Metronomic treatment of vinorelbine with oral capecitabine is tolerable in the randomized Phase 2 study XeNa including patients with HER2 non-amplified metastatic breast cancer.

BACKGROUND: Metronomic treatment is hypothesized to be less toxic and more effective as compared to standard maximal tolerable dosing treatment in metastatic cancer disease. MATERIAL AND METHODS: We tested the metronomic treatment principle with vinorelbine in a randomized phase 2 setting combined with standard capecitabine treatment in the XeNa trial with Clinical Trials.gov identifier number: NCT0141771. 120 patients with disseminated HER2 non-amplified breast cancer were included. Randomization was between Arm A: vinorelbine 60 mg/m2 day 1 + day 8 in the first cycle followed by 80 mg/m2 day 1 + day 8 in the following cycles or Arm B: vinorelbine 50 mg three times a week. Capecitabine 1000 mg/m2 twice a day for days 1-14 was administered in both arms. RESULTS: The treatment was generally well-tolerated. The response rate (RR) was 24% (arm A) versus 29% (arm B) (p = .67). The clinical benefit rate (CBR) 46.8% (arm A) versus 51.7% (arm B) (p = .72). We found a median progression-free survival (PFS) of 7.1 months (95% confidence interval [CI] 3.9-10.3) in arm A and 6.3 months (95% CI 4.1-8.5) in arm B (p = .25) whereas median overall survival (OS) was 23.3 months (95% CI 20.2-26.4) in arm A and 22.3 months (95% CI 14.3-30.3) in arm B (p = .76). CONCLUSIONS: We confirmed that the combination of vinorelbine and capecitabine was well tolerated. Metronomic treatment can be used with acceptable adverse events (AEs), but we did not find significant difference in the effect compared to the standard treatment.

The NAME trial: a direct comparison of classical oral Navelbine versus Metronomic Navelbine in metastatic breast cancer.

Chemotherapy for metastatic breast cancer (MBC) is in general given in cycles of maximum tolerated doses to potentially maximize the therapeutic outcome. However, when compared with targeted therapies for MBC, conventional and dose intensified chemotherapy has caused only modest survival benefits during the recent decades, often compromising the quality of life considerably. Navelbine is an antineoplastic agent that has shown efficacy in the treatment of a variety of cancer types, including breast cancer. Early clinical trials involving both breast cancer and lung cancer patients suggest that metronomic dosing of Navelbine might be at least as effective as classical administration (once weekly, etc.). The NAME trial compares these two strategies of Navelbine administration in MBC patients.

Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study.

PURPOSE: Anthracyclines remain a cornerstone in the treatment of primary and advanced breast cancer (BC). This study has evaluated the predictive value of a multigene mRNA-based drug response predictor (DRP) in the treatment of advanced BC with epirubicin. The DRP is a mathematical method combining in vitro sensitivity and gene expression with clinical genetic information from > 3000 clinical tumor samples. METHODS: From a DBCG cohort, 140 consecutive patients were treated with epirubicin between May 1997 and November 2016. After patient informed consent, mRNA was isolated from archival formalin-fixed paraffin-embedded primary breast tumor tissue and analyzed using Affymetrix arrays. Using time to progression (TTP) as primary endpoint, the efficacy of epirubicin was analyzed according to DRP combined with clinicopathological data collected retrospectively from patients' medical records. Statistical analysis was done using Cox proportional hazards model stratified by treatment line. RESULTS: Median TTP was 9.3 months. The DRP was significantly associated to TTP (P = 0.03). The hazard ratio for DRP scores differing by 50 percentage points was 0.55 (95% CI -0.93, one-sided). A 75% DRP was associated with a median TTP of 13 months compared to 7 months following a 25% DRP. Multivariate analysis showed that DRP was independent of age and number of metastases. CONCLUSION: The current study prospectively validates the predictive capability of DRP regarding epirubicin previously shown retrospectively allowing the patients predicted to be poor responders to choose more effective alternatives. Randomized prospective studies are needed to demonstrate if such an approach will lead to increased overall survival.

[Isoflavones have therapeutic efficacy inoestrogen deficiency].

In this review, we discuss isoflavones, which are bioactive selective estrogen receptor modulators shown to have therapeutic efficacy in reducing bone resorption and improving menopause symptoms in women with estrogen deficiency. The European Food Safety Authority reached consensus that there "is no evidence of harm" of isoflavone supplements for peri- and post-menopausal women. Bioavailable isoflavone aglycones being rich in fermented sources are shown to have enhanced effects compared to glycosides, and isoflavones represent an effective and safe new treatment for oestrogen deficient bone loss and climacteric symptoms.

Prediction of fulvestrant efficacy in patients with advanced breast cancer: retrospective-prospective evaluation of the predictive potential of a multigene expression assay.

BACKGROUND: Fulvestrant is a selective oestrogen receptor (ER) degrader used as monotherapy and combination therapy for ER positive HER2 negative advanced breast cancer (ABC) in postmenopausal women. The drug response predictor (DRP), is a mathematical algorithm based on the expression of multiple genes in the tumour. The fulvestrant DRP algorithm has previously shown effect in BC. In this study, we investigated the DRP's potential in predicting fulvestrant benefit. METHOD: Among 695 patients with ABC prospectively included in a Danish Breast Cancer Cooperative Group (DBCG) cohort we retrospectively included 226 patients who received fulvestrant as monotherapy. The DRP result was based on mRNA extracted from tumour biopsies and analysed using Affymetrix array. Primary endpoint was time to progression (TTP). RESULTS: For patients who received fulvestrant in line one to four and were previously unexposed to adjuvant endocrine therapy, we identified a hazard ratio (HR) of 0.44 (90% confidence interval (90% CI) upper limit of 1.08, one sided p = 0.066) for a predicted positive vs negative outcome. A weaker association was seen when including patients exposed to adjuvant endocrine treatment or received fulvestrant in fifth or later lines. Exploratory analyses showed that the DRP was efficient when using recent biopsies for DRP estimate and among recently treated patients. CONCLUSION: The DRP showed a potential in predicting fulvestrant treatment but was not significant in the overall analysis. Use of older biopsies, long-term endocrine treatment and multiple therapies between biopsy used for analysis and fulvestrant treatment, probably affect the predictive accuracy.

Serum HER-2 concentrations for monitoring women with breast cancer in a routine oncology setting.

BACKGROUND: The purpose of this study was to determine the positive predictive value (PPV) of positive serum human epidermal growth factor receptor-2 (HER-2) for monitoring women with breast cancer following diagnosis and treatment in a routine clinical setting. METHODS: Serum HER-2 was measured in 1348 patients with breast cancer: 837 during routine oncology clinic visits and 511 following new diagnosis. All patients with positive serum HER-2, 1/5 of negative patients from the oncology clinic, and all the newly diagnosed were followed; a total of 862 patients. Serum HER-2 was measured using the Bayer ADVIA Centaur assay. Tissue HER-2 was determined using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). IHC +3 or IHC +2 and FISH>2.0 were positive. Patients were considered to have positive serum HER-2 when at least two values were >15 ng/mL. Recurrence, progression and regression were diagnosed according to usual clinical practice. Serum HER-2 concentrations did not contribute to diagnostic decision-making or selection of treatment. RESULTS: From January 2004 to January 2009, 149 patients were found to have positive serum HER-2. Of these, 35 were tissue HER-2 positive at surgery, 69 tissue-negative and 45 were not determined. Fifty-five of 149 that were serum HER-2 positive (37%, 95% CI: 29-45) had metastases. Among the 35 tissue-positive patients, 25 had recurrence in the form of metastases and there was good correlation between recurrence/progression and increase in serum HER-2 (p<0.0003). There was also a high correlation between effect of treatment and decline in serum HER-2 (p<0.0003). Of the 69 tissue-negative patients, 29 had recurrence in the form of metastases, and there was good correlation with serum HER-2 levels (p<0.000004). In this routine application of serum HER-2, the PPV for metastases recurrence detection in both tissue-positive and tissue-negative was 54 of 104 (52%, 95% CI: 42%-62%), in tissue-positive 25 of 35 (71%, 95% CI: 54%-85%), in tissue-negative 29 of 69 (42%, 95% CI: 30%-54%). The lead time of increases in serum HER-2 before recurrence could be determined in ten tissue-positive patients was 3-24 months (mean 11.3 months), when compared to standard clinical imaging methods. CONCLUSIONS: Serum HER-2 is a useful marker for the detection of recurrence of breast cancer and for monitoring the effect of treatment, especially in tissue HER-2 positive patients.

Pan-European Expert Meeting on the Use of Metronomic Chemotherapy in Advanced Breast Cancer Patients: The PENELOPE Project.

INTRODUCTION: Metronomic chemotherapy (mCHT) is a treatment regimen in which drugs are administered frequently or continuously and that maintains low, prolonged, and pharmacologically active plasma concentrations of drugs to avoid toxicity associated with traditional chemotherapy regimens, while achieving tumor response. Despite the increasing use of mCHT in patients with metastatic breast cancer (MBC) and the endorsement of mCHT in guidelines, no consensus exists about which patients may substantially benefit from mCHT, which agents can be recommended, and in which treatment setting mCHT is most appropriate. METHODS: In October 2017, ten international experts in the management of breast cancer convened to develop a report describing the current status of the use of mCHT for the treatment of advanced breast cancer, based not only on current literature but also on their opinion. The Delphi method was used to reach consensus. RESULTS: A full consensus was reached concerning the acknowledgement that mCHT is not simply a different way of administering chemotherapy but a truly new treatment option. The best-known effect of mCHT is on angiogenesis inhibition, but exciting new data are on the way regarding potential activity on immune system activation. The experts strongly suggest that the ideal patients for mCHT are those with hormone receptor (HR)-positive tumors or those with triple-negative disease. Independently of HR status, mCHT could be an advantageous option for elderly patients, who are often under-treated simply because of their age. CONCLUSION: Current data support the use of mCHT in selected patients with MBC. FUNDING: Pierre Fabre.

Vinorelbine as first-line or second-line therapy for advanced breast cancer: a Phase I-II trial by the Danish Breast Cancer Co-operative Group.

INTRODUCTION: This study was conducted to establish the maximum tolerated dose (MTD) of intravenous vinorelbine and on the determined dose to assess efficacy and safety in patients with metastatic breast cancer previously treated with epirubicin. PATIENTS AND METHODS: Patients had histologically proven breast cancer and had received a prior epirubicin based regimen either adjuvant or as first line therapy for advanced disease. Vinorelbine was administered intravenously day 1 and 8 in a 3 weeks' schedule. Subsequently 48 additional patients were treated at one dose-level below MTD. RESULTS: Fifty-five patients were included in the dose-escalation study, which defined 40 mg/m(2) as the MTD. Neutropenia of short duration and autonomic neuropathy causing constipation were the most common dose-limiting toxicities. At the 35 mg/m(2) dose-level 60 patients were included in total. Seven (12%; 95% CI 6 to 22) had a partial response and 16 additional patients had stable disease. 27% had stable disease (clinical benefit rate 38%, 95% CI 27 to 51). The median overall survival was 45 weeks and 39% of the patients were alive after one year. DISCUSSION: The clinical benefit rate was 38% with an overall intention to treat response rate of only 12%. The results were, however, achieved with low subjective burdens of toxicity.

Cryopreservation of Circulating Tumor Cells for Enumeration and Characterization.

BACKGROUND: A blood sample containing circulating tumor cells (CTCs) may serve as a surrogate for metastasis in invasive cancer. Cryopreservation will provide new opportunities in management of clinical samples in the laboratory and allow collection of samples over time for future analysis of existing and upcoming cancer biomarkers. METHODS: Blood samples from healthy volunteers were spiked with high (∼500) and low (∼50) number of tumor cells from culture. The samples were stored at -80C with cryopreservative dimethyl sulfoxide mixed with Roswell Park Memorial Institute 1640 medium. Flow cytometry tested if cryopreservation affected specific biomarkers regularly used to detect CTCs, i.e. cytokeratin (CK) and epithelial cell adhesion molecule (EpCAM) and white blood cell specific lymphocyte common antigen (CD45). After various time intervals (up to 6 months), samples were thawed and tumor cell recovery (enumeration) was examined. Clinical samples may differ from cell line studies, so the cryopreservation protocol was tested on 17 patients with invasive breast cancer and tumor cell recovery was examined. Two blood samples were drawn from each patient. RESULTS: Biomarkers, CK, CD45, and EpCAM, were not affected by the freezing and thawing procedures. Cryopreserved samples (n = 2) spiked with a high number of tumor cells (∼500) had a ∼90% recovery compared with the spiked fresh samples. In samples spiked with lower numbers of tumor cells (median = 43 in n = 5 samples), the recovery was 63% after cryopreservation (median 27 tumor cells), p = 0.03. With an even lower number of spiked tumor cells (median = 3 in n = 8 samples), the recovery rate of tumor cells after cryopreservation did not seem to be affected (median = 8), p = 0.09. Time of cryopreservation did not affect recovery. When testing the effect of cryopreservation on enumeration in clinical samples, no difference was observed in the number of CTCs between the fresh and the cryopreserved samples based on n = 17 pairs, p = 0.83; however, the variation was large. This large variation was confirmed by clinically paired fresh samples (n = 64 pairs), where 95% of the samples (<30 CTCs) vary in number up to ±15 CTCs, p = 0.18. CONCLUSIONS: A small loss of CTCs after cryopreservation may be expected; however, cryopreservation of CTCs for biomarker characterization for clinical applications seems promising.

Phase III study of intravenous vinorelbine in combination with epirubicin versus epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast Group Trial (SBG9403).

PURPOSE: To determine whether the addition of intravenous (IV) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer. PATIENTS AND METHODS: A total of 387 patients were randomly assigned to receive IV epirubicin 90 mg/m(2) on day 1 and vinorelbine 25 mg/m(2) on days 1 and 8, or epirubicin 90 mg/m(2) IV on day 1. Both regimens were given every 3 weeks for a maximum of 1 year but discontinued prematurely in the event of progressive disease or severe toxicity. In addition, epirubicin was discontinued at a cumulative dose of 1000 mg/m(2) (950 mg/m(2) from June 1999). Prior anthracycline-based adjuvant chemotherapy and prior chemotherapy for metastatic breast cancer was not allowed. Reported results were all based on intent-to-treat analyses. RESULTS: Overall response rates to vinorelbine and epirubicin, and epirubicin alone, were 50% and 42%, respectively (P =.15). The complete response rate was significantly superior in the combination arm (17% v 10%; P =.048) as was median duration of progression-free survival (10.1 months v 8.2 months; P =.019). Median survival was similar in the two arms (19.1 months v 18.0 months; P =.50). Leukopenia related complications, stomatitis, and peripheral neuropathy were more common in the combination arm. The incidences of cardiotoxicity and constipation were similar in both arms. CONCLUSION: Addition of vinorelbine to epirubicin conferred a significant advantage in terms of complete response rate and progression-free survival, but not in terms of survival.

[Prevention of skeletal related events in patients with bone metastases from solid tumours]. / Forebyggelse af skeletrelaterede hændelser hos patienter med knoglemetastaser ved solide tumorer.

This article is based on a systematic literature search and meta-analyses of clinical data regarding effects of bisphosphonates (BP) and denosumab (DS) on preventing skeletal related events (SRE) in patients with bone metastases from solid tumours. Although there are pharmacological differences between the different types of BP no major differences were observed between BP in preventing SRE or in adverse events. Treatment with DS has in three randomised trials showed a greater effect than BP in preventing SRE. The optimal choice of bone-anti-resorptive agent should depend on the patient's general condition, renal function and treatment logistics.

Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study.

PURPOSE: To evaluate docetaxel or vinorelbine, both with trastuzumab, as first-line therapy of human epidermal growth factor receptor 2-positive advanced breast cancer. PATIENTS AND METHODS: Patients naive to chemotherapy for advanced disease were randomly assigned to docetaxel 100 mg/m(2) day 1 or vinorelbine 30 to 35 mg/m(2) on days 1 and 8, both combined with trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance dose) on day 1 every 3 weeks. The primary end point was time to progression (TTP). RESULTS: A total of 143 patients were randomly allocated to docetaxel, and 141 patients were assigned to vinorelbine. The median TTP for docetaxel and vinorelbine respectively was 12.4 months versus 15.3 months (hazard ratio [HR] = 0.94; 95% CI, 0.71 to 1.25; P = .67), median overall survival was 35.7 months versus 38.8 months (HR = 1.01; 95% CI, 0.71 to 1.42; P = .98), and the 1-year survival rate was 88% in both arms. Median time to treatment failure for study chemotherapy was 5.6 months versus 7.7 months (HR = 0.50; 95% CI, 0.38 to 0.64; P < .0001). The investigator-assessed overall response rate among 241 patients with measurable disease were 59.3% in both arms. More patients in the docetaxel arm discontinued therapy due to toxicity (P < .001). Significantly more treatment-related grade 3 to 4 febrile neutropenia (36.0% v 10.1%), leucopenia (40.3% v 21.0%), infection 25.1% v 13.0%), fever (4.3% v 0%), neuropathy (30.9% v 3.6%), nail changes (7.9% v 0.7%), and edema (6.5% v 0%) were reported with docetaxel. CONCLUSION: The study failed to demonstrate superiority of any drug in terms of efficacy, but the vinorelbine combination had significantly fewer adverse effects and should be considered as an alternative first-line option.