Reversing Hormone Resistance in Advanced Breast Cancer With Pazopanib
In this trial, the investigators propose to evaluate the role of VEGFR blockade with the
tyrosine kinase inhibitor pazopanib in combination with nonsteroidal aromatase inhibitors
(NSAI) in patients who are progressing or have relapsed on the same NSAI hormone therapy
given for advanced or early stage breast cancer. If this trial demonstrates clinical
benefit, this all oral combination could be tested in both the neoadjuvant and metastatic
settings in a randomized phase II design.
In order to investigate potential factors predicting response or resistance to pazopanib and
NSAIs, several translational studies have been incorporated into this trial.
The prognostic value of circulating tumor cells (CTC) has been demonstrated in several
studies in breast cancer, especially in advanced stage [35-38]. At UCSF in the laboratory of
Dr. John Park, the investigators have demonstrated expertise in the measurement of CTC in
patients with advanced stage breast cancer by IC/FC assay. CTC are first enriched with
immunomagnetic beads coated with EpCAM, then EpCAM+, CD45-, nucleic acid+ cells are detected
by flow cytometry. This technique is highly sensitive and reproducable, and allows sorting
of cells for molecular analysis as well as analysis of cell surface markers. In this
trial, the investigators will collect patient's peripheral blood samples every 4 weeks while
on treatment and follow any reduction of CTC.
The mechanisms of hormonal resistance includes intrinsic and acquired pathways: decreased ER
expression accounts for intrinsic resistance and the increased receptor tyrosine kinase
pathway relates to acquired resistance [40-42]. The investigators plan to analyze the
mutation of PI3K/Akt and deletion of PTEN by sequencing in CTC (depending on numbers of
cells, which in turn determines feasibility), in order to make a preliminary assessment of
potential markers of response to pazopanib.
The tumor microenvironment plays an important role in cancer development and progression.
Clinical studies have revealed that the increased T regulatory cells (Treg), high ratios of
CD4/CD8 T lymphocytes, and extra follicular B cells in primary tumors correlated with worse
overall survival [43-45]. Recently, studies from preclinical models have shown that tumor
associated macrophages (TAM) can promote pulmonary metastases in breast cancer animal
models, and in both the preclinical and clinical settings are associated with worse clinical
outcome [46-48]. TGFβ has been linked to hormonal resistance in breast cancer. The
activation of TGFβ leads to increased regulatory CD4+ T cells and decreased cytotoxic CD8+
T cells in the tumor microenvironment . A recent study in non-small cell lung cancer
suggests that baseline and post-treatment levels of cytokines, particularly IL-4 and IL-12
correlated with response to pazopanib. In this study, the investigators will collect
patient's serum to monitor the level of cytokines at baseline and during treatment, the
investigators will compare the change of cytokine level with pazopanib in each patient, and
also compare between responders and non-responders. This information may help us to identify
biomarkers that would predict response to antiangiogenic therapy and to identify possible
mechanisms of resistance.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Clinical benefit rate
The clinical benefit rate from the addition of pazopanib to a non-steroidal aromatase inhibitor (NSAI) (letrozole or anastrozole) in patients with hormone receptor positive advanced breast cancer progressing on the same NSAI hormone therapy.
Ongoing evaluation at 12 week intervals until progression or up to 2 years, whichever is first.
Hope Rugo, M.D.
University of California, San Francisco
United States: Food and Drug Administration
|UCSF Helen Diller Family Comprehensive Cancer Center||San Francisco, California 94115|
|Yale University School of Medicine/Yale Cancer Center||New Haven, Connecticut 06520|