Correlation Of Her2 Gene Amplification, Her2 And Egfr Expression (Protein And Mrna) With Lapatinib Efficacy In Women With Metastatic Breast Cancer

1007 Background: Lapatinib (L), an oral small molecule tyrosine kinase inhibitor of EGFR and HER2, is approved in combination with capecitabine for the treatment of women with HER2+ metastatic breast cancer (MBC). The optimal method to select patients (pts) for L therapy has not been determined. To address this issue, selected biomarkers were analyzed in pts from two randomized phase III MBC trials. Methods: In available BC tissue from EGF30001 pts (paclitaxel ± L in HER2-negative/unknown MBC, N=579) and EGF100151 pts (capecitabine ± L in HER2+ MBC, N=399), HER2 gene amplification was evaluated by fluorescence in situ hybridization (FISH), HER2 messenger RNA (mRNA) by reverse transcriptase-polymerase chain reaction (RT-PCR), protein expression by HercepTest immunohistochemistry (IHC), EGFR mRNA level by RT-PCR, and EGFR protein by IHC. HER2 and EGFR status was compared with clinical outcome across treatment arms to assess potential marker associations. Results: HER2 was amplified in 47% (345/733) and had IHC3+ immunostaining in 30.6% (224/730), with a significant correlation between HER2 gene and protein status (p<0.01). EGFR immunostaining (IHC 1+, 2+ or 3+) was identified in 27.9% (214/767). Any EGFR IHC correlated with EGFR mRNA levels determined by RT- PCR (R=0.59, p<0.01). HER2 gene amplification/overexpression, but not EGFR expression, was associated with significantly improved time-to-progression, objective response rate, and clinical benefit in separate and pooled analyses of both trials. No similar improvement in outcome was seen in pts with FISH-negative and IHC 1+ or 2+ tumors. mRNA expression for HER2 as performed here does not add value beyond FISH or IHC evaluation, although the mRNA sample set was small (N=138). There was no correlation between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER2 status. Conclusions: Benefit from L in women with HER2+ MBC appears to be limited to patients with positive FISH or IHC3+ intensity. Evaluation of HER2 by mRNA analysis did not improve patient selection in these studies. EGFR determination did not contribute to improved pt selection. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Roche GlaxoSmithKline Genentech, Inc., GlaxoSmithKline, Roche Genentech, Inc., GlaxoSmithKline