Abstract P4-02-26: Quantitative estrogen receptor expression affects pathologic complete response to neoadjuvant chemotherapy in patients with early-stage breast cancer with low expression of HER2
Authors: Iwase Toshiaki , Fujii Takeo , Yam Clinton , Dong Wenli , Shen Yu , Tripathy Debu , Ueno Naoto T. 
Published: March 2023

BACKGROUND Recent pooled analysis of four major clinical trials of neoadjuvant chemotherapy (NAC) indicated that tumors with low expression of HER2 (HER2-low) as defined by immunohistochemistry (IHC) could be a new subgroup of breast cancer, distinct from HER2-negative tumors. In estrogen receptor (ER)-positive/HER2-negative breast cancer, we previously reported that 9.5% ER expression by IHC was the most appropriate cutoff to predict survival outcomes. However, little is known about the effect of quantitative ER expression on NAC outcomes in patients with HER2-low breast cancer. The present study aimed to elucidate the role of quantitative ER expression as a predictive and prognostic biomarker in the newly established HER2-low subgroup. MATERIALS AND METHODS We retrospectively reviewed the charts of 2,016 patients with newly diagnosed ER- and/or progesterone receptor (PR)-positive breast cancer between January 1982 and January 2019 in an extensive clinical database at The University of Texas MD Anderson Cancer Center. Our analysis included patients whose ER%, PR%, and HER2 IHC (0 to 2+) data were available. HER2-low was defined as IHC 1+ and 2+/situ hybridization (ISH)-negative. All patients had stage II or III disease at presentation and received NAC with anthracycline and a taxane-based combination regimen. Those with ER-positive tumors also received adjuvant endocrine therapy. The primary outcome measure was pathologic complete response (pCR) rate, compared between groups using logistic regression. Secondary outcomes were progression-free survival and overall survival after NAC completion, compared using Kaplan-Meier analysis and the log-rank test. The cutoff value for ER and PR positivity was 10% in the main analysis, identified by recursive partitioning and regression trees. RESULTS Among the 2,016 patients, 1134 (56%) had cStage II and 882 (44%) had cStage III disease. For IHC HER2 levels, 739 patients had 0 (37%), 926 had 1+ (46%), and 351 had 2+ (17%). For the primary outcome, 123 patients (6%) achieved pCR. The median follow-up period was 6.78 years. During the follow-up, 571 (28%) had distant metastasis. Mean ER expression (%) increased with HER2 IHC (HER2 IHC 0: 74.2%, 1+: 76.7%, 2+: 78.2%). In the multivariate logistic model, ER-negative (p&lt; 0.0001), PR-negative (p &lt; 0.0001), and high nuclear grade (p&lt; 0.05) disease were associated with higher pCR rates. Although pCR rate did not differ among HER2 IHC groups (0 = 6.09%, 1+ = 6.26%, 2+ = 5.7%; p=0.93), significantly higher pCR rates were observed in the HER2 IHC=0/1+ and 1%≤ER&lt; 10% group (p=0.0013) than in the HER2 IHC=0/1+ and ER≥10%, and HER2 IHC=2+ and ER≥10% groups. Kaplan-Meier curves showed that patients in the ER≥10% group had marginally improved PFS (p=0.046) and significantly longer OS (p=0.004) regardless of HER2 IHC status. Multivariable analysis showed that HER IHC status did not affect survival outcomes. Exploratory analysis showed that the patients with 70% or less in ER expression and HER2 IHC 1+/2+ tumor had higher pCR rate (12.3%) compared to those with ER&gt;70% (4.1%). CONCLUSIONS Patients with ≥10% ER expression had better survival outcomes than those with ER&lt; 10% regardless of HER2 expression level. The degree of HER2 expression in the HER2-low subgroup was not an independent predictive and prognostic factor for NAC response. The cutoff for ER expression for its predictive effect on pCR needs further validation in large external datasets.

Citation Format: Toshiaki Iwase, Takeo Fujii, Clinton Yam, Wenli Dong, Yu Shen, Debu Tripathy, Naoto T. Ueno. Quantitative estrogen receptor expression affects pathologic complete response to neoadjuvant chemotherapy in patients with early-stage breast cancer with low expression of HER2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-26.