Abstract
Abstract Abstract #58 Background: Identification of molecular predictors of response is an important aspect of individualized cancer treatment. Responses to lapatinib (L), an oral inhibitor of HER2 and EGFR, approved in combination with capecitabine for HER2+ metastatic breast cancer (MBC), were evaluated in a panel of BC cell lines. Computational approaches were used to identify transcripts that quantitatively associate with response to L in the cell line panel that were then tested in 2 clinical trials.
 Methods: The clinical utility of a 6-gene predictor was tested retrospectively using a branched-chain DNA assay in paraffin-embedded archival tumor tissue from patients (pts) with HER2 negative or untested MBC tumors enrolled in a phase III trial of paclitaxel (P) vs. P+L, and from pts with HER2 positive MBC enrolled in a L monotherapy trial. Expression of HER2 transcript using the branched-chain assay was compared with HER2 fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) status; discordant cases were analyzed. Response patterns for pts with HER2+ tumors and a computational model that predicts L sensitivity or resistance is described.
 Results: Ingenuity analysis of the mRNA predictors of response to L identified in the BC cell line panel revealed saturated gene networks with HER2 as a major node. The 6-gene predictor of response was comprised of 2 genes associated with sensitivity to L: HER2 and GRB7; 4 genes associated with resistance to L: CRK, ACOT9, FLJ31079, and DDX5. Expression results for the 6 genes and progression-free survival (PFS) data were available for 159 pts on L+P. Median PFS in the branched-chain HER2+ group was 32.9 wks vs. 22.4 wks in the HER2-negative group. The 6-gene predictor was used to predict response to L in the HER2+ pts. Comparison of PFS in the 24 “L sensitive” tumors vs. 25 “L resistant” tumors indicated that the predictor, derived from cell-line analyses, had the potential to predict clinical response to L in pts treated with L+P (HR=0.58; 95% CI=0.30-1.11; p=0.07). The 6-gene predictor was further tested in an independent L monotherapy study in pts with HER2 FISH+ MBC. Comparison of PFS in the 24 “L sensitive” tumors vs. 28 “ L resistant” tumors reconfirmed the potential of the 6-gene predictor to enrich for HER2+ pts most likely to experience clinical benefit from L (HR=0.40; 95% CI=0.19-0.84; p=0.015). Further testing is ongoing.
 Conclusions: This study suggests that molecular predictors of clinical response can be developed through an analysis of response from a collection of 50 BC cell lines. The identification of a L specific 6-gene assay is promising as a clinical predictor of benefit from L in pts with HER2+ BC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 58.
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