Search

Background: In this study, we examined patients who had non-progressive disease for at least 2 years after diagnosis of inoperable locoregional recurrent or metastatic breast cancer under continuous trastuzumab treatment. Our primary goal was to assess the long-term outcome of patients with durable response to trastuzumab., Methods: 268 patients with HER2-positive inoperable locally recurrent or metastatic breast cancer and non-progressive disease for at least 2 years under trastuzumab treatment were documented retrospectively or prospectively in the HER-OS registry, an online documentation tool, between December 2006 and September 2010 by 71 German oncology centers. The study end point was time to tumor progression., Results: Overall, 47.1% of patients (95% confidence interval (CI): 39.9-54.1%) remained in remission for more than 5 years, while the median time to progression was 4.5 years (95% CI: 4.0-6.6 years). Lower age (<50 years) and good performance status (ECOG 0) at time of trastuzumab treatment initiation as well as complete remission after initial trastuzumab treatment were associated with longer time to progression. Interruption of trastuzumab therapy correlated with shorter time to progression., Conclusions: HER2-positive patients, who initially respond to palliative treatment with trastuzumab, can achieve a long-term tumor remission of several years.

A panel of international breast cancer experts formulated a declaration of consensus regarding many key issues in the use of primary systemic therapy (PST) either in clinical routine or research practice. The attainment of pathological complete response (pCR), defined as no residual invasive tumor in the surgical specimens both in breast and in axillary nodes, is one of the main goals of PST, and pCR can be used as the primary objective in prospective clinical trials. However, pCR is not a reliable endpoint with all treatment approaches, and alternatives such as Ki67 index of the residual invasive disease or after 2 weeks of PST are also potential endpoints. PST has several advantages: breast conservation and the unique opportunity to obtain information on the interaction between treatment and tumor biology. Changes in tumor biology after PST are an early phenomenon; so, an additional core biopsy performed after 14 days from treatment start should be considered in clinical trials.

Human polo-like kinase 1 (Plk1), a key regulator of mitosis, is overexpressed in various human tumors. It is a negative prognostic factor for cancer patients and a measure for the aggressiveness of a tumor. Thus, targeting Plk1 might be a promising approach for cancer therapy. Kinase inhibitors are divided in type I inhibitors, targeting the highly conserved active conformation, and the more selective type II inhibitors, targeting the inactive conformation of kinases. We analyzed our previously identified type II Plk1 inhibitor SBE13 which is able to inhibit Plk1 activity. To determine its ability to induce cell death in cancer cells, we applied kinase assays, western blot analyses, FACScan analyses, Caspase assays and immunofluorescence studies. We detected decreased cell proliferation, delayed progression through the cell cycle in lower SBE13 concentrations, a G(2)/M arrest using higher SBE13 concentrations followed by apoptosis, and abnormal mitotic figures. Notably, SBE13 did not influence activity of other kinases (Plk2, Plk3, Aurora A), indicating the selectivity of this type II Plk1 inhibitor. This study suggests that Plk1 kinase inhibitors targeting the inactive conformation of Plk1 may be considered for the development of cancer therapeutics.

Purpose: To conduct meta-analyses of randomized trials of aromatase inhibitors (AIs) compared with tamoxifen either as initial monotherapy (cohort 1) or after 2 to 3 years of tamoxifen (cohort 2)., Materials and Methods: Data submitted to the Early Breast Cancer Trialists' Collaborative Group were used in separate meta-analyses of two cohorts. Primary analyses involve postmenopausal women with tumors reported to be estrogen receptor positive. Log-rank P values are two-sided., Results: Cohort 1 comprised 9,856 patients with a mean of 5.8 years of follow-up. At 5 years, AI therapy was associated with an absolute 2.9% (SE = 0.7%) decrease in recurrence (9.6% for AI v 12.6% for tamoxifen; 2P < .00001) and a nonsignificant absolute 1.1% (SE = 0.5%) decrease in breast cancer mortality (4.8% for AI v 5.9% for tamoxifen; 2P = .1). Cohort 2 comprised 9,015 patients with a mean of 3.9 years of follow-up. At 3 years from treatment divergence (ie, approximately 5 years after starting hormonal treatment), AI therapy was associated with an absolute 3.1% (SE = 0.6%) decrease in recurrence (5.0% for AI v 8.1% for tamoxifen since divergence; 2P < .00001) and an absolute 0.7% (SE = 0.3%) decrease in breast cancer mortality (1.7% for AI v 2.4% for tamoxifen since divergence; 2P = .02). There was no convincing heterogeneity in the proportional recurrence reduction with respect to age, nodal status, tumor grade, or progesterone receptor status and no indication of an increase in nonbreast deaths with AIs in either cohort. CONCLUSION AIs produce significantly lower recurrence rates compared with tamoxifen, either as initial monotherapy or after 2 to 3 years of tamoxifen. Additional follow-up will provide clearer information on long-term survival.

Background: All women with early breast cancer, even those with small tumors and negative nodes, remain at appreciable risk of recurrence after surgery over the subsequent 10-15 years. In women with tumors expressing estrogen receptors and/or progesterone receptors, standard systemic adjuvant therapy is 5 years of tamoxifen, which substantially reduces the risk of recurrence and breast cancer-related death. Tamoxifen efficacy benefits are limited to 5 years of treatment, presumably a consequence of acquired tamoxifen resistance. The third-generation aromatase inhibitors, which are highly selective and potent in suppressing whole-body estrogen synthesis in postmenopausal women, are being investigated as alternative or complementary treatments to tamoxifen. For treatment beyond adjuvant tamoxifen for 5 years, letrozole is the only aromatase inhibitor for which clinical trial data were reported. That trial, MA.17, evaluated letrozole as extended adjuvant treatment following standard adjuvant tamoxifen in postmenopausal women with predominantly estrogen receptor--and/or progesterone receptor--positive early breast cancer., Results: Compared with placebo, letrozole markedly reduced the residual risk of recurrence, by 42%, and the improvement in disease-free survival was irrespective of patient nodal status. A significant improvement in overall survival has already been seen in the patients at highest risk, those with positive nodes., Conclusion: On the basis of these results, extended adjuvant letrozole is recommended for all patients completing 5 years of adjuvant tamoxifen, including women generally considered at minimal risk.

Background: RNA interference initiated by small interfering RNAs effectively suppresses gene expression, but the suppression is transient, which limits the therapeutic use of this technique. Polo-like kinase 1 (PLK1) is a key cell cycle regulator that is overexpressed in various human tumors. We used a xenograft mouse model to determine whether an RNA interference-based strategy that used short hairpin RNAs (shRNAs) to suppress PLK1 expression could inhibit tumor growth in vivo., Methods: HeLa S3 cervical and A549 lung cancer cell lines were transfected with plasmids containing U6 promoter-driven shRNAs against human PLK1 or control (parental or scrambled) plasmids. Plasmids were treated with the nuclease inhibitor aurintricarboxylic acid (ATA) as protection against nucleases in murine blood. Nude mice carrying xenograft tumors were injected with shRNA plasmids, and their xenograft tumor growth was assessed. Northern and western blot analyses were used to measure PLK1 mRNA and protein expression, respectively, in transfected cultured cells and in xenograft tumors. All statistical tests were two-sided., Results: Levels of PLK1 mRNA and protein were lower in HeLa S3 and A549 cancer cells transfected with PLK1 shRNA plasmids than in corresponding cells transfected with control parental or scrambled PLK1S shRNA plasmids. Proliferation of cells transfected with PLK1 shRNA was lower than that of cells transfected with either control plasmid, and proliferation of cells transfected with ATA-treated PLK1 shRNA plasmids was even lower. In mice with human xenograft tumors, PLK1 shRNA expression from ATA-treated plasmids reduced tumor growth to 18% (95% confidence interval [CI] = 12% to 26%; P =.03) and from untreated plasmids reduced tumor growth to 45% (95% CI = 26% to 64%; P =.1) of that of tumors in mice treated with scrambled control PLK1S shRNA plasmids., Conclusions: The combination of shRNA-mediated gene silencing with effective in vivo gene delivery strategies appears to generate a long-lasting silencing signal.

A central role for polo-like kinases (PLK) in regulating several stages of mitotic progression has been born out in several species. Overexpression of PLK1 is observed in the majority of hitherto analysed human tumors. PLK1 overexpression is a negative prognostic factor in patients suffering from non-small cell lung cancer, head and neck tumors, esophageal carcinomas and melanomas. In order to define the role of PLK1 for mitotic progression of human cells and for neoplastic cell growth, phosphorothioate antisense oligonucleotides (ASOs) were tested to selectively downregulate PLK1 expression in MDA-MB-435 (breast cancer), HeLa S3 (cervical carcinoma) and A549 (non-small cell lung cancer) cells. ASOs were identified which suppress PLK1 mRNA and protein in a dose-dependent and sequence-specific manner. This approach also led to reduced PLK1 serine/threonine kinase activity. Downregulation of cellular PLK1 levels in cancer cells altered cell cycle progression moderately with an elevated percentage (20-30%) of cells in G(2)/M. Furthermore, cells with reduced PLK1 protein gained a rounded phenotype with multiple centrosomes. Moreover, ASO treatment resulted in potent antiproliferative effects in cell culture. Considerable antitumor activity was observed in vivo against A549 cells. This study suggests that antisense inhibitors targeted against PLK1 at well tolerated doses may be considered as a cancer therapeutic agent.

The proliferative stimulus of the epidermal growth factor (EGF) in human epithelial cells is mediated by its binding to the external domain of the EGF receptor (EGF-R). The purpose of this study was to investigate whether growth arrest of tumors treated with anti-EGF-R MAb (EMD 55900) was dependent on EGF-R expression and distinct histopathologic criteria of those neoplasms. Nine different adenocarcinomas, squamous cell carcinomas and two neoplastic epithelial cell lines (A431 and Detroit 562), which were characterized by high EGF-R expression, were xenotransplanted onto NMRI-nu/nu mice and treated with an anti-EGF-R antibody (EMD 55900). Results revealed that EGF-R expression and distinct histopathologic growth patterns play an important role for the therapeutic effect of the EGF-R antibody treatment. Tumors with high epithelial cellularity and little connective tissue responded to EMD 55900 treatment to a greater degree of growth reduction than tumors with lower cellularity. These results will be helpful for evaluation of patients who would benefit from tumor therapy with anti-EGF-R antibody.

Background: Elderly breast cancer patients are underrepresented in clinical trials and this leads to a lack of knowledge regarding the tolerance and side effects of modern chemotherapy regimens, especially in dose-dense (dd) or dose-intensified combination. Patients and Methods: In this analysis, data from 4 German, randomized (neo-)adjuvant trials, including anthracycline-based chemotherapy, were evaluated for toxicity, compliance and feasibility. Patients were grouped according to age. Results: Of the 4,775 patients, 73.6% were < 60 years, 15.8% were 60-64 years and 10.6% were > 64 years. The patients' compliance decreased with increasing age, the rate of therapy discontinuations was 10.3%; 16.0% were > 64 years old (p < 0.001). The rate of dose reductions also increased with increasing age in the docetaxel/doxorubicin/cyclophosphamide (TAC) (p overall = 0.02) and 5-fluorouracil/epirubicin-cyclophosphamide (FE120C) (p overall < 0.001) treatment groups. Neutropenia grade 3 + 4 in patients of > 64 years was 77% in FE120C- compared to 55% in TAC-treated patients (with primary granulocyte colony-stimulating factors (G-CSFs)). The incidence of febrile neutropenia (FN) was lowest in the regimens without additional taxanes. FN in patients aged > 64 years was lower in the FE120C- than in TAC- and dd-doxorubicin/docetaxel-treated groups. Conclusion: The range and intensity of toxicity increased with age. Neutropenia did not increase significantly in the dd groups; the highest rate was seen in FE120C-treated patients. FE120C without G-CSFs is not an option in patients older than 64 years. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Receptors for luteinizing hormone-releasing hormone (LHRH) can be utilized for targeted chemotherapy of cytotoxic LHRH analogs. The compound AEZS-108 (previously AN-152) consists of [D-Lys6]LHRH linked to doxorubicin. The objectives of this first study in humans with AESZ-108 were to determine the maximum tolerated dose and to characterize the dose-limiting toxicity, pharmacokinetics, preliminary efficacy, and hormonal effects. Methods: The study included 17 women with histologically confirmed epithelial cancer of the ovary, endometrium, or breast that was metastatic or unresectable and for which standard curative or palliative measures could not be used or were no longer effective or tolerated. In each patient, immunohistochemistry of primary tumor or metastatic lesion confirmed that the tumors expressed LHRH receptors. Results: One patient each received intravenous doses of 10, 20, 40, or 80mg/m2 of AEZS-108, six received 160mg/m2 and seven 267mg/m2 at 3week intervals. Dose-limiting leukopenia and neutropenia were observed at the highest dose. A total of 6 patients, 3 patients each in both upper dose groups, showed responses to AEZS-108. The half-life of AESZ-108 was estimated to be about 2h. Conclusions: The maximum tolerated dose of AESZ-108 in the absence of supportive medication is 267mg/m2 and this dose is recommended as starting dose for therapeutic Phase II studies. [Copyright &y& Elsevier]

Abstract: Primary systemic therapy (PST) allows the observation of tumour response under treatment, but little is known regarding the typical course of clinical response during such therapy. The aim of this study is to support decision making in case of insufficient clinical response. Tumour response was assessed by palpation at different times in 436 patients with operable breast cancer from the dose-dense biweekly therapy arm of the GEPARDUO phase III trial. The predictive value of clinical response for pathologic complete response (pCR), prognostic models to assess the prognosis and individual courses of clinical response were investigated. Sensitivity and positive predictive value were low, but comparatively highest after the 3rd cycle. The predictive value of clinical response by palpation for pCR was subsequently limited. The majority of patients (68.1%) experienced a consistent decrease in tumour size during PST. The results indicate that decisions about further treatment should take place at the earliest after the 3rd cycle or 6 weeks of dose-dense PST. [Copyright &y& Elsevier]

Summary: Background: For more than 20 years, tamoxifen has been the mainstay of adjuvant endocrine therapy for women with hormone-sensitive early-stage breast cancer. However, not only does tamoxifen have potential side-effects such as an increased risk of endometrial cancer and thromboembolic events, but patients can also develop resistance to the drug. We aimed to investigate whether switching treatment of postmenopausal women with such breast cancer to anastrozole after 2–3 years of tamoxifen would be more effective than continuing on tamoxifen for a total of 5 years. Methods: We did a meta-analysis of three clinical trials—the Austrian Breast and Colorectal Cancer Study Group (ABCSG 8), Arimidex-Nolvadex (ARNO 95), and the Italian Tamoxifen Anastrozole (ITA) studies—in which postmenopausal women with histologically confirmed, hormone-sensitive early-stage breast cancer were randomised to 1 mg/day anastrozole (n=2009) after 2–3 years of tamoxifen treatment or to continued 20 or 30 mg/day tamoxifen (n=1997). We analysed the data with a stratified Cox proportional hazards model with the covariates of age, tumour size, nodal status, grade, surgery, and chemotherapy. Findings: Patients who switched to anastrozole had fewer disease recurrences (92 vs 159) and deaths (66 vs 90) than did those who remained on tamoxifen, resulting in significant improvements in disease-free survival (hazard ratiro 0·59 [95% CI 0·48–0·74]; p<0·0001), event-free survival (0·55 [0·42–0·71]; p<0·0001), distant recurrence-free survival (0·61 [0·45–0·83]; p=0·002), and overall survival (0·71 [0·52–0·98]; p=0·04). Interpretation: Our results show that the clinical benefits in terms of event-free survival seen in individual trials for those patients who switched to anastrozole translate into a benefit in overall survival. These findings confirm that clinicians should consider switching postmenopausal women who have taken adjuvant tamoxifen for 2–3 years to anastrozole. [Copyright &y& Elsevier]

Abstract: Gonadotrophin-releasing hormone analogues were investigated as adjuvant treatment for patients with node-negative, hormone-sensitive, premenopausal breast cancer. Patients were randomised to either three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy (n =378) or goserelin every 28d for 2years (n =393). During a median follow-up of 4.9 years, 123 events were observed. The first-failure event of CMF versus goserelin, respectively, was ipsilateral locoregional recurrence (18 versus 20), contralateral breast cancer (7 versus 6), distant failure (35 versus 24) and death without recurrence (2 versus 2). Forty-two (23 versus 19) deaths of any cause occurred. The estimated adjusted hazard ratio for goserelin versus CMF (intention-to-treat analysis) was 0.79 (95% CI=0.54–1.14; P =0.19). It is concluded that medical ovarian ablation with goserelin represents a valid option for premenopausal patients with node-negative breast cancer. [Copyright &y& Elsevier]