The treatment for hormone receptor-positive breast cancer includes therapies designed to block estrogenaction. Although these therapies have changed the natural history of hormone-dependent breast cancer,many tumors exhibit ofe novo or acquired endocrine resistance. Studies with human breast cancer cell linesas well as molecular profiling of primary mammary tumors have identified molecular alterations associatedwith hormonal independence and drug resistance. One of these mechanisms is overexpression of the HER2(ErbB2) protooncogene and its signaling network. Overexpression of HER2 is the only mechanism ofantiestrogen resistance for which prospective clinical data exist. However, only <10% of hormone-dependentbreast cancer express high levels of HER2, suggesting that for the majority of hormone-receptor positivebreast cancers, mechanisms of escape from endocrine therapy remain to be discovered. In addition to thesubstantial improvements of antiestrogen therapy, assays have been developed to predict the odds ofbenefit from it. These assays do not identify the molecular alteration causally associated with treatmentfailure and tumor recurrence. More recently, cancer cell proliferation as measured by Ki67immunohistochemistry in the tumor specimen after neoadjuvant hormonal therapy has been shown tocorrelate with disease-free and overall survival. These data suggest that pharmacodynamic biomarkers ofthe cellular and molecular effects of endocrine therapy in the breast tumor, likely because they incorporatethe effects of therapy, can be used to identify cancers that are highly hormone-dependent and thus sensitiveto endocrine treatment vs. those that are cfe novo resistant and/or destined to recur faster. We hypothesizethat those tumors exhibiting a marked inhibition of cell proliferation are likely to do well on adjuvant hormonaltherapy alone whereas those that do not, are destined to an early recurrence. To 1) determine if inhibition ofHER2 function reverses resistance to endocrine therapy, and 2) discover novel mechanisms associated withresistance to endocrine therapy in hormone receptor-positive tumors without HER2 overexpression, wepropose the following aims:
Aim 1 : To determine if combined neoadjuvant therapy with the aromatase inhibitor letrozole and the HER2tyrosine kinase inhibitor lapatinib induces pathologic complete responses in hormone receptor-positivebreast cancers that overexpress HER2 and establish biomarkers predictive of response to this therapy.
Aim 2 : To determine if the post-letrozole Ki67 in hormone receptor-positive/HER2-negative tumors mirrorsthe recurrence score as measured by RT-PCR of 21 selected genes in formalin-fixed tumor tissue sectionsand to use these biomarkers to discover gene expression signatures associated with hormonal dependence.
Aim 3 : To determine the mechanisms by which loss of PTEN in hormone receptor-positive breast cancercells dysregulates phosphatidylinositol-3 kinase (PI3K) signaling and generates resistance to antiestrogens.
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