pazopanib and Breast-Neoplasms

Several clinical trials have shown clinical benefit of angiogenesis inhibitors in the treatment of solid tumors. Pazopanib is a multitargeted tyrosine kinase inhibitor that is currently approved for the treatment of patients with advanced renal cell carcinoma (RCC).. In this article, the clinical development of pazopanib as it relates to breast cancer is reviewed including its evaluation in clinical trials and side effect profile. Preclinical data show the anti-tumor activity of pazopanib in animal models. Several trials of pazopanib monotherapy and combination therapy in breast cancer have been completed or are underway.. The development of biomarkers predictive of response and toxicity to angiogenesis inhibitors remains a challenging endeavor and is necessary to help guide treatment decision.

Topics: Angiogenesis Inhibitors; Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Indazoles; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Sulfonamides

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Indazoles; Lymph Nodes; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Paclitaxel; Pyrimidines; Receptor, ErbB-2; Sulfonamides

This phase II study (VEG20007; NCT00347919) with randomized and open-label components evaluated first-line lapatinib plus pazopanib therapy and/or lapatinib monotherapy in patients with human epidermal growth factor receptor type 2 (HER2)-positive advanced/metastatic breast cancer. Patients were enrolled sequentially into two cohorts: Cohort 1, patients were randomly assigned to lapatinib 1,000 mg plus pazopanib 400 mg or lapatinib 1,500 mg monotherapy; Cohort 2, patients received lapatinib 1,500 mg plus pazopanib 800 mg. The primary endpoint was week-12 progressive disease rate (PDR) for Cohort 1. The principal secondary endpoint was week-12 response rate (RR) for Cohort 2. Efficacy was assessed in patients with centrally confirmed HER2 positivity (modified intent-to-treat population [MITT]). The study enrolled 190 patients (Cohort 1, combination n = 77, lapatinib n = 73; Cohort 2, n = 40). The MITT population comprised n = 141 (Cohort 1) and n = 36 (Cohort 2). In Cohort 1, week-12 PDRs were 36.2 % (combination) versus 38.9 % (lapatinib; P = 0.37 for the difference). Week-12 RRs were 36.2 % (combination) versus 22.2 % (lapatinib). In Cohort 2, week-12 RR was 33.3 %. In Cohort 1, grade 3/4 adverse events (AEs) included diarrhea (combination, 9 %; lapatinib, 5 %) and hypertension (combination, 5 %; lapatinib, 0 %). Grades 3/4 AEs in Cohort 2 included diarrhea (40 %), hypertension (5 %), and fatigue (5 %). Alanine aminotransferase elevations >5 times the upper limit of normal occurred in Cohort 1 (combination, 18 %; lapatinib, 5 %) and Cohort 2 (20 %). Upon conclusion, the combination of lapatinib plus pazopanib did not improve PDR compared with lapatinib monotherapy, although RR was increased. Toxicity was higher with the combination, including increased diarrhea and liver enzyme elevations.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cohort Studies; Female; Humans; Indazoles; Lapatinib; Middle Aged; Neoplasm Staging; Pyrimidines; Quinazolines; Receptor, ErbB-2; Sulfonamides; Treatment Outcome

Angiogenesis is an important hallmark of breast cancer growth and progression. Pazopanib, an oral small molecule inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and KIT, has activity across a range of solid tumors. We evaluated the activity of single-agent pazopanib in recurrent or metastatic breast cancer (MBC).. Patients with recurrent breast cancer or MBC, treated with up to two prior lines of chemotherapy, were eligible to receive pazopanib, 800 mg daily until progression. The primary endpoint was the objective response rate as measured by Response Evaluation Criteria in Solid Tumors. Secondary endpoints included time to progression, the stable disease rate, and toxicity. Using a two-stage design, confirmed response in three of 18 patients was required to proceed to stage 2.. Twenty evaluable patients were treated, with a median age of 56 years; 70% were estrogen receptor positive, all were human epidermal growth factor receptor 2 negative. The majority had one or two prior lines of chemotherapy. One patient (5%) had a partial response, 11 (55%) had stable disease (SD) [four (20%) with SD > or = 6 months], and seven (35%) had progressive disease as their best response. One (5%) was not evaluable. The median time to progression was 5.3 months. Pazopanib did not cause significant severe toxicity aside from grade 3-4 transaminitis, hypertension, and neutropenia in three patients each (14% each) and grade 3 gastrointestinal hemorrhage in one patient (5%).. Pazopanib provides disease stability in advanced breast cancer. The activity seen is comparable with that of other antiangiogenic agents in this setting. Pazopanib may be of interest for future studies in breast cancer, including in combination with other systemic agents.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Breast Neoplasms; Disease Progression; ErbB Receptors; Female; Humans; Indazoles; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Recurrence, Local; Platelet-Derived Growth Factor; Pyrimidines; Sulfonamides

The growing population of young cancer survivors and a trend toward postponing pregnancy until later years in life are leading to a deeper attention towards understanding treatment-induced sequelae, and, in particular, the effects of cancer and/or treatment on fertility. Nowadays, the infertility risks potentially associated with molecular targeted therapies are not established, and clinical reports are sparse. Moreover, the increasing use of molecular targeted drugs in the adjuvant setting and in diseases with better prognosis makes preservation of fertility a major topic in current research.. Here, we report the case of an 18-year-old woman, with a 3-cm superficial lump of the right breast, who had no remarkable family or medical history. Menarche had occurred at the age of 14 years, with normal regular periods.. High-grade angiosarcoma, with metastatic progression and multiple relapse, was diagnosed.. After diagnosis, right radical mastectomy was carried out with no evidence of residual disease. No adjuvant treatment was delivered. Lymph node metastasis were found later and chemotherapy with doxorubicin 25 mg/m/day and ifosfamide 1 g/m/day (both on days 1-3) every 21 days was administered. During treatment, the patient reported menstrual irregularities but no amenorrhea. Due to further local relapse a few years later, the patient was treated for progressive metastatic disease with gemcitabine 1000 mg/m on days 1 and 8 every 21 days for 6 cycles, and underwent surgery, followed by pegylated liposomal doxorubicin, 50 mg/m on day 1 every 28 days. After further disease progression 5 years after first diagnosis, pazopanib was administered at a dose of 800 mg daily for 10 months.. The patient experienced a transient ovarian insufficiency possibly due to pazopanib. Since amenorrhea developed within 2 months from the initiation of pazopanib treatment and menses returned regularly only after discontinuation of the treatment itself.. This is the first case report that strongly suggests a correlation between pazopanib exposure and development of ovarian insufficiency. Our case tantalizes to inspire additional preclinical and clinical research on the true incidence, possible dose dependence, and reversibility of pazopanib (and other TKIs) -induced ovarian failure.

Topics: Adolescent; Breast Neoplasms; Combined Modality Therapy; Endosonography; Female; Hemangiosarcoma; Humans; Indazoles; Mastectomy; Primary Ovarian Insufficiency; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Vagina

Topics: Breast Neoplasms; Female; Humans; Hyperthermia, Induced; Indazoles; Leiomyosarcoma; Middle Aged; Pyrimidines; Sulfonamides

Treatment options for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer and resistance to endocrine therapy remain limited. An interesting therapeutic target in these patients is fibroblast growth factor receptor 1 (

Topics: Breast Neoplasms; Female; Gene Amplification; Humans; Indazoles; Middle Aged; Pyrimidines; Receptor, Fibroblast Growth Factor, Type 1; Sulfonamides

Brain metastases occur in more than one-third of metastatic breast cancer patients whose tumors overexpress HER2 or are triple negative. Brain colonization of cancer cells occurs in a unique environment, containing microglia, oligodendrocytes, astrocytes, and neurons. Although a neuroinflammatory response has been documented in brain metastasis, its contribution to cancer progression and therapy remains poorly understood. Using an experimental brain metastasis model, we characterized the brain metastatic microenvironment of brain tropic, HER2-transfected MDA-MB-231 human breast carcinoma cells (231-BR-HER2). A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor β (at tyrosine 751; p751-PDGFRβ) was identified around perivascular brain micrometastases. p751-PDGFRβ(+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte-enriched glial cells. Previously, we reported that pazopanib, a multispecific tyrosine kinase inhibitor, prevented the outgrowth of 231-BR-HER2 large brain metastases by 73%. Here, we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment. Pazopanib treatment resulted in 70% (P = 0.023) decrease of the p751-PDGFRβ(+) astrocyte population, at the lowest dose of 30 mg/kg, twice daily. Collectively, the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib, suggesting its potential to prevent the development of brain micrometastases in breast cancer patients.

Topics: Animals; Antineoplastic Agents; Astrocytes; Brain Neoplasms; Breast Neoplasms; Drug Evaluation, Preclinical; Female; Humans; Indazoles; Mice; Neoplasm Micrometastasis; Neoplasm Proteins; Neoplasm Transplantation; Neuroglia; Phosphorylation; Pyrimidines; Receptor, Platelet-Derived Growth Factor beta; Sulfonamides; Tumor Cells, Cultured; Tumor Microenvironment

Brain metastases of breast cancer contribute significantly to patient morbidity and mortality. We have tested pazopanib, a recently approved antiangiogenic drug that targets VEGFR1, VEGFR2, VEGFR3, PDGFRβ, PDGFRα, and c-kit, for prevention of experimental brain metastases and mechanism of action.. In vitro assays included B-Raf enzymatic assays, Western blots, and angiogenesis assays. For in vivo assays, HER2 transfectants of the brain seeking sublines of MDA-MB-231 cells (231-BR-HER2) and MCF7 cells (MCF7-HER2-BR3, derived herein) were injected into the left cardiac ventricle of mice and treated with vehicle or pazopanib beginning on day 3 postinjection. Brain metastases were counted histologically, imaged, and immunostained.. Treatment with 100 mg/kg of pazopanib resulted in a 73% decline in large 231-BR-HER2 metastases (P < 0.0001) and a 39% decline in micrometastases (P = 0.004). In vitro, pazopanib was directly antiproliferative to 231-BR-HER2 breast cancer cells and inhibited MEK and ERK activation in vitro despite B-Raf and Ras mutations. Enzymatic assays demonstrated that pazopanib directly inhibited the wild type and exon 11 oncogenic mutant, but not the V600E mutant forms of B-Raf. Activation of the B-Raf targets pERK1/2 and pMEK1/2 was decreased in pazopanib-treated brain metastases whereas blood vessel density was unaltered. In the MCF7-HER2-BR3 experimental brain metastasis model, pazopanib reduced overall brain metastasis volume upon magnetic resonance imaging (MRI) by 55% (P = 0.067), without affecting brain metastasis vascular density.. The data identify a new activity for pazopanib directly on tumor cells as a pan-Raf inhibitor and suggest its potential for prevention of brain metastatic colonization of HER2(+) breast cancer.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Endothelial Cells; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Indazoles; Mice; Mice, Inbred BALB C; Mice, Nude; Mutation; Proto-Oncogene Proteins B-raf; Pyrimidines; Receptor, ErbB-2; Signal Transduction; Sulfonamides; Xenograft Model Antitumor Assays

Pazopanib is an FDA approved Vascular Endothelial Growth Factor Receptor inhibitor. We previously reported that it also inhibits tumor cell B-Raf activity in an experimental brain metastatic setting. Here, we determine the effects of different B-Raf genotypes on pazopanib efficacy, in terms of primary tumor growth and anti-angiogenesis. A panel of seven human breast cancer and melanoma cell lines harboring different mutations in the Ras-Raf pathway was implanted orthotopically in mice, and tumor growth, ERK1/2, MEK1/2 and AKT activation, and blood vessel density and permeability were analyzed. Pazopanib was significantly inhibitory to xenografts expressing either exon 11 mutations of B-Raf, or HER2 activated wild type B-Raf; no significant inhibition of a xenograft expressing the common V600E B-Raf mutation was observed. Decreased pMEK staining in the responsive tumors confirmed that B-Raf was targeted by pazopanib. Interestingly, pazopanib inhibition of tumor cell B-Raf also correlated with its anti-angiogenic activity, as quantified by vessel density and area. In conclusion, using pazopanib, tumor B-Raf status was identified as a significant determinant of both tumor growth and angiogenesis.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; Indazoles; MAP Kinase Signaling System; Melanoma; Mice; Neovascularization, Pathologic; Proto-Oncogene Proteins B-raf; Pyrimidines; Sulfonamides; Xenograft Model Antitumor Assays