Title:Does Hypoxic Response Mediate Primary Resistance to Sunitinib in Untreated Locally Advanced Breast Cancer?
VOLUME: 17 ISSUE: 1
Author(s):Sofia Braga, Joana Cardoso, Saudade Andre, Margarida Brito, Pedro Sanchez, Lurdes Orvalho, Lucilia Salgado, Sergio Dias, Jose B. Pereira-Leal and Jose Luis Passos-Coelho
Affiliation:Jose de Mello Saude, Lisboa, Portugal.
Keywords:Sunitinib, neoadjuvant therapy, breast cancer, resistance, hypoxia, expression profile.
Abstract:Background: The antiangiogenic drug sunitinib has never been evaluated as single agent
in untreated breast cancer patients.
Objective: We aimed to characterize the activity of sunitinib, alone and with docetaxel, in untreated
locally advanced or operable breast cancer and to uncover the mechanisms of response.
Method: Patients were treated with an upfront window of sunitinib followed by four cycles of sunitinib
plus docetaxel. Response, resistance and toxicity were evaluated according to standard clinical
parameters, magnetic resonance imaging, positron emission tomography, standard pathology characterization,
molecular pathology and gene expression profiling.
Results: Twelve patients were included. We detected primary resistance to sunitinib in the upfront
window in untreated breast cancer, as evidenced by four non-responding patients. At surgery, five patients
had viable tumor in the breast and axilla, four had viable tumor cells in the breast alone and
three were taken off study and thus not evaluated, due to unacceptable toxicity. Early functional imaging
was useful in predicting response. There were no clinical complete responses. Comparison of
tumor gene expression profiling data between early responders and non-responders allowed us to
identify the up-regulation of VEGF and angiogenic pathways in non-responders. Specifically, in tumors
resistant to single-agent sunitinib we detected a transcriptional response to hypoxia characterized
by over-expression of several HIF1α target genes.
Conclusion: In this report of single-agent sunitinib treatment in untreated localized breast cancer patients,
we found evidence of primary resistance to sunitinib, likely mediated by up-regulation of hypoxia
responsive genes.
