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Background: This multicenter, double-blind phase II study assessed the antitumor activity and toxicity profile of docetaxel with the antiangiogenic multikinase inhibitor sorafenib or matching placebo as a first-line treatment in patients with metastatic or locally advanced HER2-negative breast cancer., Patients and Methods: Patients were randomized 1:1 to receive docetaxel 100 mg/m 2 on day 1 every 3 weeks in combination with sorafenib 400 mg bid or placebo on days 2-18 of each cycle until tumor progression, or unacceptable toxicity. Sorafenib/placebo could be continued at the investigator's discretion if docetaxel was stopped due to toxicity. Primary endpoint was progression free survival (PFS)., Results: From October 2008 to December 2013, 102 patients were randomized; 98 patients were evaluable. The trial was prematurely terminated due to slow accrual. Due to increased toxicity the dose of docetaxel was reduced to 75 mg/m 2 and an increasing sorafenib dosing schedule was implemented as part of a protocol amendment. The addition of sorafenib to docetaxel did not improve PFS (8.2 vs. 7.3 months for docetaxel/placebo; HR 0.84, log rank p = 0.43), but led to higher rates of early treatment discontinuation. There were no statistically significant differences between sorafenib dosing schedules., Conclusions: Addition of sorafenib to taxane-based first-line chemotherapy in patients with metastatic breast cancer failed to improve PFS and resulted in increased toxicity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses., Patients and Methods: Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, β = 0.8) 379 events had to be observed in the bevacizumab arms., Results: With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups., Conclusions: Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients., Clinical Trial Number: NCT 00567554, www.clinicaltrials.gov., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy., Methods: In the GeparQuinto randomised phase 3 trial, patients with untreated HER2-positive operable or locally advanced breast cancer were enrolled between Nov 7, 2007, and July 9, 2010. Patients were eligible if their tumours were classified as cT3/4a-d, or hormone receptor (HR)-negative, HR-positive with clinically node-positive and cT2 disease (cT2 cN+), or HR-positive and pathologically node-positive in the sentinel lymph node for those with cT1 disease (cT1 pN(SLN+)). Patients were randomly assigned in a 1:1 ratio to receive neoadjuvant treatment with four cycles of EC (epirubicin [90 mg/m(2) intravenously] plus cyclophosphamide [600 mg/m(2) intravenously], every 3 weeks), and four cycles of docetaxel (100 mg/m(2) intravenously every 3 weeks) with either trastuzumab (6 mg/kg intravenously, with a starting loading dose of 8 mg/kg, for eight cycles, every 3 weeks) or lapatinib (1000-1250 mg per day orally) throughout all cycles before surgery. Randomisation was done by dynamic allocation with the minimisation method of Pocock and patients were stratified by participating site, HR status, and extent of disease (cT1-3 cN0-2 vs T4 or N3). The primary endpoint was pathological complete response (defined as ypT0 and ypN0) and was analysed in all patients who received at least one cycle of EC. Participants and investigators were not masked to treatment assignment. Pathologists in centres assessing surgery outcomes were masked to group assignment. This trial is registered with ClinicalTrials.gov, number NCT00567554., Findings: Of 620 eligible patients, 309 were randomly assigned to chemotherapy with trastuzumab (ECH-TH group) and 311 to chemotherapy with lapatinib (ECL-TL group). Two patients in the ECH-TH group and three patients in the ECL-TL group did not start treatment because of withdrawal of consent or immediate surgery. 93 (30·3%) of 307 patients in the ECH-TH group and 70 (22·7%) of 308 patients in the ECL-TL group had a pathological complete response (odds ratio [OR] 0·68 [95%CI 0·47-0·97]; p=0·04). Chemotherapy with trastuzumab was associated with more oedema (119 [39·1%] vs 88 [28·7%]) and dyspnoea (90 [29·6%] vs 66 [21·4%]), and ECL-TL with more diarrhoea (231 [75·0%] vs 144 [47·4%]) and skin rash (169 [54·9%] vs 97 [31·9%]). 43 (14·0%) patients discontinued in the ECH-TH group and 102 (33·1%) in the ECL-TL group. 70 serious adverse events were reported in the ECH-TH group and 87 in the ECL-TL group., Interpretation: This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab. Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy., Funding: GlaxoSmithKline, Roche, and Sanofi-Aventis., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Safety data for combining bevacizumab, everolimus, or lapatinib with anthracycline- and taxane-based neoadjuvant chemotherapy for breast cancer are limited., Patients and Methods: The neoadjuvant GeparQuinto trial investigates the addition of (i) bevacizumab to four cycles epirubicin/cyclophosphamide (EC) followed by four cycles docetaxel (Taxotere) in patients with human epithelial growth factor receptor (HER)2-negative tumors, (ii) everolimus to weekly paclitaxel in patients with HER2-negative tumors not responding to EC ± bevacizumab, and (iii) lapatinib instead of trastuzumab to EC-docetaxel in patients with HER2-positive tumors to improve the rate of pathological complete response. Tolerable dose, need for supportive treatments, and early signals for toxic effect were evaluated in a planned safety analysis of 270 patients., Results: Treatment with chemotherapy plus bevacizumab, everolimus, or lapatinib was discontinued in 23.0%, 25.8%, and 34.5% compared with chemotherapy alone or plus trastuzumab in 19.4%, 24.1%, 3.2%, respectively. More leukopenia, infections, mucositis, and hypertension but less edema was observed by adding bevacizumab; a trend toward more thrombocytopenia, leukopenia, skin changes, and hyperlipidemia by adding everolimus; and more diarrhea, skin changes, and hot flushes but no cardiac events by substituting trastuzumab by lapatinib., Conclusions: Adding bevacizumab and everolimus to chemotherapy appeared feasible. Lapatinib at 1250 mg resulted in an increased rate of treatment discontinuations and was subsequently dose reduced to 1000 mg.

Purpose: Her2/neu protein overexpression and gene amplification is found in 20-30% of breast cancer patients and correlates with poor clinical outcome. Patients who profit from anti-Her2/neu- therapy are routinely selected by examination of tumour specimens using immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) separately. Many studies found a good correlation between both methods for score 1+ samples and for score 3+ samples, but not for score 2+ samples. In this study, we examined pleural and ascitic effusions with a combined approach using IHC and FISH on the same cells, under the following aspects: (1) frequency of Her2/neu protein expression and gene amplification in effusions; (2) correlation between score of protein expression and gene amplification; (3) impact of chromosome 17 polyploidy on Her2/neu protein expression., Methods: We examined 31 effusions from patients with breast cancer and 4 effusions from patients with ovarian cancer. Cytospins were analysed by IHC using two anti-Her2/neu antibodies and subsequently analysed by FISH with Her2/neu/CEP17 probes. Amplification was defined as: (1) Her2/neu gene copy number of more than 4 and (2) Her2/neu/CEP17 ratio of 2.0 or greater., Results: A system combining IHC and FISH was developed and 35 effusion specimens were examined. As much as 25 of them were scored as positive. All of them contained cells with heterogeneous scores. A total of 18 of the samples contained cells with scores that ranged from 0 to 3+. In the other samples scores ranged from 0 to 1+ or 0 to 2+. Cells were analysed for Her2/neu gene amplification and chromosome 17 ploidy with regard to their scores. As much as 15 of all samples had mean Her2/neu copy numbers of >4, but only 12% (n = 3) of the positive samples were amplified according to Her2/neu/CEP17 ratio. Only 22, 9% (n = 8) were polyploid (mean CEP17 > 4); but 65, 7% (n = 23) of all specimens contained single polyploid cells. In some cases up to 100% of the score 3+ cells showed chromosome 17 polyploidy. Here protein overexpression might be caused by polyploidy rather than by gene amplification. In some samples, we found single cells with gene amplification but without protein expression and cells without amplification but with protein overexpression., Conclusion: The combination of IHC and FISH allows a differentiated analysis of single cells, which is especially important for effusions that are composed of heterogeneous cells. Therefore, cells with high gene amplification and/or protein overexpression can be detected and analysed even if their amount in the sample is small. Chromosome 17 polyploidy is important in some cases but this should be further examined on a larger series.

Purpose: To evaluate the antitumor activity in terms of response rate (RR), time to progression (TTP) and survival of paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil (5-FU)/leucovorin in pretreated metastatic breast cancer (MBC)., Patients and Methods: Fifty-four patients with bidimensionally measureable disease were included during phase II. Thirty-two had anthracycline resistant disease. Treatment consisted of 5-FU (24-hour i.v. infusion) 2.0 g/m2, leucovorin (two-hour i.v. infusion prior to 5-FU) 500 mg/m2, weekly for six weeks (day 1, 8, 15, 22, 29, 36) and paclitaxel (three-hour i.v. infusion) 175 mg/m2 was administered additionally on days 1 and 22, q 50 days., Results: We observed complete remissions in 4% of patients (2 of 54), partial remissions in 55% (30 of 54), stable disease in 37% (20 of 54) and progressive disease in 4% (2 of 54). The overall RR was 59% (95% CI 48%-72%). The RR in 32 patients with anthracycline resistant disease was 59% (19 of 32). The median duration of response was 12 months (3-22), median TTP eight months (2-22) and median survival time 15 months (2-28). Neutropenia was common, but of CTC grade 2 or 3 in most patients. Nonhematologic toxicities mostly consisted of CTC grade 1 and 2 myalgia, diarrhea, mucositis, nausea and vomiting., Conclusions: Paclitaxel combined with weekly 24-hour infusional 5-FU/leucovorin is well tolerated in the second line treatment of MBC. High efficacy was documented even in the treatment of anthracycline resistant disease, which warrants further evaluations.

The cytotoxic activity of bendamustine hydrochloride was evaluated against human ovarian and breast carcinoma cell lines including cell lines resistant to cisplatin and doxorubicin in vitro. The relative degree of resistance to bendamustine hydrochloride was lower in all cell lines compared with cyclophosphamide, melphalan and BCNU, suggesting only incomplete cross-resistance. Furthermore lower levels of resistance were also observed in all breast cancer cell lines when bendamustine hydrochloride was compared with cisplatin. Bendamustine hydrochloride also presents good activity in cell line MCF 7 AD, which is approximately 80-fold resistant to doxorubicin compared with MCF 7. Basic glutathione levels and activity of glutathione-S-transferase showed no correlation to the IC50 values for bendamustine hydrochloride in the cell lines. When given at equitoxic concentrations, bendamustine hydrochloride consistently induced more DNA double-strand breaks than melphalan, cyclophosphamide or BCNU. In addition, removal of DNA double-strand breaks induced by bendamustine hydrochloride was relatively slow with the majority of DNA double-strand breaks still being detectable after 24 h. These findings indicate differences in the interaction between bendamustine hydrochloride and DNA, and may explain the lack of complete cross-resistance between bendamustine hydrochloride and the other alkylating agents.

Paclitaxel has proven to be an active agent in the treatment of breast and ovarian cancer [Seidman AD, Ann Oncol 1994, 5 (Suppl. 6), 17-22], but the optimal dose and schedule remain undefined. We performed a phase I study with a weekly 1 h infusion of paclitaxel. After premedication, patients received a 1 h infusion of paclitaxel on days 1, 8, 15, 22, 29 and 36 (every 50 days) using the following dose levels: dose level 1 70 mg/m2, dose level 2 80 mg/m2, dose level 90 mg/m2, dose level 4 100 mg/m2, 20 patients (17 breast, 3 ovarian cancer) with anthracycline- or platinum-refractory disease entered this trial. No dose limiting toxicities occurred at dose levels 1-3. 2 of the 4 patients at dose level 4 had neutropenia WHO grade 4. At all dose levels responses could be observed. Maximal tolerable dose (MTD) was reached using dose level 4. Paclitaxel, given in a weekly 1 h infusion, is safe and shows mild toxicity in heavily pretreated breast and ovarian cancer patients. We recommend dose level 3 for phase II studies.

Phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil/folinic acid (5-FU/FA) in intensively pretreated metastatic breast cancer patients prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in a phase I/II trial in outpatients: high-dose 5-FU (24-hour infusion)/FA (2-hour infusion preceding 5-FU) is given for 6 weeks (days 1, 8, 15, 22, 29, and 36), with paclitaxel (3-hour infusion) administered on days 1 and 22; 2 weeks' rest follows. Folinic acid 500 mg/m2 was administered throughout; the respective 5-FU doses for dose levels 1 through 3 were 1.5, 1.8, and 2.0 g/m2 with paclitaxel 135 mg/m2. Dose level 4 (500 mg/m2 FA, 2.0 g/m2 5-FU, and 175 mg/m2 paclitaxel) was chosen for phase II evaluation. To date, 46 patients with bidimensionally measurable disease (four each at dose levels 1, 2, and 3, and 34 at dose level 4) have been entered. The 12 patients treated at dose levels 1 through 3 were titrated to level 4 doses when phase II began; 35 patients are evaluable for response. The median age is 46 years, and the median number of metastatic sites is 2.5. Fourteen patients had received adjuvant chemotherapy, nine chemotherapy for metastasis, and 23 chemotherapy both adjuvantly and for metastasis. Of 31 anthracycline-treated patients, 27 had anthracycline-resistant disease. No dose-limiting toxicity appeared until dose level 4, when grade 3 or 4 leukopenia and diarrhea occurred in 15 and eight, respectively, of 108 cycles. Mild to moderate mucositis, hand-foot syndrome, myalgia, and nausea/vomiting occurred in 20% to 40% of cycles. One (3%) of the 35 patients had a complete response, 18 (51%) had partial responses, 14 (40%) had stable disease, and two (6%) had disease progression. Eleven (55%) of 20 evaluable patients with anthracycline-resistant disease responded (95% confidence interval, 34% to 76%). Median time to maximum response was 2 months, and the remission duration was 8+ months. Median survival time has not been reached. Paclitaxel and weekly high-dose 5-FU/FA was well tolerated and highly effective, even in patients with anthracycline-resistant metastatic breast cancer. The regimen can be administered safely to outpatients.