ovarian forms of endometriosis undergoing IVF. We suggest dienogest to be possibly more efficient treatment option for this kind of patients.

Background: Ectopic pregnancy (EP) has been reported to occur in 1.4-5.4% of all clinical pregnancies resulting from in vitro fertilization (IVF) and embryo transfer (ET). Data on factors associated with abnormal embryo implantation following assisted conception are limited. Materials and methods: A systematic review and meta-analysis was performed to determine whether there is an association between the day (cleavage-stage, D3, versus blastocyst, D5) or the type (fresh versus frozen/thawed) of ET and EP rate. Risk factors for EP were evaluated in a retrospective study of 1194 women, who achieved pregnancy at our IVF unit between 2010 and 2016. Results: Sixteen papers were considered for the meta-analysis. EP rate did not differ between D3 and D5 fresh ET groups (RR ¼ 0.99, 95%CI: 0.76-1.30) and was higher after fresh versus frozen ET (RR ¼ 1.56, 95%CI: 1.25-1.95). At our clinic, 21 (1.76%) pregnancies were documented as ectopic. The risk of EP was associated with tubal pathology (OR ¼ 3.37, 95%CI: 1.39-8.2), previous appendectomy and past chlamydial infection. Conclusions: Present meta-analysis suggests that EP rate is similar following fresh blastocyst and cleavage ETs, but is significantly reduced after frozen compared with fresh ET. Our own findings demonstrate that tubal pathology has the major impact on EP occurrence following assisted conception.

To estimate the efficacy of growth hormone (GH) co-treatment within an antagonist protocol in IVF/ICSI cycles in poor responders. A prospective observational study involving 50 patients underwent a standard antagonist protocol with or without GH co-treatment. GH was administered by a daily subcutaneous injection of 1,33 mg (equivalent to 4 IU) starting from day 1 of ovarian stimulation until the day of 10,000 human chorionic gonadotropin (hCG) triggering . Concentrations of GH, insulin-like growth factor I (IGF-I) and IGF binding protein-3 (IGFBP-3) in serum and follicular fluid were the subject matter of analysis. The GH co-treatment significantly lowered the effective dose of gonadotropins, duration of stimulation, IGFBP-3 level in serum and follicular fluid on the day of oocyte retrieval. The total number of oocytes as well as the number of metaphase II stage (MII) oocytes, two pronucleus (2 pn) zygotes, good-quality transferred embryos was significantly higher in the GH þ group. Pregnancy was achieved in patients GH þ group only. Positive correlation was found between IGF-I level in follicular fluid, dynamics of IGFBP-3 level changes during stimulation protocol and the number of good-quality transferred embryos in the GH þ group. GH administration in IVF/ICSI cycles for poor responders raises ovarian sensitivity to the gonadotropin exogenous influence, increasing number of high-quality embryos and the probability of pregnancy. ARTICLE HISTORY

We report three cases of effective management of infertility in women with a history of repeated unsuccessful IVF attempts, who have developed antibodies to hCG. A novel approach to conservative treatment of immunologic reproductive failure, suggested for selected patients, included membrane plasmapheresis, combined prednisolone, and intravenous immunoglobulin therapy. No adverse side effects were observed; all cases resulted in pregnancy and subsequent life births. In order to be given an adequate efficient treatment, women with recurrent implantation failure should be suspected for autoimmune factor of infertility and its possible association with anti-hCG autoimmunity.

Background: Elevated antibody titers to Chlamydia trachomatis are detected in up to 70% of women with tubal factor infertility (TFI). In order to evaluate the influence of past chlamydial infection on the results of IVF treatment, a prospective cohort study was performed. Materials and methods: A total of 242 women with TFI were enrolled in the study. Serum samples (n ¼ 242) and follicular fluid (n ¼ 197) were analyzed using enzyme-linked immunosorbent assay for anti-C. trachomatis IgG, IgA, IgM and anti-chlamydial heat shock protein 60 kDa IgG. Results: ''Poor response'' to ovarian stimulation was two times more frequent in seropositive subjects (22.9% versus 13.3%, p ¼ 0.039). Seropositive and seronegative women had similar IVF outcomes, expressed by clinical pregnancy (20.5% versus 25.0%), life birth (13.1% versus 20.0%) and miscarriage rates (36.0% versus 16.7%, p ¼ 0.092). Incidence of missed abortion after IVF was higher in women with previous exposure to C. trachomatis (28.0%) as compared to those without antibodies (3.3%), p ¼ 0.018. Conclusions: Anti-chlamydial antibody detection is not related to oocyte maturity, embryo quality, pregnancy and life birth rates. However, past chlamydial infection in TFI patients is associated with decreased IVF success: ''poor response'' to ovarian stimulation and missed abortion rate.

Background: Metastatic breast cancer (MBC) is usually an incurable disease and maintenance of quality of life (QoL) is one of the main aims of therapy. In patients with HER2-positive MBC taxane-based chemotherapy in combination with dual HER2 targeted therapy with trastuzumab and pertuzumab,is the standard of care. Adverse events are well-known side effects of any cytostatic treatment and can seriously impact the patients' QoL. The synergistic combination of dual HER2-targeted therapy with trastuzumab and pertuzumab plus endocrine therapy might offer a better treatment option for these patients. First clinical trials suggest an additional benefit when a CDK4/6 inhibitor is added to the combination of endocrine therapy and anti HER2 treatment. DETECT V is a randomized phase III study comparing the safety and efficacy of trastuzumab plus pertuzumab and the CDK 4/6 inhibitor ribociclib in combination with either endocrine therapy or chemotherapy. Trial design: Patients with HER2 positive and hormone-receptor positive MBC are 1:1 randomized to receive trastuzumab and pertuzumab combined with endocrine therapy and ribociclib or to chemotherapy with trastuzumab and pertuzumab followed by maintenance therapy with trastuzumab, pertuzumab, endocrine therapy and ribociclib. Chemotherapy and the endocrine agents can be chosen from a variety of available regimens according to the physicians discretion. Specific aims: The primary objective of this study is to compare safety and tolerability in both arms, as assessed by the occurrence of AEs during the treatment period. Secondary endpoints are progression free survival, overall survival, quality-adjusted survival using the quality-adjusted time without symptoms and toxicity (Q-TWiST) method. A translational program is included investigating detection and phenotyping of circulating tumor cells (CTC)-and the assessment of marker expression on CTCs in order to validate an endocrine responsiveness score. Present accrual and target accrual: The DETECT V trial started 2015 in the Dept. of Gynecology, University of Ulm and at the up to 120 sites in Germany. Until June 2018 97 patients with HER2-positive, hormone-receptor positive metastatic breast cancer have been enrolled. A sample size of 270 patients is planned. Contact information: Jens Huober, University of Ulm, Dept of Gynecology, Breast Center, jens.huober@uniklinik-ulm.de Sabrina Krause, University of Ulm, Dept of Gynecology, sabrina.krause@uniklinik-ulm.de Citation Format: Krause S, Friedl T, Fehm T, Romashova T, Fasching PA, Schneeweiss A, Müller V, Taran F-A, Polasik A, Tzschaschel M, De Gregorio A, Meier-Stiegen F, Janni W, Huober J. DETECT V/CHEVENDO – Comparison of dual HER2-targeted therapy with trastuzumab plus pertuzumab in combination with chemo- or endocrine therapy in addition with CDK4/6 inhibition in patients with HER2-positive and hormone-receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-01.