Heregulin (HRG) assessment for clinical trial eligibility testing in a molecular registry (PRAEGNANT) in Germany.

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.

Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: Results of the single-arm, phase IIIB 4EVER trial.

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.

Quality of Life Effects of an Oral Fixed Combination of Netupitant and Palonosetron in Chemotherapy-Induced Nausea and Vomiting Prevention: Real-World Evidence in Patients with Breast Cancer Receiving Anthracycline-Cyclophosphamide-Based Chemotherapy.

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.

Occurrence and characteristics of patients with de novo advanced breast cancer according to patient and tumor characteristics - A retrospective analysis of a real world registry.

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.

Implementation of CDK4/6 Inhibitors and its Influence on the Treatment Landscape of Advanced Breast Cancer Patients - Data from the Real-World Registry PRAEGNANT.

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.

Prognostic effect of low-level HER2 expression in patients with clinically negative HER2 status.

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.

International Consensus Conference for Advanced Breast Cancer, Lisbon 2019: ABC5 Consensus - Assessment by a German Group of Experts.

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.

ABC5 International Consensus Conference on Advanced Breast Cancer, Lisbon, 16 November 2019: Commentary by the German panel of experts on the ABC5 voting results.

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.

Initial experience with CDK4/6 inhibitor-based therapies compared to antihormone monotherapies in routine clinical use in patients with hormone receptor positive, HER2 negative breast cancer - Data from the PRAEGNANT research network for the first 2 years of drug availability in Germany.

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.

Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay.

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.

The impact of mammalian target of rapamycin inhibition on bone health in postmenopausal women with hormone receptor-positive advanced breast cancer receiving everolimus plus exemestane in the phase IIIb 4EVER trial.

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.

A Head to Head Comparison Between SurgiMend® - Fetal Bovine Acellular Dermal Matrix and Tutomesh® - A Bovine Pericardium Collagen Membrane in Breast Reconstruction in 45 Cases.

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®).

Continuous low-dose GM-CSF as salvage therapy in refractory recurrent breast or female genital tract carcinoma.

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.

Chemosensitivity testing using microplate adenosine triphosphate-based luminescence measurements.

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.

NADIR: A Non-Interventional Study on the Prophylaxis of Chemotherapy-Induced Neutropenia Using Lipegfilgrastim - First Interim Analysis.

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.

Cytokine expression in peripheral blood lymphocytes indicates a switch to T(HELPER) cells in patients with preeclampsia.

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.

Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma.

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.

ATP chemosensitivity testing in ovarian and breast cancer: early clinical trials.

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.

Cisplatin, doxorubicin and paclitaxel induce mdr1 gene transcription in ovarian cancer cell lines.

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.