Effects of chromosomes 1, 3, 10 and 17 alterations on patient response to trastuzumab in metastatic breast cancer.

554 Background: Amplification of Her-2 (ERBB2) in breast cancer is linked to response to trastuzumab. However, response rates are only 20-40%, with amplified ERBB2, and more specific tumor profiling is needed. The region of chromosome 17 surrounding the ERBB2 locus is rich in genes with potential cancer relevance and their variable inclusion within the ERBB2 amplicon may profoundly affect response. The genomic status of components of the growth factor signaling pathway may also affect response.,We used fluorescence in situ hybridization (FISH) to correlate genomic status of TOP2A, PTGS2, PIK3CA, AKT3, PTEN, 1q25 and the centromeres (cen) of chromosomes 3, 10, and 17 with response in metastatic ERBB2-amplified breast cancer treated with trastuzumab (alone or with non-anthracycline drugs). Average probe signals per cell, or ratios of probe signals were used to classify specimens as gained (>3 signals) or deleted (<1.5 signals), amplified (ratio>2) or not amplified (ratio<2), for respective loci. Contingency analysis was used to categorize response relative to genomic status, and p-values were calculated using Fisher's exact test (2-sided; <0.05 considered significant).,Of the 35 patients with interpretable responses and FISH, 40% (14) had response (complete or partial) to therapy and 60% (21) were not responsive (stable or progressive disease). TOP2A amplification and normal copy number of PTGS2, 1q25, and cen 10 each adversely affected response. Most significant were classifications based on TOP2A [7.1% (1/14) response when amplified, 62% (13/21) when not amplified; p=0.0015], and 1q25 [14% (2/14) response when normal, 60% (12/20; p=0.013) when deleted or gained]. Targeting improved further when TOP2A and 1q25 status were combined [15% (3/20) response for amplified TOP2A and normal 1q25; 79% (11/14) for other; p=0.0003].,Measuring the genomic status of TOP2A and/or 1q25 may allow discrimination of patients very likely to respond to trastuzumab, versus those very unlikely to respond. A 4-color FISH assay containing ERBB2, cen 17, TOP2A, and 1q25 probes may improve considerably the ability to predict patients responsive to trastuzumab. [Table: see text].