Estrogen-independent cell proliferation occurs in the majority of estrogen receptor positive (ER+)/HER2 gene-amplified primary breast cancers: Evidence from a combined analysis of two independent neoadjuvant letrozole studies

Abstract

9538 Background: Relationships between HER2 status and the efficacy of aromatase inhibitor (AI) therapy for early stage breast cancer require further study. The LET 024 neoadjuvant trial reported that ER+ and HER1+ and/or HER2+ positive (immunohistochemistry - IHC) primary tumors were more responsive to letrozole (LET) than tamoxifen. To further investigate the impact of HER2 status on the efficacy of endocrine treatment, HER2 gene amplification status was determined on 198 LET 024 trial samples, supplemented with 128 tumor samples from Edinburgh. Methods: Samples were screened by HER2 IHC, with FISH on tumors with 2+ or 3+ staining. Sample 1+ and 0+ tumors were never HER2 AMP+. Clinical and Ki67 biomarker outcomes were compared in HER2 AMP+ tumors versus HER2 AMP- tumors. All tumors were ER by central IHC testing. Results: There were too few AMP+ cases in the LET 024 trial for adequate analysis. To overcome the problem of small sample size the LET arm of the LET 024 trial and the Edinburgh LET experience were pooled. 20 LET treated HER2 AMP+ tumors exhibited a 65% clinical RR versus 70% for HER2 AMP- tumors. Mammogram data and ultrasound measurements supported the conclusion that the RR to LET was not impaired by HER2 AMP+. In contrast, LET-induced Ki67 decreases were significantly less in the HER2 AMP+ versus AMP- tumors (M-W P=0.0001) and Ki67 fell to ≤1% in only 13% of the LET-treated HER2 AMP+ tumors versus 60% of the LET-treated HER2 AMP- tumors (Fisher P=0.0001). Conclusions: Tumor regression with neoadjuvant LET was unaffected by HER2 AMP+ status. In contrast suppression of Ki67 after 3 to 4 months of treatment was greatly impeded in HER2 AMP+ tumors versus HER2 AMP- tumors. These data suggest that cell cycle regulation is partially or completely estrogen-independent in the majority of HER2 AMP+ primary tumors which may portend the development of long-term resistance to adjuvant aromatase inhibitor therapy in this patient cohort. Furthermore Ki67 analysis may prove to be an effective tool to identify other genetic events that promote estrogen independent growth and endocrine therapy resistance. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis