The 8p11.2 Amplicon Is Associated with Hormonal Treatment Resistance and a Worse Clinical Outcome: Validation by FISH, aCGH and Gene Expression Profiling.
Alejandro A Gru, Andrea L Salavaggione, Jacqueline Snyder, Yu Tao, Jeremy Hoog, Matthew J Ellis, Craig Allred. Washington University School of Medicine, St. Louis, MO
Background: The 8p11.2 region has been show to be amplified in a significant proportion of breast cancers (10-20%). Specific genes contained within the amplicon, including FGFR1, are important in breast development, cell cycle proliferation, and modulation of hormone receptors. The purpose of this study was to evaluate the relationship between the amplicon and its clinical significance expanding our previous results in a large patient population using novel molecular techinques.
Design: We analyze the status of the 8p11.2 region using Fluorescent in-situ hybridization (FISH) in three separate patient groups of the SPECS (n=139), P024 (n=173) and POL (n=84) clinical trials. The P024 and POL included patients treated with neoadjuvant letrozole and tamoxifen in clinical stage II or III hormone receptor positive breast cancers that were ineligible for surgery. Amplification was validated with the use of gene expression microarray (SPECS), and array (aCGH) comparative genome hybridization (POL). Standard clinical-pathological features (age, race, tumor type, grade, size, nodal status, ER, PgR, HER2, Ki-67, PIK3CA mutation) were obtained. The PEPI (preoperative endocrine prognostic index), breast cancer specific survival (BCSS) and relapse free survival (RFS) were obtained from previously published data. SPSS V13.0 software was used to evaluate the significance of relationships between gene copy number and the other variables (student t-test, Fisher and Chi-square tests, Kaplan-Meir curves, and Cox-Wilson regression).
Results: The 8p11.2 region was amplified in 13.8% (55/396) of patients in the SPECS, P024 and POL trials. Polysomy for the chromosome 8 was seen in up to 20% of cases. Increased gene expression correlated with amplification and polysomy by FISH and aCGH (2.18 vs 1.5, p≤0.05). The overall sensitivity and specificity of the FISH assay was 83 and 97%. Tumors with amplification had a higher Ki-67 proliferation index (10.3 vs 5.6, p=0.016), a higher prevalence of ERBB2 amplification (23% vs 5%, p=0.001) and PEPI score (3 vs 3.5, p=0.005), implicating resistance to hormonal treatment. The amplification was also associated with a lower RFS (14 vs 68 months, p=0.028) and BCSS (19 vs 82 months, p=0.052).
Conclusions: 8p11.2 region is frequenctly amplified in breast cancers. Amplification is strongly associated with a specific gene signature with a worse clinical outcome and hormonal refractoriness.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 18, Monday Morning