AKT/mTOR/HER/PI3K family genes as predictors of pCR for early stage breast cancer patients treated with the AKT inhibitor MK2206 in the I-SPY 2 TRIAL (NCT01042379)

The AKT inhibitor MK2206 (M) was one of the experimental agents evaluated in I-SPY 2, a neoadjuvant platform trial for high risk, early stage breast cancer, and graduated in the HER2+, HR-, and HR-HER2+ signatures. Based on the hypotheses that since MK2206 is an enzymatic inhibitor of AKT, response to MK2206 may be predicted by the relative pre-treatment levels of AKT kinase substrates, in pre-defined analyses we assessed 10 genes in the HER-AKT-mTOR pathway to test their association with pCR (complete pathologic response) in the MK2206 arm, in both HER2+ and HER2- subsets. We also tested 9 genes genes previously associated with response to MK2206 in vitro and in the HER2+ metastatic setting, and performed exploratory association analyses using whole-transcriptome data to identify additional predictive signals outside the HER-AKT-mTOR pathway. Fresh-frozen pre-treatment breast cancer tumors (n=150) from the neoadjuvant ISPY2 trial for high risk, early stage breast cancer were assayed using Agilent GPL16233 (n=31) or GPL20078 (n=119) expression arrays; and these data were combined into a single gene-level dataset after batch-adjusting using ComBat. For fully normalized and batch corrected data on the gene level (as used in the publication), please use "GSE149322_ExpDat_ISPY2_MK2206_n150.txt.gz" as provided in the supplementary files. The sample characteristics and their values represent: HER2: the status of the HER2 gene. 1 = positive; 0 = negative. HR: the status of hormone (estrogen and progesterone) receptors 1 = positive; 0 = negative. pCR: the status of a pathological complete response (pCR) 1 = complete response; 0 = failed complete response Arm: arm of the trial per patient - MK2206 arm' or 'Control arm'. Originally, a ComBat batch correction process was applied to the raw data on a larger group of patients (~900), which we cannot release. Linear adjustment factors from this group were derived so they can be applied to this smaller group of 150 patients. The ISPY2_LinearFit_forCombiningExp* files contain linear adjustments to go from raw to batch corrected data.