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This study presents comprehensive real-world data on the use of anti-human epidermal growth factor receptor 2 (HER2) therapies in patients with HER2-positive metastatic breast cancer (MBC). Specifically, it describes therapy patterns with trastuzumab (H), pertuzumab + trastuzumab (PH), lapatinib (L), and trastuzumab emtansine (T-DM1). The PRAEGNANT study is a real-time, real-world registry for MBC patients. All therapy lines are documented. This analysis describes the utilization of anti-HER2 therapies as well as therapy sequences. Among 1936 patients in PRAEGNANT, 451 were HER2-positive (23.3%). In the analysis set (417 patients), 53% of whom were included in PRAEGNANT in the first-line setting, 241 were treated with H, 237 with PH, 85 with L, and 125 with T-DM1 during the course of their therapies. The sequence PH → T-DM1 was administered in 51 patients. Higher Eastern Cooperative Oncology Group (ECOG) scores, negative hormone receptor status, and visceral or brain metastases were associated with more frequent use of this therapy sequence. Most patients received T-DM1 after treatment with pertuzumab. Both novel therapies (PH and T-DM1) are utilized in a high proportion of HER2-positive breast cancer patients. As most patients receive T-DM1 after PH, real-world data may help to clarify whether the efficacy of this sequence is similar to that in the approval study.

Background Eligibility criteria are a critical part of clinical trials, as they define the patient population under investigation. Besides certain patient characteristics, clinical trials often include biomarker testing for eligibility. However, patient-identification mostly relies on the trial site itself and is often a time-consuming procedure, which could result in missing out on potentially eligible patients. Pre-selection of those patients using a registry could facilitate the process of eligibility testing and increase the number of identified patients. One aim with the PRAEGNANT registry (NCT02338167) is to identify patients for therapies based on clinical and molecular data. Here, we report eligibility testing for the SHERBOC trial using the German PRAEGNANT registry. Methods Heregulin (HRG) has been reported to identify patients with better responses to therapy with the anti-HER3 monoclonal antibody seribantumab (MM-121). The SHERBOC trial investigated adding seribantumab (MM-121) to standard therapy in patients with advanced HER2-negative, hormone receptor–positive (HR-positive) breast cancer and HRG overexpression. The PRAEGNANT registry was used for identification and tumor testing, helping to link potential HRG positive patients to the trial. Patients enrolled in PRAEGNANT have invasive and metastatic or locally advanced, inoperable breast cancer. Patients eligible for SHERBOC were identified by using the registry. Study aims were to describe the HRG positivity rate, screening procedures, and patient characteristics associated with inclusion and exclusion criteria. Results Among 2769 unselected advanced breast cancer patients, 650 were HER2-negative, HR-positive and currently receiving first- or second-line treatment, thus potentially eligible for SHERBOC at the end of current treatment; 125 patients also met further clinical eligibility criteria (e.g. menopausal status, ECOG). In the first/second treatment lines, patients selected for SHERBOC based on further eligibility criteria had a more favorable prognosis than those not selected. HRG status was tested in 38 patients, 14 of whom (36.8%) proved to be HRG-positive. Conclusion Using a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials. Trial registration Clinicaltrials, NCT02338167 , Registered 14 January 2015 - retrospectively registered.

Das Mammakarzinom zählt nach wie vor zu den häufigsten Neoplasien bei Frauen in den Industrieländern. Obwohl die Inzidenz weiter steigt, nimmt die Mortalität glücklicherweise ab. Das impliziert, dass neben den verbesserten Methoden der Früherkennung auch vermehrt individuelle Therapieoptionen zur Verfügung stehen. Chemo- bzw. strahlentherapieassoziierte Nebenwirkungen sind zumindest zeitlich limitiert, wohingegen prämenopausale Frauen oft jahrelang an den Symptomen der antihormonellen Therapie leiden. Im Expertenforum soll die Frage beantwortet werden, ob mithilfe der Akupunktur diese Nebenwirkungen zufriedenstellend therapiert werden können. Breast Cancer is one of the most commonly diagnosed neoplasia in women living in industrialized countries. Although there is a modest increase in incidence, the overall mortality could be reduced. This implies that beside the improved methods of early diagnosis, there are better options of individualized therapy. Side effects of radiation and chemotherapy are time-limited, but pre-menopausal women have to tolerate side effects of antihormone therapy for years. This clinician's corner should clarify if acupuncture helps to reduce these side effects.

Inhibition of the androgen receptor (AR) is a major target of prostate cancer (PCa) therapy. However, prolonged androgen deprivation results eventually in castration-resistant PCa (CRPC) with metastasis and poor survival. Emerging evidence suggests that epithelial-mesenchymal transition (EMT) may facilitate castration-resistance and cancer metastasis in PCa. The human androgen-dependent, castration-sensitive prostate cancer (CSPC) cell line LNCaP and the CRPC cell line C4-2 are often used as a model system for human PCa. However, the role of the AR and the effect of AR antagonist (antiandrogen) treatment on the RNA expression of key factors of EMT including the long non-coding RNAs (lncRNAs) DRAIC in PCa cells remain elusive. Although as expected the established AR target genes PSA and FKBP5 are strongly induced by androgens in both cell lines, both E-cadherin and vimentin mRNA levels are upregulated by androgens in LNCaP but not in C4-2 cells by short- and long-term treatments. The mRNA levels of E-cadherin and vimentin remain unchanged by antiandrogen treatment in both cell lines. The expression of transcription factors that regulate EMT including Slug, Snail and ZEB1 and the lncRNA DRAIC were affected by androgen treatment in both cell lines. The mRNA level of Slug is upregulated by androgens and interestingly downregulated by antiandrogens in both cell lines. On the other hand, ZEB1 mRNA levels are strongly upregulated by androgens but remain unchanged by antiandrogens. In contrast, Snail mRNA levels are repressed by androgen treatment similar to DRAIC RNA levels. However, while antiandrogen treatment seems not to change Snail mRNA levels, antiandrogen treatments induce DRAIC RNA levels. Moreover, despite the strong upregulation of Zeb1 mRNA, no significant increase of the ZEB1 protein was observed indicating that despite androgen upregulation, posttranscriptional regulation of EMT controlling transcription factors occurs. SLUG protein was enhanced in both cell lines by androgens and reduced by antiandrogens. Taken together, our data suggest that the ligand-activated AR regulates the expression of several EMT key factors and antiandrogens counteract AR activity only on selected genes.

Extracts from Pygeum africanum are used in the treatment of prostatitis, benign prostatic hyperplasia and prostate cancer (Pca), major health problems of men in Western countries. The ligand‐activated human androgen receptor (AR) supports the growth of the prostate gland. Inhibition of human AR by androgen ablation therapy and by applying synthetic anti‐androgens is therefore the primary goal in treatment of patients. Here, we show that atraric acid (AA) isolated from bark material of Pygeum africanum has anti‐androgenic activity, inhibiting the transactivation mediated by the ligand‐activated human AR. This androgen antagonistic activity is receptor specific and does not inhibit the closely related glucocorticoid or progesterone receptors. Mechanistically, AA inhibits nuclear transport of AR. Importantly, AA is able to efficiently repress the growth of both the androgen‐dependent LNCaP and also the androgen‐independent C4–2 Pca cells but not that of PC3 or CV1 cells lacking AR. In line with this, AA inhibits the expression of the endogenous prostate specific antigen gene in both LNCaP und C4–2 cells. Analyses of cell invasion revealed that AA inhibits the invasiveness of LNCaP cells through extracellular matrix. Thus, this study provides a molecular insight for AA as a natural anti‐androgenic compound and may serve as a basis for AA derivatives as a new chemical lead structure for novel therapeutic compounds as AR antagonists, that can be used for prophylaxis or treatment of prostatic diseases.

Many estrogen receptor-positive breast cancer patients initially respond to treatment with antihormonal agents such as tamoxifen, but remissions are often followed by acquisition of resistance and ultimately disease relapse. The development of a rationale for the effective treatment of tamoxifen-resistant breast cancer requires an understanding of the complex signal transduction mechanisms that contribute towards loss of antiestrogen response. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells that are thought to reinforce their individual cellular effects on growth and gene responses. Increasing evidence indicates that abnormalities occurring in growth factor signaling pathways, notably the epidermal growth factor receptor (EGFR) signaling pathway, could dramatically influence steroid hormone action and may be critical to antihormonal-resistant breast cancer cell growth. Thus, inhibitory agents targeting growth factor receptors, or their intracellular pathway components, may prove clinically beneficial in antihormone refractory disease. One example, gefitinib ('Iressa', ZD1839), an EGFR-tyrosine kinase inhibitor, is an interesting therapeutic option that may provide benefit in the treatment of antihormonal-resistant breast cancer. Rapid progress with pharmacological and molecular therapeutic agents is now being made. Therapies that target growth factor signaling pathways may prevent development of resistance.

Antiestrogens block the function of estrogen receptor (ER) by binding and misfolding the AF-2 transcriptional activation region in the ligand-binding domain, inhibiting or altering its association with coactivator proteins. We describe a novel assay uniquely configured to identify aberrations in this function that may lead to antiestrogen resistance. The identification of mutations of ER that affect its function is important to current breast cancer therapies. Standard methods to detect these mutations are cumbersome and the number of described mutations is limited, reflecting this difficulty. Conventional ER analysis in the clinic demonstrates the presence of antigenic determinants of the receptor protein or estrogenic ligand binding without reflection on the critical ability of the liganded receptor to interact with transcription cofactors. Here, we describe the use of estrogenic regulation of a site-specific recombinase activity, measuring deletion of a color marker gene via FLP-ER fusion proteins, to detect functional changes in ER protein folding that affects the site where cofactors interact. The assay provides a method to readily detect single amino acid changes in ER, some with biologically important consequences. Without such a functional assay as described, phenotypic changes are likely to remain undetected and under-evaluated. It is probable that some human tumors have antihormone resistance resulting from ER mutations that either block antihormone binding or transmit antihormone binding as a positive transcriptional signal via cofactor interaction. An assay to evaluate functional ER will lead to better predictive tests of treatment modalities.