Abstract P4-02-03: HER1-4 protein up-regulation following short-term neoadjuvant endocrine therapy in patients with hormone receptor-positive HER2-negative breast cancer
Authors: Chaudhary Lubna Naaz , Jorns Julie M , Cheng Yee Chung , Kamaraju Sailaja , Burfeind John , Gonyo Mary Beth , Kong Amanda , Patten Caitlin , Yen Tina , Cortina Chandler , Carson Ebony , Johnson Nedra , Bergom Carmen , Banerjee Anjishnu , Wang Yu , Sun Yunguang , Chitambar Christopher R , Rui Hallgeir 
Published: March 2022

Abstract
Background: Patients with hormone receptor-positive (HR+) breast cancer (BC) experience significant improvement in long-term outcomes with endocrine therapy (ET). 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 HER family growth factor receptor tyrosine kinases (RTKs) represent early escape mechanisms in tumors treated with ET. Neoadjuvant endocrine therapy (NET) offers a unique opportunity to identify responsiveness of HR+ BCs and detect tumors that display up-regulation of HER RTKs. 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) were used for HER1-4, and HER2 status was further assessed by fluorescence in situ hybridization (FISH) if IHC (2+) equivocal. Up-regulation was defined as an increase of ≥ 1 in IHC scores (ordinal 0,1,2,3) or gene amplification by FISH. Chi-square tests of independence and one sample difference in proportion tests were performed. Linear regression was used to evaluate association of variables of interest with the primary outcome. A significance level of 0.05 was used throughout. Results: Thirty-seven patients with cT1-T3, cN0 HR+/HER2-negative BC were enrolled. One patient had multifocal disease resulting in 38 tumors. Patient and tumor characteristics are shown in Table 1. 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). HER1-4 proteins were significantly up-regulated in 44.7% tumors (17/38) with HER2 being the most frequently up-regulated HER RTK (p=0.035). HER3 and HER4 were down-regulated in 50% tumors (19/38). Three patients converted to HER2-positive status (IHC 3+ or FISH amplified) at surgery and received adjuvant trastuzumab-based treatment. Ki67 decreased in 71% tumors [median 3.35 (range 0.06-25.5)] and increased in 26.3% tumors [median 1 (range 0.08-3.78)]. No significant associations were identified between any clinic-pathologic covariates and change in HER1-4 protein expression on multivariate analysis. Conclusions: HER1-4 proteins were significantly up-regulated in 44.7% of tumors after short-term NET in patients with early stage HR+/HER2-negative BC, with HER2 up-regulation being the most predominant and statistically significant. Down-regulation in HER3 and HER4 were seen in 50% of tumors, however the biological and clinical significance of this finding is unclear. 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.
Table 1.Median Age (range)64yrs (42-81)Median BMI (range)28.3 (19.3-55.1)Post-menopausal, N (%)31 (83.8)Median clinical tumor size (range)1.3cm (0.5-7.7)Invasive ductal, N (%)26 (70)Grade, N (%)Low16 (43.2)Intermediate18 (47.4)High4 (10.5)Median tumor size at surgery (range)1.2cm (0.09-4)pN stage at surgery, N (%)N030 (81)N17 (19)NET, N (%)Aromatase inhibitors28 (75.6)Tamoxifen9 (24.4)
Citation Format: Lubna Naaz Chaudhary, Julie M Jorns, Yee Chung Cheng, Sailaja Kamaraju, John Burfeind, Mary Beth Gonyo, Amanda Kong, Caitlin Patten, Tina Yen, Chandler Cortina, Ebony Carson, Nedra Johnson, Carmen Bergom, Anjishnu Banerjee, Yu Wang, Yunguang Sun, Christopher R Chitambar, Hallgeir Rui. HER1-4 protein up-regulation following short-term neoadjuvant endocrine therapy in patients with hormone receptor-positive HER2-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-03.