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Previous data suggest that lipophilic statins such as fluvastatin and N-bisphosphonates such as zoledronic acid, both inhibitors of the mevalonate metabolic pathway, have anti-cancer effects in vitro and in patients. We have examined the effect of fluvastatin alone and in combination with zoledronic acid in the ATP-based tumour chemosensitivity assay (ATP-TCA) for effects on breast and ovarian cancer tumour-derived cells. Both zoledronic acid and fluvastatin showed activity in the ATP-TCA against breast and ovarian cancer, though fluvastatin alone was less active, particularly against breast cancer. The combination of zoledronic acid and fluvastatin was more active than either single agent in the ATP-TCA with some synergy against breast and ovarian cancer tumour-derived cells. Sequential drug experiments showed that pre-treatment of ovarian tumour cells with fluvastatin resulted in decreased sensitivity to zoledronic acid. Addition of mevalonate pathway components with zoledronic acid with or without fluvastatin showed little effect, while mevalonate did reduced inhibition due to fluvastatin. These data suggest that the combination of zoledronic acid and fluvastatin may have activity against breast and ovarian cancer based on direct anti-cancer cell effects. A clinical trial to test this is in preparation. [ABSTRACT FROM AUTHOR]

Background: Patients with de novo metastatic breast cancer (dnMBC) may have different clinical and pathological characteristics. In studies concerned with first-line metastatic patients, the proportion of these patients without secondary resistance mechanisms may have a large influence ont the study results. The aim of this study was to identify patient and tumor characteristics that are associated with dnMBC vs. recurrent MBC (rMBC)., Methods: This is a retrospective analysis of data prospectively collected in the PRAEGNANT metastatic breast cancer registry (NCT02338167). Firs line treated patients were eligible. Patient and tumor characteristics were compared with common disease and tumor characteristics relative to de novo metastatic status, as well as early and late recurrences after primary disease without metastases., Results: Among the 947 patients identified, 355 were included with de novo metastatic disease (37.5%). Older age and HER2-positive disease were significantly associated with a higher frequency of dnMBC. Patients younger than 50, 50-69, or 70 years or older had dnMBC frequencies of 22.7%, 44.0%, and 57.6%, respectively. HER2-positive patients had dnMBC at initial presentation in 49.1% of cases, in comparison with 21.9%, 35.5%, and 37.6% in patients with triple-negative, luminal A-like and luminal B-like breast cancer, respectively., Conclusion: Age and breast cancer subtype are associated with the frequency of first-line MBC patients. Inclusion criteria concerning age or breast cancer subtype can influence the frequency of these patients in a selected patient population and can therefore modify the number of patients with secondary resistance to specific therapies in clinical trials., Competing Interests: Conflict of interest statement V.M. has received speaker honoraria from Amgen, Astra Zeneca, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro and Nektar. A.D.H. has received honoraria from Teva, GenomicHealth, Lilly, AstraZeneca, Novartis, Pfizer, Pierre Fabre, SeaGen and Roche. P.A.F. received honoraria from Novartis, Pfizer, Roche, Amgen, Celgene, Daiichi-Sankyo, AstraZeneca, Merck-Sharp & Dohme, Eisai, Puma and Teva; his institution conducts research with funding from Novartis and Biontech. H.-C.K. has received honoraria from Carl Zeiss meditec, Theraclion, Novartis, Amgen, AstraZeneca, Pfizer, GSK, SurgVision, Onkowissen and Genomic Health/Exact Sciences, travel support from Tesaro and Daiichi Sankyo and holds stock of Theraclion and Phaon scientific. H.T. has received honoraria from Novartis, Roche, Celgene, TEVA, and Pfizer, and travel support from Roche, Celgene, and Pfizer. J.E. has received consulting fees from AstraZeneca, Daiichi Sankyo, Pfizer, Novartis, Lilly, Pierre Fabre, Roche, Tesaro; contracted research from Daiichi Sankyo, Pfizer, Lilly, Novartis, Seattle Genetics, AstraZeneca, Roche, and Odonate; and travel support from Astra Zeneca, Daiichi Sankyo, Celgene, Pfizer, Novartis, Lilly, and Tesaro. D.L. has received honoraria from Novartis, Pfizer, Amgen, Eli Lilly, Teva, Loreal, GSK, MSD, Roche, Astra Zeneca. M.W. received grants from Astra Zeneca, grants from Celgene, grants from Roche, grants from MSD and grants from Novartis during the conduct of the study. E.B. has received honoraria from Novartis, Pfizer, Amgen, Daiichi-Sankyo, and onkowissen.de. P.W. has received honoraria for scientific talks or grants from Amgen, Novartis, MSD, Pfizer, PharmaMar, Teva, Eisai, Clovis and Tesaro. C.H. has received honoraria from Roche Pharma, Pfizer, Astra Zeneca, Novartis, and Onkovis. C.M.K. received honoraria from Amgen, Astra Zeneca, Eli Lilly, MSD Sharp & Dohme, Novartis, Pfizer, Onkotrakt, PharmaMar, Riemser, Roche, Tesaro, Hilotherm, NewCo, research grants from Astra Zeneca, BMS, Immunomedics, MSD Sharp&Dohme (Merck), NewCo, Novartis, Pfizer, PharmaMar, Reimser, Roche, Seattle Genetics and travel support from Amgen, Astra Zeneca, Hexal, Immunomedics, PharmaMar, Pfizer, Tesaro, TEVA Oncology. R.W. has received honoraria from Amgen, Astra Zeneca, Celgene, Daiichi-Sankyo, Esai, Exact Science, Nanostring, GSK, Hexal, Lilly, MSD, Mundipharma, Novartis, Odonate, Pfizer, Pierre Fabre, Riemser, Roche, Sandoz, Seattle Genetics, Tesaro Bio, Teva, and Viatris. M.U. has received honoraria from Abbvie, Amgen, Astra Zeneca, BMS, Celgene, Daiichi-Sankyo, Eisai, Lilly Deutschland, Lilly Int., MSD Merck, Mundipharma, Myriad Genetics, Odonate, Pfizer, PUMA Biotechnology, Roche Pharma, Sanofi Aventis Deutschland, TEVA Pharmaceuticals Ind Ltd, Novartis, Pierre Fabre, Clovis Oncology, and Seattle Genetics. W.J. has received honoraria and research grants from Sanofi-Aventis, Novartis, Lilly, Pfizer, Roche, Chugai, Astra Zeneca, MSD, and Daiichi-Sankyo. F.A.T. has received honoraria from Hexal, Novartis, Tesaro and travel expenses from GSK. M.P.L. has received honoraria from Lilly, Pfizer, Roche, MSD, Hexal, Novartis, AstraZeneca, Eisai, Exact Sciences, Pierre-Fabre, PharmaMar and medac for advisory boards, lectures, and travel support. S.Y.B. has received honoraria from Roche Pharma, Novartis, Pfizer, MSD, Teva, Astra Zeneca. T.N.F. has received honoraria from Novartis, Roche, Pfizer, TEVA, Diachii Sankyo, Astra Zeneca and MSD. All remaining others (A.H., P.H., L.H., M.W.B, S.U., J.M., L.A.W., D.W., L.L.M.) have declared that they do not have any conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background Comprehensive data from prospective clinical trials have led to a high level of evidence establishing CDK4/6 inhibitors in combination with endocrine treatment (CDK4/6i + ET) as a standard for the treatment of HER2-negative, hormone receptor-positive (HER2- HR+) breast cancer patients in the first-line advanced therapy setting. Data on patient populations that have been treated in the real-world setting may provide an insight into changes of patient characteristics and prognosis over time. Methods The data were extracted from the prospective real-world registry PRAEGNANT (NCT02338167). Patients had to have HER2- HR+ advanced breast cancer in the first-line metastatic setting. The chosen therapies were described as well as progression-free survival (PFS) and overall survival (OS) in relation to the given therapies and time periods during which they were indicated. Results CDK4/6 inhibitors have been rapidly implemented since their introduction in November 2016. In recent years (2018 - 2022), about 70 - 80% of the patient population have been treated with CDK4/6 inhibitors, while endocrine monotherapy was given to about 10% and chemotherapy to about 15% of all patients. The prognosis was worst in patients treated with chemotherapy. Recently, mainly patients with a good prognosis are being treated with endocrine monotherapy, and patients who are treated with chemotherapy have an unfavorable prognosis. The PFS and OS of patients treated with CDK4/6i + ET have remained similar over time despite changes in patient characteristics. Conclusion A treatment with CDK4/6i + ET has rapidly become the therapy standard for patients in the first-line advanced breast cancer setting. After the implementation of CDK4/6i + ET, endocrine monotherapy is only given to patients with a very favorable prognosis, while chemotherapy is provided to patients with a rather unfavorable prognosis. These changes in patient characteristics did not seem to influence the prognosis of patients treated with CDK4/6i + ET., Competing Interests: Conflict of Interest T. E. received honoraria from AstraZeneca, Eli Lilly, Daiichi Sankyo, Gilead, GSK, Novartis, Pfizer, Roche. P. A. F. has received honoraria from Novartis, Pfizer, Roche, Amgen, Celgene, Daiichi Sankyo, AstraZeneca, Merck-Sharp & Dohme, Eisai, Puma, and Teva; his institution conducts research with funding from Novartis and Biontech. D. L. has received honoraria from Amgen, Novartis, Pfizer, Eli Lilly, Teva, Loreal, GSK, MSD, Roche, onkowissen, High5MD and AstraZeneca. A. D. H. has received honoraria from Teva, GenomicHealth, Lilly, AstraZeneca, Novartis, Pfizer, Pierre Fabre, SeaGen, and Roche. V. M. has received speaker honoraria from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, and Seattle Genetics and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Tesaro, and Nektar. H.-C. K. has received honoraria from Carl Zeiss Meditec, Theraclion, Novartis, Amgen, AstraZeneca, Pfizer, GSK, SurgVision, Onkowissen, Agendia, Gilead, Lilly, Daiichi Sankyo and Genomic Health/Exact Sciences and travel support from Tesaro and Daiichi Sankyo; he owns stocks of Theraclion and Phaon scientific. H. T. has received honoraria from Novartis, Roche, Celgene, Teva, and Pfizer and travel support from Roche, Celgene, and Pfizer. J. E. has received consulting fees from AstraZeneca, Daiichi Sankyo, Pfizer, Novartis, Lilly, Pierre Fabre, Roche, and Tesaro; contracted research from Daiichi Sankyo, Pfizer, Lilly, Novartis, Seattle Genetics, AstraZeneca, Roche, and Odonate; and travel support from Astra Zeneca, Daiichi Sankyo, Celgene, Pfizer, Novartis, Lilly, and Tesaro. M. Wa. received grants from AstraZeneca, Celgene, Roche, MSD, and Novartis during the conduct of the study. E. B. has received honoraria from Novartis, Pfizer, Amgen, Daiichi Sankyo, and onkowissen.de. P. W. has received honoraria for scientific talks and grants from Amgen, AstraZeneca, Roche, Daiichi Sankyo, Gilead, Lilly, Celgene, GSK, Novartis, MSD, Pfizer, Teva, Eisai, Clovis, and Tesaro. C. H. has received honoraria from Roche, Pfizer, AstraZeneca, Novartis, and Onkovis. C. M. K. has received honoraria from Amgen, AstraZeneca, Eli Lilly, MSD, Novartis, Pfizer, Onkotrakt, PharmaMar, Riemser, Roche, Tesaro, Hilotherm, and NewCo; research grants from AstraZeneca, BMS, Immunomedics, MSD, NewCo, Novartis, Pfizer, PharmaMar, Reimser, Roche, and Seattle Genetics; and travel support from Amgen, AstraZeneca, Hexal, Immunomedics, PharmaMar, Pfizer, Tesaro, and Teva Oncology. R. W. has received honoraria from Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Esai, Exact Science, Nanostring, GSK, Hexal, Lilly, MSD, Mundipharma, Novartis, Odonate, Pfizer, Pierre Fabre, Riemser, Roche, Sandoz, Seattle Genetics, Tesaro Bio, Teva, and Viatris. M. U. has received honoraria from Abbvie, Amgen, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Eisai, Lilly Deutschland, Lilly Int., MSD, Mundipharma, Myriad Genetics, Odonate, Pfizer, Puma Biotechnology, Roche, Sanofi Aventis Deutschland, Teva Pharmaceuticals Ind Ltd, Novartis, Pierre Fabre, Clovis Oncology, and Seattle Genetics. L. L. M. received honoraria from Amgen, AstraZeneca, Celgene, Gilead, Lilly, MSD, Novartis, Pfizer, Roche and Eisai for advisory boards, lectures and travel support. W. J. has received honoraria and research grants from Sanofi-Aventis, Novartis, Lilly, Pfizer, Roche, Chugai, AstraZeneca, MSD, and Daiichi Sankyo. F. A. T. has received honoraria from GSK, Hexal, MSD, Novartis, Pfizer, Roche and Tesaro and travel expenses from GSK. M. We. has participated on advisory boards for AstraZeneca, Lilly, MSD, Novartis, Pfizer and Roche. M. P. L. has received honoraria from Lilly, Pfizer, Roche, MSD, Novartis, AstraZeneca, Eisai, Exact Sciences, Pierre-Fabre, PharmaMar, Gilead, Daiichi Sankyo, Grünenthal, Samantree, Sysmex, pfm and medac for advisory boards, lectures, and travel support. S. Y. B. has received honoraria from Roche, Novartis, Pfizer, MSD, Teva, and AstraZeneca. T. N. F. has received honoraria from Novartis, Roche, Pfizer, Teva, Daiichi Sankyo, AstraZeneca, and MSD. A. S. received research grants from Celgene, Roche, honoraria from Amgen, AstraZeneca, Aurikamed, Bayer, Celgene, Clinsol, Connectmedica, Gilead, GSK, I-MED, Lilly, MCI Deutschland, Metaplan, MSD, Nanostring, Novartis, Onkowissen.de, Promedicis, Pfizer, Pierre Fabre, Roche, Seagen, Streamedup, Teva, Tesaro, Thieme and travel support from Celgene, Pfizer, Roche. All others (A. H., P. H., P. K., H.-M. E., M. M., D. H., L. H., M. W.B, S. U., D. W.) have declared that they do not have any conflicts of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Introduction: In a prospective non-interventional study involving 2,173 patients, we showed that use of the oral fixed combination of netupitant 300 mg and palonosetron 0.5 mg (NEPA) for prevention of chemotherapy (Ctx)-induced nausea and vomiting has beneficial effects on the quality of life (QoL) of patients with various types of cancers receiving highly or moderately emetogenic Ctx. Here, we report on the effects on QoL, effectiveness, and tolerability of NEPA in patients with breast cancer exposed to anthracycline-cyclophosphamide (AC)-based Ctx., Methods: This is a post hoc subanalysis of a prospective non-interventional study in 1,197 patients with breast cancer receiving up to 3 cycles of doxorubicin or epirubicin plus cyclophosphamide and NEPA. NEPA administration was per the summary of product characteristics., Results: In cycle 1 of Ctx, a large proportion of patients (84%) reported "no impact on daily life" (NIDL) due to vomiting; 53% of patients reported NIDL due to nausea. The complete response rate was 86/88/81% in the acute/delayed/overall phase in cycle 1, and NEPA was well tolerated throughout the study., Conclusion: The real-world beneficial effects of NEPA prophylaxis on QoL were confirmed for patients with breast cancer receiving AC. NEPA was effective with a good safety profile in this patient population in clinical practice., Competing Interests: J.S.: honoraria, travel expenses, RIEMSER Pharma GmbH. C.M.K.: honoraria, Amgen, Eli Lilly, Novartis, Mundipharma, Pfizer, PharmaMar, RIEMSER, Roche, Tesaro; consulting or advisory role, Amgen, Axios, Eli Lilly, Hilotherm, Mundipharma, NewCo, Novartis, Pfizer, RIEMSER, Roche, Tesaro; research funding, AstraZeneca, Axios, MSD Sharp & Dohme (Merck), NewCo, Novartis, Pfizer, PharmaMar, RIEMSER, Seattle Genetics, Immunomedics; travel, accommodations, expenses, Amgen, Hexal, Immunomedics, Pfizer, PharmaMar, Tesaro, Teva Oncology. C.H.: advisory board, AstraZeneca, Lilly, Pfizer, Roche. S.B.: lectures, studies and support for congress participation, Amgen, Roche, Novartis, Pfizer, Riemser, Lilly, Clovis, GSK, Onkovis, AstraZeneca, MSD. M.H.: honoraria, Pfizer, AstraZeneca, iOMEDICO, MMF, Amgen; research funding, RIEMSER, Indivumed. J.K.-S. and D.R.: nothing to disclose. E.F.: RIEMSER employee. M.K.: ad board, travel grant, Helsinn Healthcare, RIEMSER Pharma GmbH., (Copyright © 2021 by S. Karger AG, Basel.)

Purpose: Assessment of HER2 overexpression using immunohistochemistry (IHC) and/or in situ hybridisation (ISH) for the detection of HER2 amplifications is standard to identify patients for established HER2-directed treatments. Patients with lower HER2 expression levels have recently also become candidates for novel therapies targeting HER2. This study aimed to assess tumour and patient characteristics and prognosis in patients with advanced breast cancer (aBC), relative to low HER2 expression levels., Methods: PRAEGNANT is a prospective aBC registry (NCT02338167), focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis includes patients with conventionally HER2-negative aBC. Clinical outcome was compared in the groups with no (IHC score 0) or with low HER2 expression (IHC 1+, or IHC 2+/ISH negative)., Results: Low HER2 expression levels in triple-negative aBC patients did not influence progression-free survival. Overall survival appeared poorer in patients with IHC 2+ compared with patients with no HER2 expression in the unadjusted analysis (hazard ratio 2.24, 95% confidence interval 0.1.12-4.47). However, this effect was not maintained in the adjusted analysis. In HER2-negative, hormone receptor-positive patients, low HER2 expression appeared to have no effect on prognosis, neither progression-free survival nor overall survival., Conclusions: We could not demonstrate that HER2 expression at a low level and assessed in clinical routine can differentiate patients into prognostic groups. However, the prevalence of patients with a low expression makes this population interesting for clinical trials with potentially active treatments using HER2 as a target., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.D.H. has received honoraria from Teva, GenomicHealth, Celgene, AstraZeneca, Novartis, Pfizer and Roche; J.E. has received honoraria from AstraZeneca, Daiichi-Sankyo, Eisai, Lilly, Novartis, Pierre Fabre, Roche and Pfizer; M.P.L. has received honoraria from Pfizer, Lilly, Roche, MSD, Hexal, Novartis, AstraZeneca, Eisai, medac and Exact Sciences for advisory boards, lectures and travel support; B.V. has received honoraria from Novartis; F.A.T. has received honoraria from Hexal, Novartis, Tesaro and travel expenses from GSK; F.O. received speaker and consultancy honoraria from Amgen, AstraZeneca, Bayer, BMS, Boehringer, Celgene, Cellex, Chugai, Gilead, Hexal, Ipsen, Janssen-Cilag, Merck, MSD, Novartis, Riemser, Roche, Tesaro and Teva; P.H. received honoraria, unrestricted educational grants and research funding from Amgen, AstraZeneca, Eli Lilly, MSD, Novartis, Pfizer and Roche; H.T. has received honoraria from Novartis, Roche, Celgene, TEVA and Pfizer, and travel support from Roche, Celgene and Pfizer; J.E. has received honoraria from AstraZeneca, Daiichi-Sankyo, Eisai, Lilly, Novartis, Pierre Fabre, Roche and Pfizer; D.L. has received honoraria from Amgen, Eli Lilly, Pfizer, Roche, MSD, Hexal, Novartis, AstraZeneca, TEVA, Celgene, Eisai, and Loreal. M.W. has received speaker honoraria from AstraZeneca, Celgene and Novartis; V.M. has received speaker honoraria from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro and Nektar; E.B. has received honoraria from Novartis, Pfizer, Amgen, Daiichi-Sankyo and onkowissen.de; C.H. has received honoraria from Roche Pharma, Pfizer, AstraZeneca, Novartis and Onkovis; C.M.K. received honoraria from Amgen, Axios, Roche, Teva, Novartis, MSD Sharp & Dohme, Mundipharma, NewCo, Pfizer, Riemser and ZytoService, research grants from Amgen, Axios, Novartis, MSD Sharp & Dohme, NewCo, Pfizer and ZytoService, and travel support from Amgen, Paxman Inc., PharmaMar and Pfizer; R.W. has received honoraria from Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Esai, Exact Science, Nanostring, GSK, Hexal, Lilly, MSD, Mundipharma, Novartis, Odonate, Pfizer, Pierre Fabre, Riemser, Roche, Sandoz, Seattle Genetics, Tesaro Bio, Teva and Viatris; C.T. has received honoraria from Roche, Daiichi-Sankyo and AstraZeneca; M.U. has received honoraria from Abbvie, Amgen, AstraZeneca, BMS, Celgene, Daiichi-Sankyo, Eisai, Lilly Deutschland, Lilly Int., MSD Merck, Mundipharma, Myriad Genetics, Odonate, Pfizer, PUMA Biotechnology, Roche Pharma, Sanofi Aventis Deutschland, TEVA Pharmaceuticals Ind Ltd, Novartis, Pierre Fabre, Clovis Oncology and Seattle Genetics; P.A.F. received honoraria from Novartis, Pfizer, Roche, Amgen, Celgene, Daiichi-Sankyo, AstraZeneca, Merck-Sharp & Dohme, Eisai, Puma and Teva, his institution conducts research with funding from Novartis and Biontech; W.J. has received honoraria and research grants from Sanofi-Aventis, Novartis, Lilly, Pfizer, Roche, Chugai, AstraZeneca, MSD and Daiichi-Sankyo; T.N.F. has received honoraria from Novartis, Roche, Pfizer, TEVA, Diachii Sankyo, AstraZeneca and MSD; S.Y.B. has received honoraria from Roche Pharma, Novartis, Pfizer, MSD, Teva and AstraZeneca. A.S. has received honoraria from Roche, AstraZeneca, Aurikamed GmbH, Celgene, ClinSol Research GmbH, Connectmedica Sp.Z o.o., Deutsche Gesellschaft für Senologie GmbH, if-kongress management gmbh, I-MED Institute GmbH, Lilly Deutschland GmbH, Medicultus GmbH, med publico GmbH, MSD Sharp & Dohme GmbH, onkowissen.de GmbH, Pfizer GmbH, Schattauer Verlag GmbH, Promedicis GmbH, Tesaro Bio Germany GmbH and W. Zuckschwerdt Verlag GmbH; H.-C.K. has received honoraria from Carl Zeiss Meditec, Theraclion, Novartis, Amgen, AstraZeneca, Pfizer, GSK, SurgVision, Onkowissen and Genomic Health/Exact Sciences, travel support from Tesaro and Daiichi-Sankyo and holds stock of Theraclion and Phaon scientific. All remaining others (A.H., L.H., L.A.W., M.W.B., P.W., D.W.) have declared that they do not have any conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Treatment with CDK4/6 inhibitors and endocrine therapy (CDK4/6i + ET) is a standard for patients with advanced hormone receptor-positive, HER2-negative (HR + HER2-) breast cancer (BC). However, real-world data on the implementation of therapy usage, efficacy, and toxicity have not yet been reported., Methods: The PRAEGNANT registry was used to identify advanced HR + HER2- BC patients (n = 1136). The use of chemotherapy, ET, everolimus + ET, and CDK4/6i + ET was analyzed for first-line, second-line, and third-line therapy. Progression-free survival (PFS) and overall survival (OS) were also compared between patients treated with CDK4/6i + ET and ET monotherapy. Also toxicity was assessed., Results: CDK4/6i + ET use increased from 38.5% to 62.7% in the first 2 years after CDK4/6i treatment became available (November 2016). Chemotherapy and ET monotherapy use decreased from 2015 to 2018 from 42.2% to 27.2% and from 53% to 9.5%, respectively. In this early analysis no statistically significant differences were found comparing CDK4/6i + ET and ET monotherapy patients with regard to PFS and OS. Leukopenia was was seen in 11.3% of patients under CDK4/6i + ET and 0.5% under ET monotherapy., Conclusions: In clinical practice, CDK4/6i + ET has been rapidly implemented. A group of patients with a more unfavorable prognosis was possibly treated in the real-world setting than in the reported randomized clinical trials. The available data suggest that longer follow-up times and a larger sample size are required in order to identify differences in survival outcomes. Studies should be supported that investigate whether chemotherapy can be avoided or delayed in this patient population by using CDK4/6i + ET., Competing Interests: Declaration of competing interest A.S. received honoraria from Roche, AstraZeneca, Aurikamed GmbH, Celgene, ClinSol Research GmbH, Connectmedica Sp.Z o.o., Deutsche Gesellschaft für Senologie GmbH, if-kongress management gmbh, I-MED Institute GmbH, Lilly Deutschland GmbH, Medicultus GmbH, med publico GmbH, MSD Sharp & Dohme GmbH, onkowissen.de GmbH, Pfizer GmbH, Schattauer Verlag GmbH, Promedicis GmbH, Tesaro Bio Germany GmbH, W. Zuckschwerdt Verlag GmbH. J.E. received honoraria from AstraZeneca, Celgene, Novartis, Lilly, Pfizer, Pierre Fabre, Roche and TEVA and travel support from Celgene, Pfizer, TEVA, and Pierre Fabre. D.L. received honoraria from Amgen, AstraZeneca, Celgene, Lilly, Loreal, MSD, Novartis, Pfizer, Tesaro, Teva. M.W.B reports support from Novartis, Merck Sharp & Dohme, AstraZeneca, Roche, Amgen, Eisai, paid to his institution. E.B. received honoraria from Novartis, Celgene, Riemser, Pfizer, Hexal, Amgen, onkowissen.de for consulting, clinical research management or medical education activities. P.A.F. received honoraria from Novartis, Pfizer, Roche, Amgen, Celgene, Daiichi-Sankyo, AstraZeneca, Merck-Sharp & Dohme, Eisai, Puma and Teva. His institution conducts research with funding from Novartis and Biontech. T.N.F. reports personal fees from Roche, personal fees from Novartis, personal fees from Pfizer, personal fees from Daichii Sankyo, personal fees from Lilly, personal fees from MSD, outside the submitted work. P.H. received honoraria, unrestricted educational grants and research funding from Amgen, AstraZeneca, Eli Lilly, MSD, Novartis, Pfizer, and Roche. A.D.H. received honoraria from Teva, GenomicHealth, Celgene, AstraZeneca, Novartis, Pfizer, and Roche. C.H. received honoraria from Amgen, Celgene, Oncovis, Roche, and Pfizer. J.H. received honoraria from Astra Zeneca, MSD, Lilly, travel grants from Novartis and research grants from Novartis, Celgene. E.R. reports personal fees from Roche, Pfizer, Amgen, Novartis, Tesaro, Astra Zeneca, Celgene, Pierre Fabre and Riemer, non-financial support from Olympus GmbH, personal fees from Riemser, outside the submitted work. W.J. received research grants and honoroaria from Novartis, Pfizer, Amgen, Chugai, Roche, Genomic-Health, AstraZeneca, Lilly. H.-C.K. received honoraria from Carl Zeiss meditec, TEVA, Theraclion, Novartis, Amgen, AstraZeneca, Pfizer, Janssen-Cilag, GSK, LIV Pharma, and Genomic Health. C.M.K. received honoraria from Amgen, Axios, Roche, Teva, Novartis, MSD Sharp & Dohme, Mundipharma, NewCo, Pfizer, Riemser, and ZytoService, research grants from Amgen, Axios, Novartis, MSD Sharp & Dohme, NewCo, Pfizer, and ZytoService, and travel support from Amgen, Paxman Inc., PharmaMar, and Pfizer. M.P.L. has participated on advisory boards for AstraZeneca, MSD, Novartis, Pfizer, Eisai, Genomic Health, Tesaro and Roche and has received honoraria for lectures from MSD, Lilly, Roche, Novartis, Pfizer, Genomic Health, AstraZeneca, medac and Eisai. V.M. received speaker honoraria from Amgen, Astra Zeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, Novartis, Roche, Teva, Janssen-Cilag and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro and Nektar. N.N. received consultancy honoraria from Janssen-Cilag and travel support from Novartis. F.O. received speaker and consultancy honoraria from Amgen, AstraZeneca, Bayer, BMS, Boehringer, Celgene, Cellex, Chugai, Gilead, Hexal, Ipsen, Janssen-Cilag, Merck, MSD, Novartis, Riemser, Roche, Tesaro, Teva. H.T. received honoraria from Novartis, Roche, Celgene, TEVA, and Pfizer and travel support. F.-A. T. received honoraria from Astra Zeneca, Genomic Health and Novartis. C.T. received honoraria from Amgen, Astra-Zeneca, Celgene, Novartis, Pfizer, and Roche. M.U. reports support paid to his institution from Abbvie, Amgen GmbH München, Astra Zeneca, BMS, Celgene GmbH München, Daiji Sankyo, Eisai GmbH München, Janssen Cilag, Johnsen&Johnsen, Lilly Deutschland, Lilly Int., MSD Merck, Mundipharma, Myriad Genetics GmbH Zürich, Odonate, Pfizer GmbH Berlin, PUMA Biotechnology, Riemser, Roche Pharma AG, Grenzach Wyhlen, Sanofi Aventis Deutschland GmbH, Sividon Diagnostics Köln, TEVA Pharmaceuticals Ind. Ltd. und. Berlin(.)P.W. received honoraria from Amgen, AstraZeneca, Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar, Roche, TEVA, Eisai Clovis and Tesaro. She participated in advisory boards of Amgen, AstraZeneca, Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar, Roche, TEVA, Eisai Clovis and Tesaro. Her institution received research grants from Amgen, AstraZeneca, MSD, Novartis, Pfizer, Pharmamar, Clovis and Tesaro. R.W. received honoraria from Agendia, Amgen, Astra Zeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Daiichi-Sankyo, Esai, Genomic Health, Glaxo Smith Kline, Lilly, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva. M.W. received speaker honoraria from AstraZeneca, Celgene, and Novartis. S.Y.B. reports personal fees from Novartis and Pfizer, both outside the submitted work. All remaining authors (J.S., E.K., M.G., L.H., B.V., D.W.) have declared that they do not have any conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.

The Advanced Breast Cancer Fifth International Consensus Conference (ABC5) which focuses on the diagnosis and treatment of advanced breast cancer was held in Lisbon on November 14 - 16, 2019. The aim of the conference is to standardize the treatment of advanced breast cancer worldwide using evidence-based data and to ensure that patients with advanced breast disease anywhere in the world are treated appropriately and have access to the latest therapies. This year, the emphasis was on new developments and study results from patients with advanced breast cancer as well as precision medicine. The collaboration with patient advocates from all over the globe is also an important goal of the ABC Conference, which is why the international ABC panel also included a number of patient advocates. We present a commentary on the voting results of the ABC5 panelists in Lisbon by a working group of German breast cancer specialists together with the implications for routine clinical care in Germany. The commentary is based on the recommendations of the Breast Commission of the German Gynecological Oncology Working Group (AGO). This commentary is useful, it includes country-specific features for the ABC consensus., Competing Interests: Conflict of Interest/Interessenkonflikt Prof. Michael Untch: honoraria paid to his employer (for adboard participation, presentations) and travel grants from Amgen, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Eisai, Janssen Cilag, Johnson & Johnson, Lilly Deutschland, Lilly International, MSD Merck, Mundipharma, Myriad Genetics, Odonate, Pfizer, PUMA Biotechnology, Riemser, Roche, Sanofi Aventis, Sividon Diagnostics, Teva Pharmaceuticals Ind. Ltd. PD Dr. med. Rachel Würstlein received honoraria from Agendia, Amgen, AstraZeneca, Boehringer Ingelheim, Carl Zeiss, Celgene, Daiichi Sankyo, Eisai, Genomic Health, GSK, Lilly, MSD, Mundipharma, NanoString, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, Puma Biotechnology, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva. Prof. Diana Lüftner received honoraria from Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Esai, Genomic Health, GSK, Lilly, MSD, Mundipharma, Novartis, Pfizer, Pierre Fabre, Puma Biotechnology, Riemser, Roche, Tesaro Bio, Teva. Renate Haidinger has no conflict of interest. Prof. Peter A. Fasching received honoraria from Roche, Pfizer, Celgene, Daiichi Sankyo, Merck Sharp & Dohme, Myelo Therapeutics, Eisai, Puma, Lilly, Novartis, AstraZeneca, and his institution received research funding from BionTech and Cepheid. Prof. Christoph Thomssen received honoraria from Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Lilly, MSD, Mundipharma, MEDA, Novartis, Roche, Tesaro, Vifor. Prof. Nadia Harbeck received honoraria for lectures and/or consultancy work from Amgen, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Sandoz/Hexal, Seattle Genetics. Dr. med. Doris Augustin has no conflict of interest. Dr. med. Susanne Briest has no conflict of interest. Dr. med. Johannes Ettl received honoraria from AstraZeneca, Roche, Celgene, Novartis, Lilly, Pfizer, Pierre Fabre, Teva and travel grants from Celgene, Lily, Novartis, Pfizer, Teva, Pierre Fabre. Prof. Frank Förster received honoraria from Roche, Novartis, AstraZeneca, Eisai, Lilly, Pfizer, Tesaro, MSD, Celgene. Dr. med. Christian Kurbacher received honoraria from Amgen, Axios, Eli Lilly, Hilotherm, Mundipharma, NewCo, Novartis, Pfizer, Riemser, Roche, Tesaro. Research funding from AstraZeneca, Axios, MSD Sharp & Dohme, NewCo, Novartis, Pfizer, PharmaMar, Riemser, Seattle Genetics. Honoraria from Amgen, Eli Lilly, Novartis, Mundipharma, Pfizer, PharmaMar, Riemser, Roche, Tesaro; travel grants and other expenses from Amgen, Hexal, Pfizer, PharmaMar, Tesaro, Teva Oncology. Prof. Hans-Joachim Lück has no conflict of interest. Dr. med. Norbert Marschner received speakerʼs fees from Lilly, Roche, Novartis, Clovis, GSK, Amgen, Mylan, Eisai, Mundipharma, Novella, SEAGEN, and travel grants from Lilly, Roche. Dr. med. Lothar Müller received travel grants from octapharm and Medac. Prof. Volkmar Müller received honoraria from Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, and honoraria for consultancy work from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro, Nektar. Dr. med. Isabel Radke received honoraria and/or travel grants from Amgen, AstraZeneca, Celgene, Genomic Health, Novartis, Pierre Fabre, Pfizer, Roche, Teva. Prof. Eugen Ruckhäberle received honoraria from Amgen, AstraZeneca, Pharma Mar, Celgene, Daiichi Sankyo, Eisai, GSK, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Clovis Oncology, Teva. Dr. med. Iris Scheffen received honoraria from Amgen, Celgene, MSD, Novartis, Pfizer, Roche. Eva Schumacher-Wulf has no conflict of interest. Dr. med. Moritz Schwoerer received honoraria for adboard participation from Roche. Dr. med. Dieter Steinfeld-Birg received honoraria from Amgen, Hexal, Roche, Teva, Novartis. Dr. med. Katja Ziegler-Löhr received honoraria from Celgene, Novartis, Oncovis, Roche, Tesaro./ Prof. Michael Untch: Honorare an den Arbeitgeber (für Adboard-Teilnahme, Präsentationen) und Reiseunterstützung von Amgen, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Eisai, Janssen Cilag, Johnson & Johnson, Lilly Deutschland, Lilly International, MSD Merck, Mundipharma, Myriad Genetics, Odonate, Pfizer, PUMA Biotechnology, Riemser, Roche, Sanofi Aventis, Sividon Diagnostics, Teva Pharmaceuticals Ind. Ltd. PD Dr. med. Rachel Würstlein erhielt Honorar von Agendia, Amgen, AstraZeneca, Boehringer Ingelheim, Carl Zeiss, Celgene, Daiichi Sankyo, Eisai, Genomic Health, GSK, Lilly, MSD, Mundipharma, NanoString, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, Puma Biotechnology, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva. Prof. Diana Lüftner erhielt Honorar von Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Esai, Genomic Health, GSK, Lilly, MSD, Mundipharma, Novartis, Pfizer, Pierre Fabre, Puma Biotechnology, Riemser, Roche, Tesaro Bio, Teva. Renate Haidinger hat keinen Interessenkonflikt. Prof. Peter A. Fasching erhielt Honorare von Roche, Pfizer, Celgene, Daiichi Sankyo, Merck Sharp & Dohme, Myelo Therapeutics, Eisai, Puma, Lilly, Novartis, AstraZeneca und seine Institution erhielt Forschungsunterstützung von BionTech und Cepheid. Prof. Christoph Thomssen erhielt Honorar von Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Lilly, MSD, Mundipharma, MEDA, Novartis, Roche, Tesaro, Vifor. Prof. Nadia Harbeck erhielt Honorare für Vorträge und/oder Beratung von Amgen, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Lilly, MSD, Novartis, Odonate, Pierre Fabre, Pfizer, Roche, Sandoz/Hexal, Seattle Genetics. Dr. med. Doris Augustin hat keinen Interessenkonflikt. Dr. med. Susanne Briest hat keinen Interessenkonflikt. Dr. med. Johannes Ettl erhielt Honorar von AstraZeneca, Roche, Celgene, Novartis, Lilly, Pfizer, Pierre Fabre, Teva und Reiseunterstützung von Celgene, Lily, Novartis, Pfizer, Teva, Pierre Fabre. Prof. Frank Förster erhielt Honorar von Roche, Novartis, AstraZeneca, Eisai, Lilly, Pfizer, Tesaro, MSD, Celgene. Dr. med. Christian Kurbacher erhielt Honorar von Amgen, Axios, Eli Lilly, Hilotherm, Mundipharma, NewCo, Novartis, Pfizer, Riemser, Roche, Tesaro. Forschungsunterstützung von AstraZeneca, Axios, MSD Sharp & Dohme, NewCo, Novartis, Pfizer, PharmaMar, Riemser, Seattle Genetics. Honorare von Amgen, Eli Lilly, Novartis, Mundipharma, Pfizer, PharmaMar, Riemser, Roche, Tesaro; Reiseunterstützung und sonstige Ausgaben von Amgen, Hexal, Pfizer, PharmaMar, Tesaro, Teva Oncology. Prof. Hans-Joachim Lück hat keinen Interessenkonflikt. Dr. med. Norbert Marschner erhielt Vortragshonorare von Lilly, Roche, Novartis, Clovis, GSK, Amgen, Mylan, Eisai, Mundipharma, Novella, SEAGEN und Reisekostenerstattung von Lilly, Roche. Dr. med. Lothar Müller erhielt Reiseunterstützung von octapharm und Medac. Prof. Volkmar Müller erhielt Honorar von Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, und Beratungshonorar von Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro, Nektar. Dr. med. Isabel Radke erhielt Honorar und/oder Reiseunterstützung von Amgen, AstraZeneca, Celgene, Genomic Health, Novartis, Pierre Fabre, Pfizer, Roche, Teva. Prof. Eugen Ruckhäberle erhielt Honorar von Amgen, AstraZeneca, Pharma Mar, Celgene, Daiichi Sankyo, Eisai, GSK, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Clovis Oncology, Teva. Dr. med. Iris Scheffen erhielt Honorar von Amgen, Celgene, MSD, Novartis, Pfizer, Roche. Eva Schumacher-Wulf hat keinen Interessenkonflikt. Dr. med. Moritz Schwoerer erhielt Honorar für Adboard-Teilnahme von Roche. Dr. med. Dieter Steinfeld-Birg erhielt Honorar von Amgen, Hexal, Roche, Teva, Novartis. Dr. med. Katja Ziegler-Löhr erhielt Honorar von Celgene, Novartis, Oncovis, Roche, Tesaro.

Background: The objective of the IMPROVE study was patients' preference for either endocrine-based therapy or combined chemo- and anti-angiogenic therapy in advanced HR-positive/HER2-negative breast cancer., Methods: In this randomized, cross-over phase IV study, 77 patients were recruited in 26 sites in Germany. Patients were randomized 1:1 to receive either capecitabine plus bevacizumab (Cap+Bev) as first-line therapy followed by cross-over to everolimus plus exemestane (Eve+Exe) as second-line therapy (Arm A) or the reverse sequence (Arm B). The primary endpoint was patients' preference for either regimen, assessed by the Patient Preference Questionnaire 12 weeks after cross-over. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and quality of life (QoL)., Results: 61.5% of patients preferred Cap+Bev (p = 0.1653), whereas 15.4% preferred Eve+Exe and 23.1% were indecisive. Physicians showed a similar tendency towards Cap+Bev (58.1%) as the preferred regimen versus Eve+Exe (32.3%). Median first-line PFS was longer for Cap+Bev than for Eve+Exe (11.1 months versus 3.5 months). Median second-line PFS was similar between Cap+Bev and Eve+Exe (3.6 months versus 3.7 months). Median OS was comparable between Arm A (28.8 months) and Arm B (24.7 months). 73.0% and 52.6% (first-/second-line, Cap+Bev) and 54.1% and 52.9% (first-/second-line, Eve+Exe) of patients experienced grade 3/4 TEAEs. No treatment-related deaths occurred. QoL and treatment satisfaction were not significantly different between arms or treatment lines., Conclusions: Patients tended to favor Cap+Bev over Eve+Exe, which was in line with physicians' preference. Cap+Bev showed superior first-line PFS, while QoL was similar in both arms. No new safety signals were reported., Trial Registration: EudraCT No: 2013-005329-22. Registered on 19 August 20.

The 5th International Consensus Conference for Advanced Breast Cancer (ABC5) took place on November 14-16, 2019, in Lisbon, Portugal. Its aim is to standardize the treatment of advanced breast cancer based on the available evidence and to ensure that all breast cancer patients worldwide receive adequate treatment and access to new therapies. This year, the conference focused on developments and study results in the treatment of patients with hormone receptor-positive/HER2-negative breast cancer as well as precision medicine. As in previous years, patient advocates from around the world were integrated into the ABC conference and had seats on the ABC consensus panel. In the present paper, a working group of German breast cancer experts comments on the results of the on-site ABC5 consensus votes by ABC panelists regarding their applicability for routine treatment in Germany. These comments take the recommendations of the Breast Committee of the Gynecological Oncology Working Group ( Arbeitsgemeinschaft Gynäkologische Onkologie ; AGO) into account. The report and assessment presented here pertain to the preliminary results of the ABC5 consensus. The final version of the statements will be published in Annals of Oncology and The Breast ., Competing Interests: Prof. Christoph Thomssen received honoraria from Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, Lilly, MSD, Mundipharma, MEDA, Novartis, Roche, Tesaro, and Vifor. Prof. Diana Lüftner received honoraria from AstraZeneca, Celgene, Pfizer, Novartis, Amgen, Roche, Loreal, Teva, Tesaro, and Eli Lilly. Prof. Michael Untch received honoraria to the employer (for AdBoard participation, presentations) and travel grants from Amgen, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Eisai, Janssen Cilag, Johnson & Johnson, Lilly Deutschland, Lilly International, MSD Merck, Mundipharma, Myriad Genetics, Odonate, Pfizer, PUMA Biotechnology, Riemser, Roche, Sanofi Aventis, Sividon Diagnostics, and TEVA Pharmaceuticals Ind. Ltd. Renate Haidinger, Dr. med. Doris Augustin, Dr. med. Susanne Briest, Dr. med. Lidia Perlova-Griff, Prof. Hans-Joachim Lück, Dr. med. Norbert Marschner, and Eva Schumacher-Wulf have no conflict of interests. PD Dr. med. Rachel Würstlein received honoraria from Agendia, Amgen, AstraZeneca, Boehringer Ingelheim, Carl Zeiss, Celgene, Daiichi Sankyo, Eisai, Genomic Health, GSK, Lilly, MSD, Mundipharma, NanoString, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, Puma Biotechnology, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, and Teva. Prof. Nadia Harbeck received honoraria for consulting and/or lectures from Agendia, Amgen, Astra Zeneca Celgene, Genomic Health, Lilly, MSD, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics. Dr. med. Johannes Ettl received honoraria from Astra Zeneca, Roche, Celgene, Novartis, Lilly, Pfizer, Pierre Fabre, TEVA and travel support from Celgene, Lily, Novartis, Pfizer, TEVA, and Pierre Fabre. Prof. Peter A. Fasching received honoraria from Roche, Pfizer, Celgene, Daiichi-Sankyo, TEVA, Marck Sharp and Dohme, Myelo Therapeutics, Macrogenics, Eisai, Puma, Lilly, Novartis, and AstraZeneca and he received grant from BioTech, Cepheid, and Novartis. Prof. Frank Förster received honoraria for consulting and/or lectures from Roche, Novartis, AstraZeneca, Eisai, Lilly, Pfizer, Tesaro, MSD, and Celgene. Dr. med. Christian Kurbacher received honoraria for a consulting or advisory role from Amgen, Axios, Eli Lilly, Hilotherm, Mundipharma, NewCo, Novartis, Pfizer, Riemser, Roche, Tesaro; research funding from AstraZeneca, Axios, MSD Sharp and Dohme, NewCo, Novartis, Pfizer, PharmaMar, Riemser, and Seattle Genetics; honoraria from Amgen, Eli Lilly, Novartis, Mundipharma, Pfizer, PharmaMar, Riemser, Roche, and Tesaro; and a travel grant, accommodations and expenses from Amgen, Hexal, Pfizer, PharmaMar, Tesaro, and TEVA Oncology. Dr. med. Lothar Müller received travel grants from octapharm and Medac. Prof. Volkmar Müller received honoraria from Amgen, Astra Zeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, and Teva and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro, and Nektar. Dr. med. Isabel Radke received honoraria and/or travel grants from Amgen, Astra Zeneca, Celgene, Genomic Health, Novartis, Pierre Fabre, Pfizer, Roche, and Teva. Prof. Eugen Ruckhäberle received honoraria from Amgen, AstraZeneca, Pharma Mar, Celgene, Daiichi Sankyo, Eisai, GSK, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Clovis Oncology, and Teva. Dr. med. Iris Scheffen received honoraria from Amgen, Celgene, MSD, Novartis, Pfizer, and Roche. Dr. med. Moritz Schwoerer received honoraria for adboard participation from Roche. Dr. med. Dieter Steinfeld-Birg received honoraria for studies and/or consulting from Amgen, Hexal, Roche, Teva, and Novartis. Dr. med. Katja Ziegler-Löhr received honoraria from Celgene, Novartis, Oncovis, Roche, Tesaro., (Copyright © 2020 by S. Karger AG, Basel.)

Objectives: The non-interventional study (NIS) NADIR (DRKS00005711) evaluated the effectiveness and safety of prophylaxis with lipegfilgrastim, a glycopegylated granulocyte-colony stimulating factor, in 2500 patients undergoing chemotherapy in routine clinical practice. Primary objective was the incidence of chemotherapy-induced severe neutropenia, febrile neutropenia (FN), and neutropenia-associated complications. Methods: NADIR was a prospective NIS conducted in 201 study centers in Germany. Results: The analysis included 2489 patients. Main tumor types were breast cancer ( n  = 1198, 48.1%), lung cancer ( n  = 303, 12.2%), non-Hodgkin lymphoma (NHL; n  = 337, 13.5%), and prostate cancer ( n  = 111, 4.5%). Nine hundred and ten (36.6%) patients were aged ≥65 years (regarded as "elderly" patients). Severe neutropenia (CTCAE grade 3/4) was reported in 26.8% ( n  = 666) and 25.2% ( n  = 229) of the total population and elderly patients, respectively. FN was documented in 2.7% ( n  = 68) of the total population vs 3.0% ( n  = 27) of elderly patients. Primary prophylaxis with lipegfilgrastim among patients with high risk of FN (>20%) was documented in 83.5% of the total population and 75.1% of elderly patients. Infections (CTCAE grade 3/4) were documented in 99 patients (4.0%) in the total population vs 47 (5.1%) elderly patients. Fatal infections were reported in 14 (0.6%) patients in the total population vs 11 (1.2%) elderly patients. Overall, most frequent lipegfilgrastim-related adverse events (AEs) included bone pain (8.0%), anemia (3.2%), leucocytosis (2.7%), and thrombocytopenia (2.5%). Of the patients, 18.0% had ≥1 documented serious AE; none of the fatal events (2.7%) was lipegfilgrastim-related. Conclusions: Lipegfilgrastim administered to patients with solid tumor/NHL undergoing chemotherapy in routine clinical practice showed similar effectiveness and safety compared to the pivotal trials.

In BOLERO-2, adding everolimus to exemestane resulted in a twofold increase in median progression-free survival (PFS) vs exemestane in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (aBC) after progression on a non-steroidal aromatase inhibitor (NSAI). Here, we report on the open-label, single-arm, phase IIIB 4EVER trial (NCT01626222). This trial evaluated the clinical effectiveness of everolimus plus exemestane in postmenopausal women with HR+, HER2- aBC who had progressed on or after an NSAI, but with no restrictions on the time of progression after NSAI, prior chemotherapy for advanced disease or previous exemestane. The primary endpoint was overall response rate (ORR; i.e. the percentage of patients with a best overall response of complete or partial response per RECIST 1.1) within the first 24 weeks of treatment. Secondary endpoints included PFS, overall survival, safety and health-related quality of life. Between June 2012 and November 2013, 299 patients were enrolled at 82 German centers: 281 patients were evaluable for efficacy and 299 for safety. The ORR was 8.9% (95% confidence interval [CI]: 5.8-12.9%). Median PFS was 5.6 months (95% CI: 5.4-6.0 months). The most frequent grade 3/4 adverse events were stomatitis (8.4%), general physical health deterioration (6.7%), dyspnea (4.7%) and anemia (4.3%). The ORR in 4EVER was lower than in BOLERO-2, likely due to inclusion of patients with more advanced disease and extensive pretreatment. These data confirm the clinical benefits and known safety profile of everolimus plus exemestane in postmenopausal women with HR+, HER2- aBC., (© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Breast cancer and its treatments are associated with a detrimental effect on bone health. Here we report the results of an exploratory analysis assessing changes in levels of biomarkers of bone metabolism in patients enrolled in the phase IIIb 4EVER study., Methods: The 4EVER trial investigated everolimus in combination with exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer. In this prespecified exploratory analysis, changes in biomarkers of bone turnover were assessed in patients from baseline to weeks 4, 12, and 24. The serum bone markers assessed were procollagen type 1 N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTX), osteocalcin, parathyroid hormone (PTH), and 25-hydroxyvitamin D (25-OH-vitamin D). On-treatment changes in bone markers over time were described per subgroup of interest and efficacy outcomes., Results: Bone marker data were available for 241 of 299 enrolled patients. At the final assessment, P1NP, osteocalcin, PTH, 25-OH-vitamin D (all P  < 0.001), and CTX ( P  = 0.036) were significantly decreased from baseline values per the Wilcoxon signed-rank test. At the last assessment (24 weeks or earlier), levels of serum CTX and PTH were significantly lower ( P  = 0.009 and P  = 0.034, respectively) among patients with vs. without prior antiresorptive treatment (ART). Serum CTX levels were significantly lower ( P  < 0.001), and 25-OH-vitamin D concentrations significantly higher ( P  = 0.029), at the last postbaseline assessment in patients receiving concomitant ART vs. those without ART. Changes from baseline in PTH and 25-OH-vitamin D concentrations to the final assessment were significantly smaller in patients with prior ART. Lower baseline serum concentrations of osteocalcin and PTH were associated with clinical response (partial vs. non-response) at 24 weeks. High serum levels of CTX and P1NP at baseline were risk factors for progression at 12 weeks., Conclusions: These exploratory analyses support use of everolimus plus exemestane for the treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, and add to the body of evidence suggesting a potentially favorable impact of everolimus on bone turnover., Trial Registration: NCT01626222. Registered 22 June 2012 , https://clinicaltrials.gov/ct2/show/NCT01626222.

Background/aim: The use of acellular dermal matrices (ADM) has become a widely used option in breast reconstruction. A great deal of literature is available, totaling over 3,200 ADM reconstructions. Head-to-head comparisons between SurgiMend® and Tutomesh® are not yet reported. These are the first comparative clinical data reported on the use of Tutomesh® in breast reconstruction. Postoperative complication rates and costs for these devices were evaluated., Patients and Methods: This is a retrospective analysis of a 2-year experience with both SurgiMend® - fetal bovine acellular dermal matrix and Tutomesh® - a bovine pericardium collagen membrane in breast reconstruction in 45 cases from 2014-2015., Results: Forty-five patients received a total of 45 implant-based reconstructions using SurgiMend® (18 cases; 40%) or Tutomesh® (27 cases; 60%). Gross complication rates were 27.8% for SurgiMend® and 37.0% for Tutomesh® including hematoma, postoperative skin irritation, infection, red breast syndrome and revision surgery. The most common complication was postoperative red breast syndrome. Severe complications requiring revision surgery did not differ significantly in patients treated with SurgiMend® (0 cases, 0%) compared to Tutomesh® (1 case, 3.7%)., Conclusion: This retrospective analysis shows similar overall clinical complication rates for Tutomesh® and SurgiMend®. Severe complication rates are comparable to those reported in literature for both products. Although the retrospective nature of this work limits its clinical impact, it is possible to opt for the cheaper alternative (Tutomesh®)., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Catumaxomab (CATU) is a trifunctional antibody approved for intraperitoneal (i.p.) treatment of malignant ascites (MA) related to carcinomas expressing the epithelial cell-adhesion molecule (EpCAM). CATU is mostly given to hospitalized patients, although outpatient treatment seems appropriate in selected individuals. This observational trial sought to obtain more detailed information regarding the feasibility of CATU in outpatients with MA related to various gynecologic tumors, including epithelial ovarian (EOC) and metastatic breast cancer (MBC)., Materials and Methods: A total of 30 patients were included, 17 with EOC, 7 with MBC, and 6 with other malignancies. The patients had failed a median of 5 (range 1-12) previous systemic treatments. CATU was administered via an indwelling i.p. catheter at four increasing doses (i.e., 10, 20, 50, and 150 µg) given at 4-day intervals over 2 weeks. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 4.03. Puncture-free survival (PuFS) was calculated from the start of CATU until the next puncture for MA, death, or loss to follow-up. Overall survival (OS) was calculated from the start of CATU to death from any reason or loss to follow-up. We also investigated various clinical parameters to predict PuFS and OS. These included age, tumor type, performance status, intensity of pretreatment, presence of extraperitoneal metastases, relative lymphocyte count at baseline, patient adherence to therapy, and the patients' ability to undergo systemic treatment after CATU., Results: CATU was exclusively given on an outpatient basis, and 19 patients (63.3%) received all four planned i.p. instillations. Toxicity was the reason for discontinuation in only 2 patients. Toxicity was generally manageable, with abdominal pain, nausea/vomiting, fatigue, and fever the predominant adverse effects. Secondary hospitalization was necessary for 7 patients (23.3%), with a general deteriorated condition in 5 and fever/infection or abdominal pain in 1 patient each. Subsequent systemic treatment was possible in 11 patients (36.7%). Only 5 patients (16.7%) required a second puncture after i.p. CATU. The median PuFS was 56 days, and the median OS was 79.5 days. Positive predictors of both PuFS and OS were performance status, absence of extraperitoneal tumor, the capability to receive all four CATU infusions, and the ability to undergo subsequent systemic treatment., Conclusion: Outpatient i.p. CATU therapy for MA related to various gynecologic carcinomas is safe and effective in producing good ascites control in most individuals, allowing for subsequent systemic therapy in a substantial proportion of patients., Implications for Practice: Intraperitoneal treatment with the trifunctional antibody catumaxomab (CATU) was possible in a selected population of 30 outpatients with malignant ascites due to epithelial female genital tract or breast carcinoma. Toxicity was largely manageable. Patients in good condition at baseline, without extraperitoneal tumor and/or liver metastases, and with the ability to complete all four planned CATU instillations and the capability of undergoing subsequent systemic therapy benefited the most in terms of both puncture-free and overall survival. Outpatient i.p. CATU is safe and effective in a selected group of patients with malignant ascites due to various gynecologic malignancies and could be cost-saving compared with an inpatient approach., (©AlphaMed Press.)

Background: The non-interventional study (NIS) NADIR was designed to assess the effectiveness and safety of lipegfilgrastim, a novel glycopegylated granulocyte-colony stimulating factor, in reducing the risk of both febrile and severe neutropenia., Methods: Here, the interim analysis of NIS Nadir performed under real-world conditions at 80 oncology practices across Germany is reported. For a patient to be included, lipegfilgrastim at a subcutaneous single dose of 6 mg had to be administered during at least 1 cycle of the chemotherapy under consideration., Results: The interim analysis included 224 patients. Median patient age was 61.1 years (interquartile range 51.2-70.2 years). Main tumor type was breast cancer followed by lung cancer, and non-Hodgkin's lymphoma (46.0, 13.4, and 10.7%, respectively). When lipegfilgrastim was given as primary prophylaxis, no patient developed febrile neutropenia (FN). 1.3% of patients developed FN when primary prophylaxis was withheld. Only 68.6% of patients undergoing chemotherapy and at high risk (> 20%) of developing FN were treated with lipegfilgrastim during the first cycle, exposing disparity between real-world practices and current treatment guidelines. Lipegfilgrastim was well tolerated. The only grade 3/4 treatment-related adverse event was anemia in 1 patient., Conclusion: Lipegfilgrastim was effective and safe when administered for the prevention of chemotherapy-induced neutropenia under real-world conditions., (© 2015 S. Karger GmbH, Freiburg.)

Ovarian carcinomas show considerable heterogeneity of origin, both in terms of site and tissue. The most important and also most frequent of these tumors arise from the coelomic epithelium and are therefore characterized as epithelial ovarian carcinomas (EOC). EOC is often large and advanced at the time of presentation, so that cells are readily obtainable from surgical specimens or effusions. While the primary tumor may be chemosensitive, they often develop resistance and may do so rapidly. Due to the easy access to tumor cells and its biological behavior, EOC is considered to be an ideal model to investigate principal mechanisms of both antineoplastic drug sensitivity and resistance. Although studies on primary EOC cells are now preferred for many of these investigations, EOC cell line studies remain important too. This chapter gives an overview over major techniques required to establish and maintain primary EOC cell cultures and to initiate and cultivate permanently growing EOC cell lines.

The primary aim of this randomized trial was to determine response rate and progression-free survival following chemotherapy in patients with platinum-resistant recurrent ovarian cancer, who had been treated according to an ATP-based tumour chemosensitivity assay in comparison with physician's choice. A total of 180 patients were randomized to assay-directed therapy (n=94) or physician's-choice chemotherapy (n=86). Median follow-up at analysis was 18 months. Response was assessable in 147 patients: 31.5% achieved a partial or complete response in the physician's-choice group compared with 40.5% in the assay-directed group (26 versus 31% by intention-to-treat analysis respectively). Intention-to-treat analysis showed a median progression-free survival of 93 days in the physician's-choice group and 104 days in the assay-directed group (hazard ratio 0.8, 95% confidence interval 0.59-1.10, not significant). No difference was seen in overall survival between the groups, although 12/39 (41%) of patients who crossed over from the physician's-choice arm obtained a response. Increased use of combination therapy was seen in the physician's-choice arm during the study as a result of the observed effects of assay-directed therapy in patients. Patients entering the physician's-choice arm of the study during the first year did significantly worse than those who entered in the subsequent years (hazard ratio 0.44, 95% confidence interval 0.2-0.9, P<0.03). This small randomized clinical trial has documented a trend towards improved response and progression-free survival for assay-directed treatment. Chemosensitivity testing might provide useful information in some patients with ovarian cancer, although a larger trial is required to confirm this. The ATP-based tumour chemosensitivity assay remains an investigational method in this condition.

Ovarian cancer is currently the most lethal gynecologic malignancy in Europe and the US. Platin analogues and paclitaxel demonstrate high remission rates, but unfortunately the efficacy of cytostatic agents is limited by the development of multidrug resistance (mdr). Clinical paclitaxel resistance is often associated with mdr1 overexpression. In a recent study, we introduced a highly specific quantitative real-time reverse transcriptase polymerase chain reaction for the quantification of mdr1 transcripts. In the present study, we demonstrate that primary tumor cells from patients with recurrent ovarian cancer overexpress mdr1. To evaluate mdr1 expression, we collected tumor cells from 77 ovarian cancer patients (13 chemotherapy-naive ovarian cancer, 64 recurrent ovarian cancer). Cancer cells were aspirated from 49 solid specimens (63%) and 28 ascitic fluids (37%). Subsequently, cancer cells were exposed in 221 short-term cultures either to blank medium (control) or to a single anticancer drug, cisplatin, doxorubicin or paclitaxel. The drug concentrations applied referred to clinical relevant doses. mdr1 mRNA expression was significantly higher in specimens from recurrent ovarian cancer incubated in paclitaxel than in specimens from chemotherapy-naive ovarian cancer. No significant differences were detectable between the mean value of mdr1 mRNA expression in tumor specimens from recurrent ovarian cancer incubated in cisplatin or doxorubicin. Differences within the untreated patients group were also not statistically significant. The result of this study confirms clinical observations, as well as in-vitro studies based on tumor cell lines, that paclitaxel resistance is correlated with mdr1 overexpression.

There is debate regarding the direct effect of bisphosphonates against visceral metastases from solid tumors, despite their proven efficacy against the skeletal complications of metastasis. The aim of this study was to determine whether zoledronic acid showed direct activity against five ovarian cell lines and tumor-derived cells, and whether addition of zoledronic acid to cytotoxic agents increased their cytotoxicity. In this study we used a standardized ATP-based tumor chemosensitivity assay (ATP-TCA) to measure the activity of alendronate, clodronate and zoledronic acid in five ovarian carcinoma cell lines and human solid tumors (breast, lung, ovarian, unknown primary carcinoma, and cutaneous and uveal melanoma) (n=34). We also tested the combination of zoledronic acid with paclitaxel and cisplatin in tumor-derived cells. All five cell lines exhibited greater sensitivity to bisphosphonates than the tumor-derived cells and in all five the IC50 for zoledronic acid was less than 4 muM. In the tumor-derived cells, zoledronic acid showed concentration-dependent inhibition with a median IC50 for all tumors tested of 17 muM and evidence of apoptosis (caspase activation). Simultaneous addition of zoledronic acid to cisplatin or paclitaxel showed no major increase in cytotoxicity. We conclude that the activity of bisphosphonates was greater in cell lines than in tumor-derived cells. However, the pattern of activity of bisphosphonates was the same in cell lines and tumor derived cells. This study suggests a direct, or possibly an indirect, effect of zoledronic acid and other nitrogen-containing bisphosphonates against neoplastic cells, but simultaneous addition with cisplatin or paclitaxel does not substantially increase the activity of the cytotoxic agent.

Granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]) is a powerful cytokine that is able to stimulate the generation of dendritic cells. Adjuvant treatment with continuous low-dose GM-CSF has been shown to prolong survival of stage III/IV melanoma patients. Data on continuous low-dose GM-CSF therapy in tumors other than prostate cancer are still lacking. This pilot trial was initiated in order to evaluate the efficacy and tolerability of continuous low-dose GM-CSF as salvage in various chemotherapy-refractory carcinomas. A total of 19 patients who had failed a median of 4 prior chemotherapies were included. Their malignancies included metastatic breast cancer, recurrent ovarian carcinoma, metastatic endometrial carcinoma, and recurrent squamous cell cancer of the cervix uteri. Continuous low-dose GM-CSF was delivered subcutaneously at a daily starting dose of 125 microg. GM-CSF was increased at 25-microg increments until a maximum of 250 microg was reached or when mild leukocytosis (10-20 g/L) was achieved, providing that the relative eosinophil count did not exceed 15%. Therapy was continued until progression or refusal by the patient. Toxicity was generally mild. Only one patient was withdrawn due to grade 3 fatigue. In three additional patients, temporary dose reduction was necessary because of grade 1 injection site reactions, which recovered spontaneously. Mild to moderate leukocytosis was obvious in 10 patients. Systemic hypersensitivity-like reactions did not occur and no patient required hospitalization for other life-threatening side effects. The objective response rate was 37%: 1 complete and 6 partial responses, 4 disease stabilizations, 8 progression of disease. Median response duration was 6 months. Notably, 6 of 7 responders but only 1 of 8 patients with disease progression developed leukocytosis during therapy. Therefore, we conclude that continuous low-dose GM-CSF has substantial activity in heavily pretreated patients with either metastatic breast cancer or female genital tract cancer. Achievement of mild leukocytosis seems to be a predictor of response.

During the last two decades, novel nonclonogenic methods for pretherapeutic chemosensitivity testing have been developed that are likely to overcome major technical limitations of older assays such as low evaluability rates, low degree of standardization and reproducibility, lack of technical robustness, and poor methodological efficacy. Among these, the microplate adenosine triphosphate (ATP)-based tumor chemosensitivity assay (ATP-TCA) has gained particular merits for ex vivo chemosensitivity testing of native nonhematological tumors including cancers of the breast, ovary, gastrointestinal tract, cervix and corpus uteri, and lung; malignant melanomas; gliomas; sarcomas; and mesotheliomas. For this indication, the ATP-TCA can now be considered the best documented and validated technology. This assay, which is now commercially available, provides a highly reproducible, easy-to-handle kit technique; low technical failure rates; and a high methodological efficacy requiring only 1 x 106 tumor cells to test four to six different drugs or combinations. In ovarian and breast carcinomas, the predictive accuracy is > 90%, with a positive predictive value of 85-90% and a negative predictive value near 100%, respectively. In primary ovarian cancers, the ATP-TCA has been found to accurately predict both clinical response and survival. In two prospective clinical trials in patients with heavily pretreated ovarian cancer, chemotherapy individually selected by the ATP-TCA has been found to triple the response rates and nearly double the survival compared to empirically chosen regimens. Consequently, this assay, which is now under phase III evaluation, has successfully been used in new agent development to screen for novel chemotherapy regimens for the treatment of patients with breast and ovarian carcinoma and melanoma, respectively. This chapter highlights the recent preclinical and clinical experience with this promising technology and gives a detailed description of all the technical aspects of the ATP-TCA.

This study was performed to evaluate the role of protein kinase C (PKC) activity in the development of chemoresistance in clinical breast cancer cells. To simulate the clinical situation, native tumor cells derived from 10 patients with advanced breast cancer were brought into short-term cultures, and treated with anthracyclines (doxorubicin, mitoxantrone), paclitaxel and combinations, respectively. After 3 days of incubation, we determined total PKC activity relative to each control incubated with blank medium. Furthermore, we determined the chemoresistance against these drugs from each cell population separately. Relative PKC activity ranged from 14 to 249%; 64% (37 of 58) of the breast cancer cell suspensions were considered chemoresistant. There was a non-significant trend to a higher relative PKC activity in resistant cells compared to non-resistant cells (p=0.058), regardless of the antineoplastic agent investigated. The individual variability in both PKC activity and chemoresistance pattern revealed that dysregulated PKC activity mediates resistance to antineoplastics. In order to achieve clinical value, evaluation of more data concerning the PKC signal-transduction pathway is necessary. New protocols of cancer treatment will require this information in order to be successful.

Background: It is well known that the acceptance of the fetoplacental unit in human pregnancy requires maternal immune tolerance, which is thought to be regulated locally by the placenta. Therefore an anti-inflammatory cytokine such as IL-10 plays a critical role in different pregnancy disorders including preeclampsia. In the present study, we examined the expression of both proinflammatory (TNF-alpha, IL-1beta, IL-2) and immunoregulatory (IL-6, IL-10) cytokines from normal term and preeclamptic patients in human trophoblast cultures., Methods: Eleven patients with preeclampsia and 11 patients with a normal pregnancy at term were included in the study. Trophoblast cells isolated from placentas were cultured up to 48 h under standard tissue culture conditions and cytokine release was determined by ELISA. IL-10 synthesis was significantly decreased in the third trimester in preeclamptic patients in comparison with the control group., Results: There were no significant differences in IL-1beta, IL-2, IL-6 or TNF-alpha expression but a significant alteration in IL-10 release in trophoblast cultures in vitro in term placentas from preeclamptic patients compared with normal pregnancy., Conclusions: Because IL-10 is a potent regulator of anti-inflammatory immune response these abnormalities may be associated with the inadequate placental development in preeclampsia.

Background: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints., Methods: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125)., Results: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months)., Conclusion: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centres.

The long-term results for patients with recurrent ovarian cancer (ROC) are poor. There is a need to optimize treatment strategies to improve outcome by avoiding ineffective regimens which are often associated with exacerbated side-effects. Individualized chemotherapy regimens guided by a chemosensitivity assay (ATP-tumor chemosensitivity assay) have already been used successfully to direct chemotherapy. Taking the results of this assay into account, application of drug combinations appears more advisable. Here we present a systematic evaluation of toxicities seen with individualized chemotherapy for ROC. A total of 62 patients who received 314 cycles of antineoplastic therapies were evaluated. Three single agents (topotecan, paclitaxel and gemcitabine) and five combinations (cisplatin/gemcitabine, carbopatin/gemcitabine, gemcitabine/treosulfan, mitoxantrone/paclitaxel and carboplatin/paclitaxel) were examined. With respect to myelotoxicity, most single agents except topotecan revealed favorable results in comparison to drug combinations. However, this observation lacks statistical significance. Generally, severe myelosuppression was rare. The highest incidence of leukopenia was seen in regimens with mitoxantrone/paclitaxel or gemcitabine/treosulfan, respectively. Thrombocytopenia accompanied most commonly a topotecan therapy. In the present study combination regimens tend to be more toxic than monotherapies. When response rates are comparable, empirically chosen treatment combination therapies should only be practiced in carefully planned clinical studies.

The clinical observation of the multidrug resistance (MDR) phenotype is often associated with overexpression of the mdrl gene, in particular with respect to ovarian cancer. However, until now the mdrl-inducing potential of commonly used antineoplastics has been only incompletely explored. We performed short-term cultures of six ovarian cancer cell lines (MZOV4, EF027, SKOV3, OAW42, OTN14, MZOV20) exposed to either blank medium or cisplatin, doxorubicin or paclitaxel at concentrations related to the clinically achievable plasma peak concentration. A highly specific quantitative real-time RT-PCR was used to detect the Mdr1 transcripts. Mdrl mRNA contents were calibrated in relation to coamplified GAPDH mRNA. Mdrl mRNA was detectable in each cell line. In 13 out of 18 assays (72%) the specific anticancer drug being tested induced mdr1 transcription. No decrease in mdr1 mRNA concentration was observed. Our data suggest that mdr1 induction by antineoplastics is one of the reasons for failure of ovarian cancer therapy but may vary individually.

After disappointing results achieved with older chemosensitivity tests such as the human tumor clonogenic assay (HTCA) during the 1980s, the last decade has seen a renaissance of the concept of individualized chemotherapy in oncology, markedly stimulated by the development of newer nonclonogenic assays. These methods appear to be able to overcome major technical limitations associated with older assays, now allowing for successful testing of most of the tumor specimens submitted. Currently, the ATP-based tumor chemosensitivity assay (ATP-TCA) can be regarded as the most sophisticated assay to investigate both solid samples and effusions derived from patients with various organ tumors. During the last 5 years, the ATP-TCA has been used successfully to screen for novel drug combinations for further clinical use in both ovarian and breast cancer such as mitoxantrone plus paclitaxel (NT) and treosulfan plus gemcitabine (TG), respectively. Clinical trials that have been set up in heavily pretreated patients with recurrent ovarian or breast cancer have convincingly confirmed the high activity of these combinations previously demonstrated in preclinical investigations using the ATP-TCA. In a recent phase II trial performed in 59 patients with relapsed ovarian carcinoma, ATP-TCA-directed therapy was able to triple the response rate and to double the survival time, compared with published empirical chemotherapy regimes. Preliminary results with ATP-TCA-directed therapy in breast cancer also evidenced promising response rates. These results have been confirmed by additional prospective clinical trials using other types of modern nonclonogenic assays. A phase III trial that is now actively recruiting patients with platinum-refractory ovarian cancer to verify the promising phase II studies will prove the further value of the ATP-TCA as a predictor applicable in routine clinical oncology.

Objective: The aim of this study was to determine the dose-limiting toxicities (DLTs) and maximum tolerated doses (MTDs) of a docetaxel-carboplatin regimen in patients with locally advanced cervical cancer (LACC) or recurrent cervical cancer. The regimen was administered weekly, with a maximum of 12 courses., Patients and Methods: Twenty patients were treated with with a total of 145 cycles of weekly carboplatin and docetaxel. The starting dose of docetaxel was 25 mg/m(2) with increments of 5 mg/m(2) until a final dose of 35 mg/m(2) was reached. Dose-escalation of docetaxel was followed by carboplatin at AUC 2, AUC 2.5, and AUC 3, respectively. Defined dose-limiting toxicities were WHO grade (G) 3 hematotoxicity, G4 mucositis, and G2 neurotoxicity. The response status of the patients was assessed using the common ECOG response criteria., Results: Two of four patients developed a DLT at dose level 4. Nonhematological toxicity was generally mild, except for ubiquitous complete alopecia. The MTD was reached at docetaxel 35 mg/m(2) and carboplatin AUC 2 mg/mL.min. The overall response rate was 65% in the entire group of evaluable patients and 77% in patients with primary LACC, with two cases of pathological complete response., Conclusion: This dose-dense regimen was well-tolerated and could be administered on an outpatient basis.

Trophoblast injury may be one of the possible causes of fetal distress associated with chemotherapy administered during pregnancy. The purpose of this study was to investigate the ex vivo chemosensitivity of normal trophoblasts (NTB) against commonly used antineoplastic agents. Using the newly developed ex vivo ATP-based trophoblast assay (ATP-TBA), 31 NTB freshly sampled from human placentas (gestational week 7-42) were tested against dactinomycin (Act-D), 5-fluorouracil (5-FU), 4-OOH-cyclophosphamide (4-HC), vincristine (VCR) and methotrexate (MTX) alone or in combination with calcium folate (LV). All agents were studied at concentrations relevant to clinical dosages normally used for chemotherapy of solid neoplasms. Of 31 samples studied with the ATP-TBA, 20 (65%) were evaluable. VCR, Act-D and 4-HC were the most active drugs with 55, 45 and 45% of samples responding ex vivo. Antimetabolites were less active, producing ex vivo response rates of 25 (MTX) and 20% (5-FU), respectively. MTX activity was largely neutralized by adding LV. The chemosensitivity of NTB showed considerable inter-individual variations and did not decrease with increasing gestational age. We therefore conclude that NTB of any gestational age exhibit considerable ex vivo sensitivity against common anticancer agents which is comparable to that observed for various solid tumors. The ATP-TBA may be helpful in planning future trials with both single agents and drug combinations in order to standardize and optimize chemotherapy during pregnancy., (Copyright 2002 Lippincott Williams & Wilkins.)

Liposomal doxorubicin (Caelyx/Doxil) has been shown to be active in around 20% of recurrent ovarian cancers. As yet, there is little clinical data on combinations of existing agents with liposomal doxorubicin, despite considerable clinical experience with soluble doxorubicin in combination. In this study, we have used an ATP-based tumor chemosensitivity assay to determine the relative efficacy of high concentrations of doxorubicin tested in combination with cisplatin, treosulfan, 5-fluorouracil (5-FU) or vinorelbine against cells obtained from recurrent ovarian tumor tissue. The results show little enhancement of the efficacy of high concentrations of doxorubicin by 5-FU, cisplatin, or treosulfan. However, vinorelbine+liposomal doxorubicin showed additive inhibition, and this combination is worthy of further testing in clinical trials.

Background: Development of resistance to anticancer drugs is a major concern in clinical oncology and might be particularly involved in the secondary treatment failure frequently seen in ovarian cancer. Clinical observation of the multidrug resistance (MDR) phenotype is often associated with overexpression of the mdr1-gene. However, until now the mdr1-inducing potential of commonly used antineoplastics has been only incompletely explored., Materials and Methods: We perfomed short-term cultures of 7 established ovarian cancer cell lines exposed to either blank medium or one of three single anticancer drugs (cisplatin, doxorubicin, paclitaxel) at concentrations related to the clinically achievable plasma peak concentration. Mdr1-transcripts were detected using the highly specific quantitative real time RT-PCR. To calibrate each approach, mdr1-mRNA content was calculated in relation to co-amplified GAPDH-mRNA., Results: Mdr1-mRNA was detectable in each cell line. In 13 assays (62%) the specific anticancer drug being tested induced mdr1-transcription. No decrease in mdr1-mRNA concentration was observed. The method described here is easy to perform and could be of striking value in predicting the development of tumor chemoresistance., Conclusion: Our data indicate that mdr1-induction by antineoplastics is one of the reasons for failure of ovarian cancer therapy but may vary from one individual to another.

We sought to determine whether cytokine expression in peripheral blood mononuclear cells is altered in patients with preeclampsia and in patients with a history of recurrent spontaneous abortion (RSA). Twenty-four patients with preeclampsia and twenty patients with a history of RSA were included into the study. Two control groups consisted of twenty healthy pregnant and twenty healthy non-pregnant women. The intracellular expression of interleukin-2 (IL-2), interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) were determined in peripheral blood mononuclear cells (PBMCs) by flow cytometry as a measure of cytokine production. IL-2 synthesis was significantly elevated in the third trimester in preeclamptic patients in comparison with the control group. Non-pregnant women with RSA showed a significantly lower expression of IFN-gamma compared to the non-pregnant control group. Our data suggest an abnormal immune response in preeclamptic patients characterised by a shift to a predominantly Th1-type immunity.

Chemotherapy for recurrent ovarian carcinoma (ROC) produces response rates of 10-80% depending on the prevalence of platinum resistance. Most patients relapse within 1 year and median progression-free survival is generally no more than 6 months. Newly developed ATP chemosensitivity assays (ATP-TCA) offer the opportunity for individualized therapy and have shown promising results compared to standard regimens. We report on an unusual case of long-term survival in a patient with stage III c ovarian cancer failing postoperative platinum-based high-dose treatment who subsequently underwent repeated chemotherapy over a period of 4 years. The chemotherapy protocol was selected by pretherapeutic ex vivo ATP-based chemosensitivity testing of autologous tumor tissue. To our knowledge, this is one of the few cases of ROC in which partial remissions using conventionally dosed chemotherapy were achieved repeatedly despite a unfavorable relapse-free interval after high-dose chemotherapy for primary disease. We conclude that ATP-TCA-directed chemotherapy for ROC can select active and tolerable regimens even in difficult therapeutic situations in which no standards recommendation exists.

Cutaneous and uveal melanoma both have a poor prognosis and chemotherapy is usually unsuccessful. We have previously reported the activity of a number of cytotoxic agents against metastatic cutaneous and primary choroidal uveal melanoma using an ex vivo adenosine triphosphate (ATP)-based chemosensitivity assay (ATP-TCA). In this study we compare the results obtained with the two types of melanoma. Cutaneous melanoma deposits in skin and lymph nodes (n = 58) and choroidal melanomas (n = 77) were tested using the ATP-TCA. Analysis of the data based on an arbitrary threshold for sensitivity shows that both types of melanoma exhibit heterogeneity of sensitivity to all the agents and combinations tested. With all the single agents except gemcitabine, cutaneous melanomas showed greater sensitivity in the assay, though this did not achieve statistical significance. This was also true with the drug combinations, with the exception of treosulfan + gemcitabine, which had similar activity in each type of melanoma. Of all the single agents tested, doxorubicin (47% of specimens classed as sensitive), vinorelbine (43%), treosulfan (41%) and paclitaxel (33%) showed the greatest activity with cutaneous melanoma. In the uveal melanoma samples, mitoxantrone (33%), gemcitabine (22%) and treosulfan (21%) showed the greatest activity. In contrast to the cutaneous melanomas, 13% of the uveal melanomas were sensitive to paclitaxel, 4% were sensitive to doxorubicin and 11% were found to be sensitive to vinorelbine. Both tumour types showed greater sensitivity to combinations of cytotoxic agents. The combination of treosulfan + gemcitabine was universally effective, with 72% of cutaneous melanomas and 80% of uveal melanomas exhibiting activity at the level selected to indicate sensitivity in the assay, though this will not necessarily indicate a similar level of clinical sensitivity.

Due to its pivotal role in signal transduction, the universal tumor suppressor PTEN (also termed MMAC or TEP) is one of the putative candidates for involvement in tumorigenesis of several tissues. Although involvement of PTEN in tumorigenesis was shown in different tissues, no data are available concerning PTEN activity in response to antineoplastic agents. Therefore, we assayed the PTEN activity exposed to either blank medium or the commonly used anti-cancer drugs cisplatin, adriamycin or paclitaxel, respectively, in three different concentrations. PTEN activity was determined using the Malachite Green assay basing upon dephosphorylation of phosphatidylinositol-3,4,5-triphosphate (PIP3) by the PTEN enzyme and subsequent determination of inorganic phosphate released. Although the three different anti-cancer drugs assayed act with different cellular modes, the antineoplastics influenced PTEN activity in a similar manner: at low concentrations tested all three antineoplastics significantly increased PTEN activity. However, increasing drug concentrations exhibited a decline but not a total loss of PTEN activity. The data indicate that PTEN activity is increased following cytotoxic drug exposure and, thereby, exhibits its suppressive function. However, the decrease of PTEN activity in response to increasing drug concentrations suggests an aberration of total functional activity. As far as the regulative checkpoint PTEN is abolished, tumor cells might evade cell death pathways resulting in increased proliferation of cancer cells. This might be a general event in refractory tumor cells surviving chemotherapy.

For many decades, invasive cervical cancer has been considered more or less chemoresistant and chemotherapy has been limited to patients presenting with overt metastatic disease or those suffering from pelvic recurrences which could not be advised to secondary local treatments. However, more than 20 different single agents are considered active in cervical cancer. Recent cooperative clinical trials have demonstrated the superiority of multi-modality strategies for patients with high-risk cervical cancer. These studies integrating chemotherapy as part of the primary therapeutic concept have provided the most significant improvement of locally advanced disease in more than three decades. This review summarizes current standards of chemotherapy for invasive cervical cancer and shows new developments which may improve systemic treatment of the disease.

Objective: To assess the diagnostic value of maternal CA 125 in patients with symptomatic first trimester pregnancy and to evaluate the prognostic significance of CA 125 versus beta-hCG in early pregnancies with intact fetal heartbeat, complicated by vaginal bleeding., Study Design: Two prospective open-label studies with longitudinal follow-up in the second trial., Setting: Academic Department of Obstetrics and Gynecology, University of Cologne., Patients: Study 1: 168 patients presenting between gestational weeks 6 and 12 with: extrauterine pregnancy, 29; missed abortion, 50; incomplete spontaneous abortion, 38; imminent abortion, 33; and normal pregnancy (no history of endometriosis or ovarian mass), 18. Study 2: Fifty consecutive patients with vaginal bleeding during gestational weeks 6-12 all of whom having demostrable fetal heartbeat. Eighteen patients finally aborted whereas the remainder had normally continuing pregnancy until term., Main Outcome Measure: Study 1: Single serum determinations of CA 125 and beta-hCG were correlated with the different disorders observed. Study 2: Two sequential measurements of serum CA 125 and beta-hCG performed within a 5-7 days interval were related to the outcome of pregnancy as indicated by changes of the ultrasound presentation, miscarriage, future hospitalization, or delivery., Results: Study 1: Patients with vaginal bleeding generally had higher median CA 125 values (38 IU/ml; range 1.3-540) compared to non-bleeding patients (17.8 IU/ml; range 1.0-157). No statistically significant differences in regard to median serum CA 125 levels between symptomatic and normal pregnancies occurred: normal pregnancy, 25.5 IU/ml (range 3.2-97); ectopic pregnancy, 26 IU/ml (range 1.3-157); missed abortion, 19.1IU/ml (range 1-242); threatened abortion, 48 IU/ml (range 5.2-540); spontaneous abortion, 40 IU/ml (range 5.4-442). Study 2: Initial CA 125 levels did not differ significantly between both groups of patients with 27/32 non-aborters and 13/18 aborters showing concentrations below 65 IU/ml. After 5-7 days, CA 125 in all patients who eventually aborted remained high or increased whereas non-aborters all had constantly low or steeply declining CA 125 measures. beta-hCG increased in all non-aborters but also in 13/18 aborters during the 5-7 day interval., Conclusion: Single serum measurements of CA 125 in symptomatic first trimester pregnant patients failed to discriminate spontaneous abortion, ectopic or normal pregnancies. However, sequential determinations of maternal CA 125 measurements appear to be a highly sensitive prognostic marker in patients with viable pregnancy at risk for abortion.

Proteinkinase C (PKC) is involved in carcinogenesis, proliferation, and metastatic spread of breast cancer. New anticancer strategies have been developed with PKC as a potential target for therapeutic intervention. However, most of the encouraging preliminary data were observed in breast cancer cell lines only. Insignificant information is available concerning clinical breast cancer cells. Our aim was to investigate the involvement of PKC in clinical breast carcinoma cells. To this end, we set up short-term cultures (3 days) of native tumor cells derived from 12 patients with advanced breast cancer. Addition of commonly used antineoplastics, including both single agents and combinations (tamoxifen, Adriamycin, paclitaxel, Adriamycin plus paclitaxel, epirubicin plus 4-OOH-cyclophosphamide, mitoxantrone, mitoxantrone plus vinorelbin, vinorelbin), simulated the clinical situation. In relation to each control we determined total PKC activity and quantified the PKC-zeta isoform. In 6 patients, no obvious alteration of PKC activities was detected. In the remainder, either inhibition or augmentation of PKC activity in the presence of cytostatics was detected. However, no tendency could be observed concerning the influence of the therapeutics on PKC activity. PKC-zeta expression was much more heterogeneous than activity assays. Although anticancer drugs influenced PKC-zeta expression, the results showed no uniformity with regard to PKC-zeta expression. Moreover, PKC-zeta expression did not correlate with total PKC activity, indicating a differential expression of different PKC isoenzymes. Therefore, we conclude that both PKC activity and PKC-zeta expression differ individually. More data concerning this topic are necessary prior to offering a clinically useful PKC-tailored regimen.

We analyzed tumor tissues from 14 patients with invasive squamous cell carcinoma of the cervix for aberrations of chromosome 17 and p53 expression. All but 3 patients were negative for p53 protein expression, the protein being detected in 2 International Federation of Obstetrics and Gynecology stage IIa cancers and 1 stage Ib G3 carcinoma. Significant cytogenetic aberrations in the form of losses and gains of chromosome 17 were diagnosed in 9 and 7 patients, respectively. There was no correlation with tumor prognosis, clinical stage or histologic grade. According to most reports, almost all cervical carcinomas contain integrated human papilloma virus (HPV) and express E6 oncoproteins. Increasing evidence suggests that E6 protein interaction leads to p53 mutation in HPV-infected cervical epithelium. Since most cervical tumors are infected with HPV, and the tumors originate through p53 gene mutation caused by the said interaction, which leads subsequently to the overexpression of p53 oncoprotein, lack of the latter in the remaining 11 cervical tumors may either be the result of technical shortcomings, or the tumor may arise in such circumstances through a p53-independent pathway. On the other hand, 2 of 3 stage IIa cancers and 1 Ib G3 carcinoma were found to be p53 positive, thus supporting the notion that p53 inactivation is a relatively late event in the progression of cervical cancer., (Copyright 2001 S. Karger AG, Basel)

The cardiotoxicity of anthracyclines has largely prevented dose intensification, but the use of liposomal preparations (e.g. Caelyx/Doxil) allows much higher intra-tumoral concentrations to be achieved without cardiotoxicity. However, it is uncertain how much this will improve response rates over standard anthracycline therapy. The ATP-based chemosensitivity assay (ATP-TCA) has been used to develop new regimens for several tumor types, to investigate the molecular basis of chemosensitivity and shows considerable promise as a clinical method for individualizing chemotherapy. In this study, we have used the ATP-TCA to determine the concentration responsiveness of tumor-derived cells to concentrations of doxorubicin. The 22 tumor samples included were obtained from 20 heavily pretreated patients with recurrent ovarian cancer. Eight had previous anthracycline exposure, four as part of the CAP regimen. The results show more than 95% inhibition at clinically achievable concentrations in 11 of 22 tumors tested. Of the rest, seven showed a plateau effect between 80 and 95% inhibition, suggesting that there might be a subset of resistant cells present that is not inhibited by high concentrations of doxorubicin. Two tumors showed complete resistance and neither of these had previously received anthracycline therapy. As it has been suggested that gemcitabine might enhance anthracycline sensitivity in combination and we have had good results with gemcitabine modulation of alkylating agents in the assay, we have tested the combination of doxorubicin+gemcitabine under assay conditions in 11 tumors with little indication of improvement. In conclusion, doxorubicin at concentrations achievable with liposomal preparations shows strong ex vivo activity against pretreated recurrent ovarian cancer in just over half of the cases tested.

The relationship between apoptosis and chemosensitivity remains complex. We tested the chemosensitivity of 45 patients with advanced breast cancer (BC) ex vivo against anthracyclines (A: doxorubicin, epirubicin), taxanes (T: paclitaxel, docetaxel), cisplatin (DDP) and CMF and any correlation with the expression of p53, Bcl-2 and apoptosis. Viable cells were processed for ex vivo ATP Tumor Chemosensitivity Assay (ATP-TCA). Immunohistochemistry was performed in corresponding tumor samples. Apoptosis prior to chemotherapy was assayed using a TUNEL Test. Of 45 BC tested, 18 (40%) were p53+ and 37 (82%) showed high Bcl-2 expression. Apoptosis was detected in 29 (64.4%) specimens. The Ex vivo Response Rate (EVRR) for T was 75.6% in all cases. This was the highest rate among the 4 drugs tested followed by CMF (66.7%). For A and DDP the positive rates were lower (27.6% and 10.6%, respectively). A significant correlation (r = 0.589, p < or = 0.01) was found between tumors which were sensitive to A and DDP. There was no association between chemosensitivity and apoptosis. Moreover tests for p53 and Bcl-2 did not show a correlation to ex vivo chemosensitivity. Pretreatment apoptotic parameters are unlikely to predict the individual response of breast cancer to antineoplastic agents.

New anti-cancer strategies have been developed with respect to proteinkinase C (PKC) as a potential target for therapeutic intervention in patients with advanced breast cancer. Using cell lines, most of the preliminary data are encouraging but insufficient information is available concerning clinical breast cancer cells. Thus, we decided to clarify the involvement of PKC in clinical breast carcinoma cells. We isolated viable tumor cells from fluids or tissue burden of eleven patients with advanced breast cancer. Performance of short term cultures supplemented with commonly used antineoplastics mimicked the clinical situation. We determined the ex vivo chemosensitivity pattern of each cell population. Additionally, we analysed total PKC activity and quantified the PKC-isoform eta. All assays showed a heterogeneous highly variable distribution of the data investigated. No tendency could be observed regarding the influence of the therapeutics on PKC activity, PKC-eta expression or chemoresistance, respectively. Moreover, changes in neither PKC-eta expression, PKC activity nor chemoresistance induced by a particular drug in an individual tumor necessarily predicted the same reaction in another tumor to this agent. Therefore, we concluded that more explorative data concerning this topic are required prior to the development of a clinically useful therapy regimen with PKC as the major target.

We evaluated the in vitro cytotoxicity of topotecan (TPT), versus cisplatin, etoposide (VP-16) and paclitaxel (PTX) in four squamous cell cancer cell lines of the cervix uteri and vulva. Four established human squamous cancer cell lines from the cervix uteri (A-431, Ca Ski and C-33) and vulva (CAL-39) were used. The cytotoxic effects of the agents were examined using the ATP-Tumor Chemosensitivity Assay (ATP-TCA). In addition to the single agents, the following combinations were tested: TPT+cisplatin, TPT+VP-16 and TPT+PTX. Three cell lines (C-33, Ca Ski and CAL-39) were highly sensitive to TPT, but one cell line (A-431) was less sensitive. Furthermore, the cytotoxic activity of TPT was superior to that of cisplatin in Ca Ski and C-33 cells, but inferior in CAL-39 and A-431. TPT was also more active than VP-16 in CAL-39 and Ca Ski. On the other hand, the cytotoxic activity of TPT was weaker than PTX in C-33, CAL-39 and A-431. TPT increased the cytotoxic activity of cisplatin and VP-16 in C-33, Ca Ski and A-431. However, synergistic features were observed only in A-431 cells. TPT also enhanced the cytotoxic activity of PTX in A-431 and Ca Ski. In CAL-39 and C-33, however, increased cytotoxic activity occurred only at higher drug concentrations, whereas antagonism was observed at lower drug concentrations. In conclusion, our results suggest that TPT has a significant cytotoxic effect on most squamous cell cancer cell lines which may be superior to cisplatin, VP-16 and PTX in some instances. Furthermore, TPT is likely to potentiate the cytotoxic activity of these agents in individual cell lines tested.

The combination of paclitaxel and doxorubicin or epirubicin is highly active against metastatic breast cancer, yet may produce congestive heart failure. Liposome-encapsulated doxorubicin is a new formulation of doxorubicin with no dose-limiting cardiac toxicity. Twenty-one patients with metastatic breast cancer were treated with pegylated liposomal doxorubicin (20 mg/m2, day 1) and paclitaxel (100 mg/m2, days 1 and 8) for six cycles every 2 weeks. All patients had had relapse or progression on one to five previous chemotherapies. We observed two patients with complete and eight patients with partial remissions (48% response rate). Eight of the 10 responders had had previous therapy with epirubicin, doxorubicin or mitoxantrone. The mean remission duration was 5 months. Disease progression due to brain metastasis occurred in five cases. Severe side effects (grade 3 WHO) were alopecia (100%), skin toxicity in 29%, neuropathy in 24% and mucositis in 13%. Leukopenia (grade 4 WHO) was observed in 48%, but there was no cardiac toxicity, no death and no hospitalization. The combination of weekly paclitaxel and liposomal doxorubicin every 2 weeks is highly effective in previously treated patients. Based on the doses we administered, we recommend 15 mg/m2 liposomal doxorubicin every 2 weeks and 80 mg/m2 paclitaxel weekly.

We report on a 72-year-old patient developing Stewart-Treves syndrome (STS) of the right arm 9 years after curative irradiation for ipsilateral stage III breast cancer. Facing the poor track record of both irradiation and chemotherapy in this highly malignant lymphangiosarcoma, amputation was recommended but refused by the patient. Therefore, limb conserving-therapy using three courses of intra-arterial mitoxantrone (MX) and paclitaxel (PTX) was attempted. This novel chemotherapy protocol was selected by pretherapeutic ex vivo ATP-based chemosensitivity testing of autologous tumor tissue. The patient experienced complete response, which was subsequent histologically confirmed by compartment resection. When developing recurrent STS outside of the perfused area 6 months after primary therapy, the patient was retested and reinduced with three other courses of intraarterial MX/PTX which again produced durable complete remission. This case demonstrates the benefit of indivdualized therapy in this prognostically desperate disease allowing both limb conservation and maintained quality of life.

Ovarian carcinomas are known to rapidly develop drug resistance against chemotherapeutic agents. This phenomenon is often associated with the expression of pl70-glycoprotein. A high rate of transcription of the corresponding mdr1-gene in resistant tumors is reported. Amplification of the mdr1-gene has been observed in tumor cell lines exposed to cytotoxic drugs; however, significant information is lacking as to whether this holds true in clinical carcinomas. To fill this gap, we investigated the rate of gene amplification of the mdr1-gene in 63 recurrent ovarian carcinomas and we determined the resistance pattern of these cells using an ex vivo assay. The tumors showed varying ex vivo resistance patterns which did not correlate to clinical parameters. Amplification of the mdr1-gene was not observed in any of the cancer specimens. Therefore, we conclude that mdr1-gene amplification is not a common pathway for the development of chemoresistance in clinical ovarian carcinomas.