Successful personalized care of breast cancer patients is critically dependent on accurately applying predictive markers of treatment response. The specific objective of this proposal is to identify reliable biomarkers, derived from proteins, DNA aberrations, and gene expression patterns, in paraffin-embedded primary breast tumors that predict response to adjuvant trastuzumab (an antibody directed against HER2). These patients were enrolled in the landmark NCCTG-sponsored adjuvant N9831intergroup trial (EA Perez-PI) that led to dramatic changes in the clinical care of HER2-positive breast cancer patients. Our overall hypothesis is that tissue markers associated with EGF-family signaling pathways will predict those patients more likely to respond to adjuvant trastuzumab.
Our specific aims i nclude three translational studies: 1) To determine the tissue expression of select proteins involved in the mechanisms of trastuzumab activity and resistance using conventional immunohistochemistry and Automated Quantitative Analysis (AQUA);2) To determine DNA aberrations of specific genes that have been suggested to be associated with trastuzumab response using fluorescence in situ hybridization;and 3) To identify gene expression patterns predictive of trastuzumab benefit using DASL, a gene expression profiling system specifically designed for paraffin tissue. Our multidisciplinary team has the experience to accomplish these important translational protein- and gene-based studies within the proposed timeline. We have collected all relevant specimens to conduct this investigation as well as the clinical follow-up data related to disease free and overall survival. Results from these correlative studies using the well-defined N9831 patient population will provide a better understanding of individual variation of benefit to adjuvant trastuzumab and will identify opportunities for therapeutic intervention for patients at increased risk of recurrence. As this is achieved, it will be possible to more effectively tailor therapy with the greatest efficiency and fewest side effects. Positive results from these proposed correlative studies will also allow us to design further phase II and III clinical trials addressing our overall goal of individualized therapy for patients with breast cancer.

Public Health Relevance

Biomarker identification and validation studies are necessary to successfully achieve personalized medicine. This is critically important in the adjuvant management of patients with resected HER2-positive breast cancer as trastuzumab treatment significantly increases disease free and overall survival, but is associated with potential toxicities. Our study proposes biomarker tissue correlative studies to help identify those patients most likely to benefit from this treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Biomarkers Study Section (CBSS)
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Song, Min-Kyung H
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Mayo Clinic Jacksonville
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Perez, Edith A; Ballman, Karla V; Mashadi-Hossein, Afshin et al. (2017) Intrinsic Subtype and Therapeutic Response Among HER2-Positive Breaty st Tumors from the NCCTG (Alliance) N9831 Trial. J Natl Cancer Inst 109:
Reinholz, Monica M; Chen, Beiyun; Dueck, Amylou C et al. (2017) IGF1R Protein Expression Is Not Associated with Differential Benefit to Concurrent Trastuzumab in Early-Stage HER2+ Breast Cancer from the North Central Cancer Treatment Group (Alliance) Adjuvant Trastuzumab Trial N9831. Clin Cancer Res 23:4203-4211
Perez, Edith A; Ballman, Karla V; Tenner, Kathy S et al. (2016) Association of Stromal Tumor-Infiltrating Lymphocytes With Recurrence-Free Survival in the N9831 Adjuvant Trial in Patients With Early-Stage HER2-Positive Breast Cancer. JAMA Oncol 2:56-64
Perez, Edith A; Thompson, E Aubrey; Ballman, Karla V et al. (2015) Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial. J Clin Oncol 33:701-8
Perez, Edith A; Baehner, Frederick L; Butler, Steven M et al. (2015) The relationship between quantitative human epidermal growth factor receptor 2 gene expression by the 21-gene reverse transcriptase polymerase chain reaction assay and adjuvant trastuzumab benefit in Alliance N9831. Breast Cancer Res 17:133
Perez, Edith A; Romond, Edward H; Suman, Vera J et al. (2014) Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 32:3744-52
Dueck, Amylou C; Reinholz, Monica M; Geiger, Xochiquetzal J et al. (2013) Impact of c-MYC protein expression on outcome of patients with early-stage HER2+ breast cancer treated with adjuvant trastuzumab NCCTG (alliance) N9831. Clin Cancer Res 19:5798-807
Kalari, Krishna R; Necela, Brian M; Tang, Xiaojia et al. (2013) An integrated model of the transcriptome of HER2-positive breast cancer. PLoS One 8:e79298
Mahoney, Douglas W; Therneau, Terry M; Anderson, S Keith et al. (2013) Quality assessment metrics for whole genome gene expression profiling of paraffin embedded samples. BMC Res Notes 6:33
Perez, Edith A; Dueck, Amylou C; McCullough, Ann E et al. (2013) Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial. J Clin Oncol 31:2115-22

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