Abstract P4-07-33: Differences in Treatment Outcomes Between Patients with HER2-Low versus HER2-Zero, Hormone Receptor-Positive Advanced-Stage Breast Cancer Treated with CDK4/6 Inhibitors
Authors: Sharaf Baha’ , Abu-Fares Hala , Tamimi Faris , Al-Sawajneh Suhaib , Salama Osama , Daoud Rand , Alhajahjeh Abdulrahman A. , Al-lababidi Sawsan , Abdel-Razeq Hikmat 
Published: March 2023

Abstract
Background: The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors transformed the care of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2 (HER2)-negative (HR+/HER2−) advanced-stage breast cancer (aBC). Breast cancers with no expression of HER2 are recently classified into two groups: HER2-Zero subtype which include those with HER2-immunohistochemistry (IHC) score of 0 (IHC-0) and “HER2-low”, defined as HER2-IHC score of 1+ or (2+ with negative in situ hybridization (ISH) assay). There is increasing interest in the HER2-low subtype which is becoming a new distinct entity with promising data from recently reported clinical trials using novel anti-HER2 antibody-drug conjugates (ADC) in this subgroup. This study investigates the differences in treatment outcomes between patients with aBC with HER2-low versus those with HER2-Zero (IHC-0) disease treated with CDK4/6 inhibitors and endocrine therapy (ET). Methods: We retrospectively reviewed patients with (HR+/HER2−) aBC who received CDK4/6 inhibitors with an aromatase inhibitor (AI) or fulvestrant from June 2017 to May 2020 at a single cancer center. Data was extracted from patients’ electronic medical records and from our institutional cancer registry. Progression-free survival (PFS), defined as the time from the initiation of CDK4/6 inhibitors to the date of radiological or clinical progression or death, and was estimated by the Kaplan-Meier method and compared by the log-rank test. Multivariate Cox regression modeling was performed with covariates including progesterone receptor (PR) status, prior chemotherapy, site of metastasis (visceral versus bone-only disease), line of treatment (first-line or beyond), menopausal status, age (less than or ≥ 45) and number of metastatic sites (&lt; or ≥ 3). P-value &lt; 0.05 was considered statistically significant. Results: During the study period, a total of 256 patients with advanced-stage breast cancer who received ET and CDK4/6 inhibitors (ribociclib in all patients) were included, median age was 48 (22-87) years. Majority (n=162, 63.3%) received ribociclib as a first-line therapy while the others had it as a second line and beyond. 136 (53.1%) patients had de novo metastatic disease, and 122 (47.7%) were premenopausal. In total, 114 (44.5%) of the patients where HER2-Zero (IHC-0), while 142 (55.5%) others had HER2-low disease as defined above. The overall response rate (ORR) for the HER2-Zero group was 52% versus 39% for the HER2-low group (P= 0.005).The median PFS was 23.0 (95% confidence interval [CI], 19-40) months for HER2-Zero versus 17.0 (95% CI 14-20,) months for HER2-low; P= 0.0035. In multivariate analysis, HER2-low expression remained significant determinant of inferior PFS after adjusting for other factors including the line of treatment (aHR:2.10, 95% CI 1.03-4.27, P=0.041), age (aHR 2.20, 95% CI 1.29-3.77, P=0.004)), number of metastasis (aHR:1.96, 95% CI 1.32-2.91, P=0.001), and site of metastasis (aHR:1.64, 95%CI 1.058-2.55, P=0.027). Conclusion: In patients with advanced-stage breast cancer treated with CDK4/6 inhibitors and ET, level of HER2 negativity may affect treatment outcomes; patients with HER2-Zero had better PFS compared to those with HER2-low disease. These findings, if confirmed in larger studies, should help oncologists select patients with HER2-low for better treatment options including a combination of anti-HER2 therapy and CDK4/6 inhibitors.
Citation Format: Baha’ Sharaf, Hala Abu-Fares, Faris Tamimi, Suhaib Al-Sawajneh, Osama Salama, Rand Daoud, Abdulrahman A. Alhajahjeh, Sawsan Al-lababidi, Hikmat Abdel-Razeq. Differences in Treatment Outcomes Between Patients with HER2-Low versus HER2-Zero, Hormone Receptor-Positive Advanced-Stage Breast Cancer Treated with CDK4/6 Inhibitors [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 P4-07-33.