Project 1: Resistance to Antiestrogen Therapy in Hormone Receptor-Positive Breast Cancer
The standard treatment for hormone receptor-positive breast cancer includes therapies designed to block estrogen action such as tamoxifen and aromatase inhibitors. Although these therapies have changed the natural history of hormone-dependent breast cancer, many tumors exhibit de novo or acquired endocrine resistance. Studies with human breast cancer cell lines as well as molecular profiling of primary mammary tumors have identified several molecular alterations associated with hormonal independence and drug resistance. One of these mechanisms is overexpression of the HER2 (ErbB2) protooncogene and its signaling network. Overexpression of HER2 is arguably the only mechanism of antiestrogen resistance for which clinical data exist. However, only ≤10% of hormone-dependent breast cancer express high levels of HER2, suggesting that for the majority of estrogen receptor-positive breast cancers, mechanisms of escape from endocrine therapy remain to be discovered. In addition to the substantial improvements of antiestrogen therapy, assays have been developed to predict the odds of benefit from it. These assays, however, do not identify the molecular alteration or pathway causally associated with treatment failure and tumor recurrence. More recently, cancer cell proliferation as measured by Ki67 immunohistochemistry in the tumor specimen after neoadjuvant hormonal therapy has been shown to correlate with disease-free and overall survival. These data suggest that pharmacodynamic biomarkers of the cellular and molecular effects of endocrine therapy in the tumor, likely because they incorporate the effects of therapy, can be used to identify breast cancers that are highly hormone-dependent and thus sensitive to endocrine treatment vs. those that are de novo resistant and/or destined to recur earlier. We hypothesize that those tumors exhibiting a marked inhibition of cell proliferation are likely to do well on adjuvant hormonal therapy alone whereas those that do not, are destined to an earlier recurrence. Therefore, to determine if therapeutic inhibition of HER2 reverses resistance to endocrine therapy, discover novel mechanisms potentially associated with resistance to endocrine therapy, and identify molecular therapeutics that can reverse this resistance, we propose the following specific aims:
Aim 1: To determine if combined neoadjuvant therapy with the aromatase inhibitor letrozole and the HER2 tyrosine kinase inhibitor lapatinib induces pathologic complete responses (CRs) in hormone receptor-positive/HER2+ breast cancers and establish biomarkers predictive of response to this therapy. The induction of pathologic CRs would have important clinical implications as it will identify patients in which combined adjuvant antiestrogen and anti-HER2 therapy has a high likelihood of success in the absence of chemotherapy.
Aim 2: To determine if the post-letrozole Ki67 in ER+/HER2-negative tumors mirrors the recurrence score as measured by RT-PCR of 21 selected genes in formalin-fixed tumor sections and to use these biomarkers to discover gene expression signatures associated with response or resistance to estrogen deprivation. Identification of targetable molecules or pathways with a causal association with resistance to endocrine therapy in this exploratory aim can be followed with appropriate mechanism-based exploratory clinical trials.
Aim 3: To determine the mechanisms by which loss of PTEN in hormone receptor-positive breast cancer cells results in activation of phosphatidylinositol-3 kinase (PI3K), hormone independence, and resistance to antiestrogen therapy. Identification of mechanisms of PI3K activation in PTEN-deficient breast cancer cells should direct attention to testable pathway inhibitors and molecular therapeutics with preferential activity against this type of breast cancers.