Abstract HER2-14: HER2-14 HER-2 low status in early stage invasive lobular carcinoma of the breast: associated factors and outcomes in an institutional series
Authors: Rothschild Harriet T. , Clelland Elle , Patterson Anne , Molina-Vega Julissa , Kaur Mandeep , Abel Mary Kathryn , Symmans W. Fraser , Schwartz Christopher J. , Mukhtar Rita 
Published: March 2023

Abstract
Objectives: The concept of human epidermal growth factor receptor 2 (HER2)-low status has been proposed as a potential treatment target for breast cancers previously considered to be HER2-negative. Defined by an immunohistochemistry (IHC) score of 1+ or 2+ and negative fluorescent in situ hybridization (FISH) for HER2, HER2-low status predicts significant clinical benefit from novel therapeutic compounds in recent clinical trials. The prevalence and clinical implications of HER2-low status in patients with early stage invasive lobular carcinoma (ILC) has not been described. We aimed to describe the clinicopathologic features and prevalence of HER2-low status in ILC, and identify any potential differences in clinical outcome. Methods: We evaluated stage I-III ILC tumors from a prospectively maintained institutional database of patients where both IHC and FISH testing for HER2 status was performed as standard clinical care. Tumors were classified as HER2 negative (IHC=0), HER2-low (IHC=1+ or 2+ and negative FISH), or HER2 positive (IHC=3+ or FISH ratio ⇒2). Data were analyzed in Stata 16.1 using chi-squared tests, t-tests, and Cox proportional hazards models for disease free survival (DFS). Results: 666 ILC tumors with available HER2 status were available for analysis. The mean age at diagnosis was 59.8 years (range 21-91). The majority of patients had stage I disease (63.1%) with an average follow up time of 6.7 years (standard deviation [5.4]). Overall, 184 (27.6%) tumors were HER2 negative, 434 (65.1%) were HER2-low, and 48 (7.2%) were HER2 positive. There were no associations between HER2 status and age, menopausal status, body mass index, tumor stage, grade, presence of lymphovascular invasion, or molecular assay results. Hormone receptor status was significantly associated with HER2 status, with HER2 positive tumors significantly less likely to be estrogen receptor (ER) positive than both HER2 negative and HER2-low tumors (89.6% versus 97.3% and 96.8% respectively, p=0.03). HER2-low tumors were also significantly more likely to have progesterone receptor (PR) positivity (86.6% compared to 79.9% of HER2 negative and 72.9% of HER2 positive tumors, p = 0.01). This difference remained significant when comparing just HER2-low to HER2 negative cases (p=0.034). While there were no differences in use of neoadjuvant or adjuvant chemotherapy by HER2 status, HER2-low patients were significantly more likely to undergo mastectomy versus lumpectomy when compared to HER2 negative and HER2 positive patients (53.7% versus 38.0% and 43.8% respectively, p= 0.001). In a multivariable Cox proportional hazards model adjusting for tumor size, number of positive nodes, ER/PR status, and local therapy received, patients with HER2-low status had worse DFS than those with HER2 negative tumors (hazard ratio 2.0, 95% confidence interval 1.0 - 4.1, p=0.05). Conclusions: In this analysis of 666 early stage ILC cases, we found that most tumors were HER2-low, and that those with HER2-low disease were significantly more likely to have PR positive tumors and to undergo mastectomy. When adjusting for these variables, we identified a difference in DFS between HER2 negative and HER2-low early stage ILC. These findings support the contention that HER2-low and HER2 negative disease represent two different clinical entities. Further investigation of the potential benefit of HER2 targeted therapy in ILC, which predominately lacks HER2-amplified disease, is needed to ensure optimal outcomes in this understudied tumor type.
Citation Format: Harriet T. Rothschild, Elle Clelland, Anne Patterson, Julissa Molina-Vega, Mandeep Kaur, Mary Kathryn Abel, W. Fraser Symmans, Christopher J. Schwartz, Rita Mukhtar. HER2-14 HER-2 low status in early stage invasive lobular carcinoma of the breast: associated factors and outcomes in an institutional series [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 HER2-14.