Therapies for breast cancer (BC) should be guided by biological features, such as endocrine or HER2/neu dependence. Pre-clinical and early clinical data suggest synergism between PI3K/Akt and EGFR signaling inhibition in BC. We hypothesize that BC with low PTEN levels or Akt hyperactivation will have a higher response to combined blockade of the EGFR and PI3K/Akt signaling, and the microarray analysis of tumors that respond to the treatment combination will resemble established EGFR and PI3K/Akt/mTOR dependence gene signatures. As a future independent breast cancer translational researcher, with the necessary mentorship from Dr. Arteaga and Dr. Rothenberg and full institutional support beyond the allowable costs of this award, I propose a clinical trial in the metastatic setting, in which the correlative studies would help predict clinical responses, impacting future patient selection and trial design. In this research proposal, we will: (1) Determine the safety profile and efficacy of the mTOR inhibitor everolimus and the EGFR inhibitor erlotinib combination in a phase l/ll clinical trial for patients with metastatic BC;(2) Determine biomarkers of response to the erlotinib/everolimus combination in BC. PTEN, pAkt, pS6, and EGFR (IHC) and PI3K mutations on exons 9 and 20 sequenced in collected paraffin blocks will be correlated with clinical outcome in Aim 1;and (3) Determine if gene expression profiling can identify gene expression signatures that will predict sensitivity to EGFR and mTOR inhibitors. We will identify a signature suggestive of EGFR and mTOR dependence using the clinical outcome on the clinical trial as the supervising parameter, in addition to mining the generated data sets from all collected material to answer if previously established EGFR and PI3K/Akt/mTOR gene signatures will predict response to treatment. We will also correlate IHC results of Aim 2 with the subtypes of breast cancer determined by molecular classification based on their gene expression (luminal A, luminal B, HER2?, and basal-like). Relevance to public: This research will focus on discovery of a """"""""molecular signature"""""""" based on genes and proteins involved in breast cancer's growth and survival, which will help identify groups of breast cancer patients that may benefit from new treatment combinations that target these particular genes and proteins. This research could impact design of future clinical trials, their answers could ultimately reduce breast cancer mortality.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23CA127469-05
Application #
8539284
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lim, Susan E
Project Start
2009-09-24
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$163,944
Indirect Cost
$12,144
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Mayer, Ingrid A; Abramson, Vandana G; Formisano, Luigi et al. (2016) A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. Clin Cancer Res :
Abramson, Vandana G; Mayer, Ingrid A (2014) Molecular Heterogeneity of Triple Negative Breast Cancer. Curr Breast Cancer Rep 6:154-158
Li, Xia; Arlinghaus, Lori R; Ayers, Gregory D et al. (2014) DCE-MRI analysis methods for predicting the response of breast cancer to neoadjuvant chemotherapy: pilot study findings. Magn Reson Med 71:1592-602
Mayer, Ingrid A; Arteaga, Carlos L (2014) PIK3CA activating mutations: a discordant role in early versus advanced hormone-dependent estrogen receptorýýýpositive breast cancer? J Clin Oncol 32:2932-4
Mayer, Ingrid A; Abramson, Vandana G; Isakoff, Steven J et al. (2014) Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 32:1202-9
Mayer, Ingrid (2013) Role of mTOR inhibition in preventing resistance and restoring sensitivity to hormone-targeted and HER2-targeted therapies in breast cancer. Clin Adv Hematol Oncol 11:217-24
Castel, Liana D; Hartmann, Katherine E; Mayer, Ingrid A et al. (2013) Time course of arthralgia among women initiating aromatase inhibitor therapy and a postmenopausal comparison group in a prospective cohort. Cancer 119:2375-82
Iams, Wade; Beckermann, Kathyrn Eby; Neff, Anne T et al. (2013) Thrombotic microangiopathy during docetaxel, trastuzumab, and carboplatin chemotherapy for early-stage HER2+ breast cancer: a case report. Med Oncol 30:568
Rimawi, Mothaffar F; Mayer, Ingrid A; Forero, Andres et al. (2013) Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol 31:1726-31
Geisberg, Carrie A; Abdallah, Wissam M; da Silva, Monica et al. (2013) Circulating neuregulin during the transition from stage A to stage B/C heart failure in a breast cancer cohort. J Card Fail 19:10-5

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