Phase III Study of N,N-Diethyl-2-[4-(Phenylmethyl) Phenoxy]Ethanamine (BMS-217380-01) Combined With Doxorubicin Versus Doxorubicin Alone in Metastatic/Recurrent Breast Cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19

Purpose N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is a novel agent that augments chemotherapy cytotoxicity in vitro and in vivo. A phase II trial combining DPPE and doxorubicin (DOX) in metastatic breast carcinoma showed increased response over that expected with DOX. We report a phase III trial comparing DOX with DPPE plus DOX in metastatic or recurrent breast cancer. Patients and Methods Anthracycline-naive women with measurable metastatic disease were randomly assigned to receive, every 21 days, either DOX 60 mg/m2 intravenously or DOX during the last 20 minutes of an 80-minute infusion of DPPE (5.3 mg/kg), in both cases to cumulative DOX doses of 450 mg/m2. Patients receiving DPPE were aggressively premedicated to ameliorate toxicity. End points included progression-free survival (PFS), response rate (RR), and response duration (RD), quality of life (QOL), toxicity, and overall survival (OS). Results A planned interim analysis failed to detect an RR difference more than 5%. The study was closed to additional accrual and all DPPE was discontinued. The final analysis was conducted as planned after 256 progression events (median follow-up, 20.5 months). There was no significant difference in RR, RD, or PFS between arms. DPPE plus DOX was statistically superior to DOX in OS (hazard ratio, 0.66; 95% CI, 0.48 to 0.91; P = .021). DPPE plus DOX was associated with more gastrointestinal and CNS toxicity. No consistent influence on QOL was detected. Conclusion This study demonstrated no advantage in RR, RD, or PFS but significantly superior OS for DPPE plus DOX. Additional studies of DPPE are warranted.

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Paclitaxel plus carboplatin versus paclitaxel plus epirubicin as first-line treatment for metastatic breast cancer: Efficacy and safety results of a randomized, phase III trial.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.1087 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 1087-1087

Author(s):

Zhongsheng Tong ◽

Shufen Li ◽

Yehui Shi ◽

Xu Wang ◽

Chen Wang ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Metastatic Breast Cancer ◽

Response Rate ◽

Metastatic Breast ◽

Progression Free Survival ◽

Phase Iii ◽

First Line ◽

Free Survival ◽

Significant Difference

1087 Background: Paclitaxel/carboplatin combinations are highly active in metastatic breast cancer (MBC). We conducted a randomized, phase III, non-inferiority trial comparing paclitaxel/carboplatin (TP) with paclitaxel/epirubicin (TE) as first-line therapy for MBC. Progression-free survival (PFS) was the primary efficacy endpoint. Secondary endpoints included response rate, overall survival, tolerability, and quality of life (QoL). Methods: From June 2009 to January 2015, 231 patients were randomly assigned, 115 of whom were randomized to TP and 116 to TE. Baseline characteristics were relatively well-balanced in the two treatments. Results: After a median follow-up of 29 months, no significant difference was observed between the two treatments in objective response rate (ORR) (38.3% vs. 39.7%, respectively). Both the progression-free survival (p=0.158) and overall survival (p=0.369) were very similar between the two treatments. Both regimens were well tolerated. The main toxicities were myelosuppression, gastrointestinal reactions, and alopecia. TP showed higher grades 3–4 alopecia and higher nausea (p<0.05). TE showed higher incidence of myelosuppression than TP (p<0.05) (Table). Those patients whose epirubicin cumulative dose was more than 1000 mg/m2 did not suffer worse cardiotoxicity. Conclusions: Our study suggests that TP arm is an effective therapeutic alternative for patients with MBC, especially in those previously exposed to epirubicin in the adjuvant setting. TP has some advantages, such as less cost and less side effects (myelosuppression and fatigue). Clinical trial information: NCT02207361. [Table: see text]

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Current perspectives on aromatase inhibitors in breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.11.2460 ◽

1994 ◽

Vol 12 (11) ◽

pp. 2460-2470 ◽

Cited By ~ 46

Author(s):

P E Goss ◽

K M Gwyn

Keyword(s):

Breast Cancer ◽

Aromatase Inhibitors ◽

Metastatic Breast ◽

Phase Iii ◽

Future Application ◽

In Vivo Experiments ◽

Estrogen Production ◽

New Generation

PURPOSE AND DESIGN: One way to deprive hormone-dependent breast cancer of estrogen is to prevent its synthesis. This is achievable by inhibiting the aromatase cytochrome P-450 (P-450arom) enzyme complex responsible for the ultimate step in estrogen production. A new generation of specific and selective aromatase inhibitors is currently under investigation. The purpose of this review is to outline the preclinical test systems for screening these inhibitors, to summarize the preclinical and clinical data published to date, and to discuss the future application of these inhibitors in the management of breast cancer. RESULTS AND CONCLUSION: Disadvantages to the use of earlier inhibitors are described. In vitro and in vivo experiments that reflect the potency and selectivity of new inhibitors are highlighted. From preliminary clinical trials, these inhibitors appear to have excellent pharmacokinetic profiles and produce few side effects when administered orally. Activity against postmenopausal metastatic breast cancer has been demonstrated for the agents reviewed. They are all now in phase III testing to determine their relative efficacy in this setting. Their application in combination with both hormone therapy and chemotherapy, in premenopausal metastatic disease, and in the adjuvant setting in both premenopausal and postmenopausal women remains to be defined.

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Evaluation of Sirt1 And Foxo’s In Primary Tumor And Distant Organ Metastasis Invaded By Benign And Highly Metastatic Breast Carcinoma Cells Under In Vitro And In Vivo Conditions.

10.21203/rs.3.rs-183690/v1 ◽

2021 ◽

Author(s):

Sayra Dilmac ◽

Nilay Kuscu ◽

Ayse Caner ◽

Sendegul Yildirim ◽

Burcak Yoldas ◽

...

Keyword(s):

Breast Cancer ◽

Primary Tumor ◽

Metastatic Breast ◽

Signal Pathways ◽

Breast Cancers ◽

Primary Tumors ◽

Metastatic Breast Carcinoma ◽

Liver Tissues

Abstract Breast cancer is the second most common cancer in women. In malignant breast cancers, tumor cells have the potential to metastasize to distant organs through the lymphatic system and blood circulation. The aim of this study is to evaluate the expression of SIRT1 and FoxO proteins in metastatic and nonmetastatic breast cancer cells and distant organs metastasis. In our study, SIRT1, p53, p21, and FoxO proteins have been evaluated in metastatic 4TLM and non-metastatic 67NR cell lines by immunocytochemistry in vitro and also in mice breast cancer model in vivo. Cells were orthotopically injected to mammary fat pads of 8-10 weeks old Balb/c female mice. Primary tumor, lung and liver tissues were removed and expressions of these proteins were evaluated by immunohistochemistry, western blot and RT-PCR. In addition, signal pathways that are related to SIRT and FoxO proteins were examined by using IPA core analysis. TCGA database was browsed for investigation of different genes.In primary tumors, SIRT1, p21, p53, E2F1 and FoxO expressions were higher in 67NR compared to 4TLM. In metastatic lung and liver tissues, the expression levels of SIRT1, FoxO1, FoxO3a and FoxO4 proteins were increased in 4TLM compared to 67NR. IPA and TCGA analysis have also revealed that SIRT1 and FoxO proteins are lower in primary tumors, but increased in metastatic stages. In conclusion, in primary tumors SIRT1 and FoxO expressions were decreased in 4TLM compared to 67NR. Moreover, SIRT1 and FoxO, especially expressed in metastatic cells. High level of FoxO expressions in metastatic stages in TNBC patients also supports its association with metastasis. Our findings suggest that SIRT1 and FoxO’s have crucial role in tumor progression metastatic process in breast cancer.

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Phase III Comparative Study of Vinorelbine Combined With Doxorubicin Versus Doxorubicin Alone in Disseminated Metastatic/Recurrent Breast Cancer: National Cancer Institute of Canada Clinical Trials Group Study MA8

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.12.2385 ◽

2000 ◽

Vol 18 (12) ◽

pp. 2385-2394 ◽

Cited By ~ 112

Author(s):

B. Norris ◽

K.I. Pritchard ◽

K. James ◽

J. Myles ◽

K. Bennett ◽

...

Keyword(s):

Breast Cancer ◽

Vinca Alkaloid ◽

Metastatic Breast ◽

Response Duration ◽

Recurrent Breast Cancer ◽

Phase Iii ◽

Phase Iii Study ◽

Grade 3 ◽

Recurrent Breast

PURPOSE: This phase III study was performed to determine the superiority of doxorubicin (DOX) and vinorelbine (VNB) (arm 1) versus DOX alone (arm 2) in metastatic breast cancer (MBC) for overall survival (OS), time to treatment failure (TTF), toxicity, and quality of life (QOL). PATIENTS AND METHODS: Three hundred three patients were randomized to DOX 50 mg/m2 intravenously (IV) on day 1 and VNB 25 mg/m2 IV on days 1 and 8 (arm 1) or DOX 70 mg/m2 IV on day 1 (arm 2). Both regimens were given every 3 weeks until a cumulative DOX dose of 450 mg/m2. After 16 of the first 65 randomized patients experienced febrile neutropenia (FN), the doses were reduced to DOX 40 mg/m2 on day 1 and VNB 20 mg/m2 on days 1 and 8 versus DOX 60 mg/m2 on day 1. Eligible patients were vinca alkaloid and anthracycline naive. Chemotherapy was first-line or second-line for MBC. RESULTS: Three patients were ineligible. Thus, 300 patients were assessable for toxicity and to determine time to disease progression (TTP), TTF, and OS. Two hundred eighty-nine patients were assessable for response, and 99 responders were assessable for response duration (RD). The response rates, QOL, and median RD, TTP, and TTF were not significantly different between the arms. Median OS was 13.8 months for arm 1 versus 14.4 months for arm 2 (P = .4). Grade 3 or 4 granulocytopenia was equivalent in both arms but more grade 3/4 neurotoxicity, mild venous toxicity, and FN were seen on arm 1. CONCLUSION: The survival with DOX and VNB is not superior to DOX alone in MBC.

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Osteoblast-Derived Paracrine and Juxtacrine Signals Protect Disseminated Breast Cancer Cells from Stress

Cancers ◽

10.3390/cancers13061366 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1366

Author(s):

Russell Hughes ◽

Xinyue Chen ◽

Natasha Cowley ◽

Penelope D. Ottewell ◽

Rhoda J. Hawkins ◽

...

Keyword(s):

Breast Cancer ◽

Cell Survival ◽

Cancer Cells ◽

Cancer Cell ◽

Breast Cancer Cells ◽

Metastatic Breast ◽

Accessory Cell ◽

Cancer Cell Survival

Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER+) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth.

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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)

Journal of Clinical Oncology ◽

10.1200/jco.2004.11.503 ◽

2004 ◽

Vol 22 (12) ◽

pp. 2313-2320 ◽

Cited By ~ 46

Author(s):

Bent Ejlertsen ◽

Henning T. Mouridsen ◽

Sven T. Langkjer ◽

Jorn Andersen ◽

Johanna Sjöström ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Response Rate ◽

Complete Response Rate ◽

Metastatic Breast ◽

Progression Free Survival ◽

Complete Response ◽

Phase Iii ◽

Severe Toxicity ◽

Free Survival

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/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8, or epirubicin 90 mg/m2 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 1,000 mg/m2 (950 mg/m2 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.

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Bevacizumab and Breast Cancer: A Meta-Analysis of First-Line Phase III Studies and a Critical Reappraisal of Available Evidence

Journal of Oncology ◽

10.1155/2012/417673 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 50

Author(s):

José R. Rossari ◽

Otto Metzger-Filho ◽

Marianne Paesmans ◽

Kamal S. Saini ◽

Alessandra Gennari ◽

...

Keyword(s):

Breast Cancer ◽

Fixed Effects ◽

Meta Analysis ◽

Metastatic Breast ◽

Progression Free Survival ◽

Phase Iii ◽

First Line ◽

Statistical Estimates ◽

Treatment Indications ◽

Phase Iii Studies

Background. Randomized studies have shown different magnitude of bevacizumab benefit in the treatment of advanced breast cancer. Regulatory agencies have modified bevacizumab treatment indications across different regions. In this study, we perform a meta-analysis of phase III studies aiming to interrogate the magnitude of bevacizumab benefit for the treatment of first-line HER2-negative metastatic breast cancer (MBC).Methods. Data from studies E2100, AVADO and RIBBON-1 were used to calculate the benefit of bevacizumab in terms of tumor overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Combined statistical estimates of hazard ratios (HR) and odds ratios were calculated using fixed-effects or random-effects models.Results. A total of 2,695 patients were evaluated. Combining bevacizumab with different chemotherapy backbones resulted in a 30% risk reduction of PFS events (HR = 0.70; 95% confidence interval [CI], 0.57–0.86) and increased ORR (odds ratio 1.81; 95% CI, 1.53–2.14). No OS benefit could be demonstrated (HR = 0.95; 95% CI, 0.85–1.06). Bevacizumab significantly increased the incidence of adverse events such as proteinuria, hypertension and cardiovascular events.Conclusions. Bevacizumab combined with chemotherapy in the first-line treatment of MBC significantly improved ORR and PFS, but also increased grade 3-4 toxicities. No significant OS advantage was observed.

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Development of a Novel 3D Bioprinted In Vitro Nano Bone Model for Breast Cancer Bone Metastasis Study

MRS Proceedings ◽

10.1557/opl.2014.941 ◽

2014 ◽

Vol 1724 ◽

Cited By ~ 1

Author(s):

Benjamin Holmes ◽

Wei Zhu ◽

Lijie Grace Zhang

Keyword(s):

Breast Cancer ◽

Bone Metastasis ◽

Metastatic Breast ◽

Bone Microstructure ◽

Bone Model ◽

Skeletal Complications ◽

3D Printed ◽

Breast Cancer Bone Metastasis

ABSTRACTBreast cancer (BrCa) is the second commonest cause of cancer-related deaths in women. The metastatic breast cancer exhibits a high affinity to bone, leading to debilitating skeletal complications associated with significant morbidity and poor prognosis. Traditional in vitro and in vivo BrCa bone metastasis models contain many inherent limitations with regards to controllability, reproducibility, and flexibility of design. Thus, the objective of this research is to use a 3D bioprinting system and nanomaterials to recreate a biomimetic and tunable bone model suitable for the effective simulation and study of metastatic BrCa invading and colonizing a bone environment. For this purpose, we designed and 3D printed a series of scaffolds, comprised of a bone microstructure and nano hydroxyapatites (nHA, inorganic nano components in bone). The size and geometry of the bone microstructure was varied with 250 and 150 µm pores, in repeating square and hexagon patterns, for a total of four different pore geometries. 3D bioprinted scaffolds were subsequently conjugated with nHA, using an acetylation chemical functionalization process and then characterized by scanning electron microscope (SEM). SEM imaging showed that our designed microfeatures were printable with the predesigned resolutions described above. Imaging further confirmed that acetylation effectively attached nHA to the surface of scaffolds and induced a nanoroughness. Metastatic BrCa cell 4 h adhesion and 1, 3 and 5 day proliferation were investigated in the bone model in vitro. The cell adhesion and proliferation results showed that all scaffolds are cytocompatible for BrCa cell growth; in particular the nHA scaffolds with small hexagonal pores had the highest cell density. Given this data, it can be stipulated that our 3D printed nHA scaffolds may make effective biomimetic environments for studying BrCa bone metastasis.

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Verminoside from Pseudolysimachion rotundum var. subintegrum sensitizes cisplatin-resistant cancer cells and suppresses metastatic growth of human breast cancer

Scientific Reports ◽

10.1038/s41598-020-77401-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Changhu Lee ◽

Hyung Won Ryu ◽

Sahee Kim ◽

Min Kim ◽

Sei-Ryang Oh ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Metastatic Breast ◽

Human Breast ◽

Mesenchymal Transition ◽

Bioactive Component ◽

Metastatic Growth

AbstractBreast cancer is one of the most common cancers in women and is associated with a high mortality rate. The majority of deaths resulting from breast cancer are attributable to metastatic growth; in addition, chemoresistance is a major concern in the treatment of patients with breast cancer. However, limited drugs are available for the treatment of metastatic breast cancer. In this study, the chemoadjuvant effects of a methanolic extract from the leaves of Pseudolysimachion rotundum var. subintegrum (NC13) and an active component isolated from the plant, verminoside (Vms), were evaluated. Furthermore, their potent anti-metastatic activities were validated in vitro and in vivo in animal models. The anti-metastatic and chemosensitizing activities of NC13 and Vms on cisplatin treatment were found to be partly mediated by suppression of the epithelial–mesenchymal transition of cancer cells. Collectively, our results implied that NC13 and its bioactive component Vms could be developed as effective chemoadjuvants in combination with conventional therapeutics.

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