Abstract No. 
2017 San Antonio Breast Cancer Symposium
December 5-9

Analysis of biomarkers for response and resistance to the AKT inhibitor MK-2206 in the neoadjuvant I-SPY 2 trial for stage II-III high-risk breast cancer

Wolf D, Yau C, Brown-Swigart L, Hirst G, Schmidt E, Townson S, Cristescu R, Investigators I-SPY2TRIAL, Asare S, Berry D, Esserman L, van'tVeer L, Tripathy D, Chien, J,

Background: The AKT inhibitor MK2206 (M) was one of the experimental agents evaluated in I-SPY 2, and graduated in the HER2+, HR-, and HR-HER2+ signatures. In I-SPY 2, all patients received at least standard chemotherapy (paclitaxel followed by doxorubicin/cyclophosphamide; T->AC). HER2- patients were randomized to receive M+T- >AC vs. T->AC. For HER2+ patients, M was administered in combination with trastuzumab (M+H+T->AC vs. H+T->AC). We hypothesize that genes in the AKT signaling axis may specifically predict response to M and tested expression levels of 10 genes: AKT1, EGFR, ERBB2, ERBB3, NRG1, IGF1R, PIK3CA, PTEN, STMN1, and MTOR. We also evaluated 9 additional genes previously shown to associate with response to M in vitro and through exploratory analyses in the metastatic setting: STARD3, TM7SF2, ALDH4A1, PRODH, SELENBP1, G3BP1, SMCR7L, TCTEXD2, and PHEX. 

Methods: Data from 150 patients (M: 94 and concurrent controls: 56) were available. Pre-treatment biopsies were assayed using Agilent 44K (32627; n=119) or 32K (15746; n=31) expression arrays; and these data were combined into a single gene-level dataset after batch-adjusting using ComBat. All I-SPY 2 qualifying biomarker analyses follow a pre-specified analysis plan. We used logistic modeling to assess biomarker performance. A biomarker is considered a specific predictor of M response if it associates with response in the M arm but not the control arm, and if the biomarker x treatment interaction is significant (likelihood ratio test, p<0.05). This analysis is also performed adjusting for HR and HER2 status as covariates, and within receptor subsets, sample size permitting. Our statistics are descriptive rather than inferential and do not adjust for multiplicities of other biomarkers outside this study. 

Results: Consistent with M graduation in the HER2+ signature, two candidate biomarkers on the HER2 amplicon (ERBB2, STARD3) associate with pCR in the M arm, but not in the control arm. In addition, G3BP1, a component of the RAS signaling pathway, associates with non-pCR in the M arm. However, biomarker x treatment interactions for these genes are not significant, and all three associations to response in M lose significance in a model adjusting for HR and HER2 status. Within the HER2+ subset, IGF1R is associated with non-pCR in M. Within the TN subset, higher levels of NRG1 and PIK3CA, upstream activators of AKT, associate with pCR in the M arm. 

Conclusion: Following our pre-specified analysis, none of the candidate markers tested succeed as specific predictors of response to MK2206 in I-SPY 2. However, several genes in the AKT pathway associate with response to M, and in particular PIK3CA levels within the TN subset may merit further evaluation in future trials. 

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