Abstract PD7-07: Neoadjuvant endocrine therapy helps identify HER2 up-regulation in patients with hormone receptor-positive HER2-negative breast cancer
Authors: Chaudhary Lubna N , Jorns Julie M , Cheng Yee Chung , Kamaraju Sailaja , Gonyo Mary Beth , Kong Amanda , Patten Caitlin , Yen Tina , Cortina Chandler , Carson Ebony , Johnson Nedra , Bergom Carmen , Banerjee Anjishnu , Wang Yu , Chitambar Christopher R , Rui Hallgeir 
Published: February 2021

Abstract
Background: Endocrine therapy provides significant improvement in the long-term outcomes of patients with hormone receptor-positive (HR+) breast cancer (BC). However, metastatic recurrences of endocrine resistant disease develop in about 20-25% of patients and remain a major cause of BC mortality. Up-regulation of the HER2 growth factor receptor represents a common escape strategy used by cancer cells to survive and continue to proliferate in an ER-independent manner. Neoadjuvant endocrine therapy (NET) offers a unique opportunity to identify responsiveness of HR+ BCs and detect tumors that display up-regulation of HER2, an early endocrine resistance mechanism. Methods: A single arm, interventional, exploratory clinical trial evaluating four weeks of NET in early stage HR+/HER2-negative BC patients was conducted at our institution (NCT03219476). The primary objective was to assess changes in HER protein expression (HER1-4) from diagnostic core biopsies to surgically resected tumors treated with NET. Secondary objectives included assessment of other molecular markers, tumor proliferation and volumetric responses. Optimized protocols for immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were used to assess HER2 status in the pre- and post-treatment tumor specimens. Chi-square and t-tests were performed. Linear regression multivariate analysis was performed to evaluate association of covariates with the primary outcome with 80% power at a significance level of 0.05. Here we present the changes in HER2 protein expression with NET in this study. Up-regulation was defined as an increase of ≥ 1 in IHC scores (ordinal 0,1,2,3) or gene amplification by FISH. Results: Thirty-seven patients with cT1-T3, cN0 HR+/HER2-negative BC were enrolled. Median age at diagnosis was 64 yrs (42-81) and median BMI was 28.3 (19.3-55.1). Most patients were post-menopausal (83.8%). Median tumor size clinically was 1.3 cm (0.5-7.7). Most tumors were low (42.1%) or intermediate (47.4%) grade and invasive ductal histology was seen in 70%. Median tumor size at surgery was 1.2 cm (0.09-4). One patient had a complete pathologic response (pCR) at surgery. Seven patients had pN1 disease at surgery (six with 1 lymph node involved, one with pN1mi). There was no significant change in ER-positivity between pre and post-treatment specimens. However, a trend towards decrease in PR-positivity was seen in post-treatment tumors consistent with functional ER pathway disruption (p=0.08). On HER2 protein assessment by IHC, most patients had IHC 0 (37.8%) or IHC 1+ (54%) at diagnosis. Significant up-regulation in HER2 protein was seen in 46% (17/37) of patients (p=0.0004), whereas down-regulation was detected in only 5% (2/37) and no change in the remaining 49% (18/37). Three patients converted to HER2-positive status (IHC 3+ or FISH amplified) at surgery and received adjuvant trastuzumab-based treatment. No significant associations were identified between any clinicopathologic covariates and change in HER2 protein expression. Conclusions: HER2 was up regulated in 46% of tumors after short-term NET in patients diagnosed with early stage HR+/HER2-negative BC. Short-term NET is a promising strategy to identify HR+ tumors that up-regulate HER2 as an early escape pathway and endocrine resistance mechanism. Patients with such HER2 up-regulated tumors after NET may benefit from HER2-directed therapies upon disease recurrence or as adjuvant combination therapy. These findings need to be further explored in larger randomized clinical trials.
Citation Format: Lubna N Chaudhary, Julie M Jorns, Yee Chung Cheng, Sailaja Kamaraju, Mary Beth Gonyo, Amanda Kong, Caitlin Patten, Tina Yen, Chandler Cortina, Ebony Carson, Nedra Johnson, Carmen Bergom, Anjishnu Banerjee, Yu Wang, Christopher R Chitambar, Hallgeir Rui. Neoadjuvant endocrine therapy helps identify HER2 up-regulation in patients with hormone receptor-positive HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD7-07.