Abstract P6-04-10: Comprehensive gene and protein assessment of the role of Her2 in the response to neoadjuvant Letrozole suggests patients without amplification may also benefit from anti-Her2 treatment

Abstract Background: Older postmenopausal patients with large operable or locally advanced oestrogen receptor positive, invasive breast cancers are candidates for treatment with neoadjuvant letrozole. HER2 positivity is a potential marker for early endocrine therapy resistance. In this study we have evaluated the effects of HER2 amplification, gene and protein expression at diagnosis and following 14 and 90 days of treatment with neoadjuvant Letrozole. Methods: 70 postmenopausal women with large operable and locally advanced oestrogen receptor (ER) positive invasive breast cancers were treated with neoadjuvant letrozole. Response was assessed by 3D ultrasound. Sequential core biopsies were taken at 0, 14 days and 3 months of treatment. 12 patients were HER2 positive (either 3+ or 2+ FISH positive), 20 were HER2 2+ FISH negative and 38 were HER2 negative (0 or +). Results: 43 patients were responders to letrozole and 17 were non-responders. 7 of the 17 non-responders were HER2 positive. Analysing response in two groups (HER2 2+ and 3+ together versus 0 or +) there was a greater difference in response rate between these two groups than when splitting into conventional HER2 positive and negative groups (P < 0.0001). In non-responding patients HER2 gene expression levels from the microarrays taken at baseline were significantly higher than the HER2 expression in responding patients (p = 0.01). There was also an increase in HER2 gene expression seen during the first 14 days of treatment in non-responding but not responding patients (p = 0.08). Rank product analysis of gene expression identified 34 down-regulated genes and 7 up-regulated genes which were shared between the HER2 2+ FISH negative samples and samples which were HER2 3+ or HER2 2+ FISH positive. Conclusion: This large cohort of patients treated with neoadjuvant letrozole shows that: HER2 expression correlates with response to letrozole. A better cut off for prediction of response to letrozole is the split between 0 and + versus 2+ and 3+ rather than the traditional 3+. Patients with increased MRNA expression at diagnosis for HER2 have a significantly lower response rate to neoadjuvant letrozole. Endocrine therapy together with anti-HER2 therapies should be considered for patients having neoadjuvant endocrine therapy for cancers which over express HER2. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-10.