Abstract PD07-08: Integrated Genomic Analysis before and after Brief Exposure to Trastuzumab (T): The11q13 and 17q12 Amplicons Are Associated with Response to T+Chemotherapy in Early Stage HER2 Positive Breast Cancer

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Abstract Background: The receptor tyrosine kinase HER2 is overexpressed in 18-20% of breast cancers and is the target of the highly effective therapy, trastuzumab. Coamplicons are frequent in HER2 amplified tumors, yet their role in response to T is not defined. To identify amplicons which might predict response to T in patients we performed gene expression and copy number analysis in tumor tissue from a preoperative trial with brief exposure to T, followed by T+C. Methods: Fresh tumor core biopsies were taken before at a 2 week timepoint after a single dose of T (8mg/m2) from 80 HER2-overpressing, early breast cancer patients enrolled on a clinical trial of T>T+C. Nucleic acids were extracted using Qiagen AllPrep and were analyzed with Illumina Ref8 and Illumina QUAD 610 SNP arrays. Eight commonly amplified regions (11q13, 14q32, 17q12, 20q13, 21q22, 8p22, 8q24) were identified by FISH probe coordinates and copy number calculated using the GPHMM algorithm. Amplification was defined as 4 or more copies of the amplicon. Gene expression was analyzed in Bioconductor using LIMMA analysis. Genomic biomarkers were compared pathologic complete response (pCR) vs objective response (CR+PR) and non-response (SD+PD) by RECIST criteria at the surgical timepoint. Results: There were 50 tumor pairs with adequate RNA for gene expression and 40 baseline tumors for copy number analysis with 28 paired samples. In the 40 baseline biopsies, the 11q13 amplicon was present in 14/40 (35%) of tumors but never seen in tumors with a pCR (t-test; p=0.004975). Of note, in the tumors with amplification of 11q13 there was no evidence of change in copy number after exposure to T, however numbers were small (7 pairs). Gene expression of the 11q13 region showed no significant change in common amplicon genes after one dose of T. The 17q12 amplicon, which harbors the HER2 locus, was amplified in 35/40 (87.5%) of cases - copy number was not associated with response, however, HER2 and GRB7 gene expression levels significantly declined in pCR tumors compared with Conclusions: Integrated genomic analysis after brief exposure to T may provide useful predictors for response to T+C in early stage, HER2 positive breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD07-08.

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