The major subgroups of breast cancer, based on combined expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), have important implications in breast cancer etiology, systemic therapies prescribed, effectiveness of such therapies, and both recurrence and survival outcomes. The HER2-positive subtype comprises 15-25% of all invasive breast cancers, and is a highly aggressive subtype. Prior to targeted therapy, HER2+ tumors portended some of the worst prognoses. The development of trastuzumab (Herceptin(r)) has resulted in marked improvement in outcomes for women with HER2+ breast cancers. HERA, a randomized three-arm multi-centre comparison of 1 year and 2 years of trastuzumab versus no trastuzumab in women with HER2+ primary breast cancer that have completed adjuvant chemotherapy, demonstrated a significant improvement in disease-free survival among women with HER2-positive breast cancer who received 2 years of trastuzumab. TransHERA, a supplement to HERA, aims to collect, store and analyze breast cancer tissue and serum from all patients in the HERA trial. Overall, TransHERA aims to allow identification of protein, genetic and molecular factors that might lead to new targets for the treatment of breast cancer or to a better understanding of the molecular characteristics that are associated with the differential likelihood of response to trastuzumab therapy. Our objective is to identify gene signature(s) through molecular profiling that will allow for the selection of patients most likely to derive benefit from HER2-directed therapies. To meet these goals we plan the following:
Specific Aim 1 : To conduct expression profiling of FFPE specimens from the HERA phase III clinical trial on the cDNA-mediated Annealing, Selection, extension and Ligation (DASL) platform in order to identify biomarkers prognostic of outcome and predictive of response to trastuzumab in HER2+early breast cancer patients. DASL analysis will be performed on RNA prepared from ~1,000 FFPE samples from the HERA clinical trial. A variation of supervised principal component analysis will be used for identifying differential treatment effect and developing a predictive model. A signature set of genes will be selected based upon their ability to prognosticate outcome (overall or within a treatment arm) and predict improved outcome with trastuzumab using DFS as the primary endpoint and overall survival (OS) as the secondary endpoint. Potential biomarkers will be validated by qRT-PCR. Predictive biomarkers will be prospectively validated in a subsequent study.
The HER2-positive subtype comprises 15-25% of all invasive breast cancers, and is a highly aggressive tumor with a poor prognosis. The development of trastuzumab (Herceptin(r)) has resulted in improvements of survival for most women with HER2+ breast cancers;however;a percentage of women still receive no appreciable benefit. We hypothesize that variations in specific characteristics of cancer-related genes could predict responsiveness to breast cancer therapy;therefore, we will investigate tumor features that may contribute to inter-individual variability of response to treatment.
