Abstract HER2-19: HER2-19 Impact of HER2 low status on clinical outcomes in participants with 1-3 positive lymph nodes, HR+/HER2- breast cancer with recurrence score </25 randomized to endocrine therapy +/- chemotherapy: results from SWOG S1007 (RxPONDER)

Abstract Background: HER2 low breast cancer, defined as tumors with HER2 IHC expression 1+ or 2+ without HER2 gene amplification, represents a potential new therapeutic subgroup of metastatic breast cancer (BC). However, the clinical significance of HER2 low status in early BC remains unclear. Previously, the RxPONDER trial (NCT01272037), a prospective, randomized trial of endocrine therapy (ET) vs. chemoendocrine therapy (CET) in women with lymph node positive (LN+) BC, demonstrated invasive disease-free survival (IDFS) with ET vs CET varies by menopausal status. We evaluated the impact of HER2 low vs zero status in the RxPONDER trial (SWOG S1007), stratified by menopausal status and treatment groups. Methods: Eligibility criteria included women >/18 years of age with hormone receptor-positive (HR+), HER2-negative (HER2-) BC, Recurrence Score (RS) </25, 1-3+ LN and no contraindications to taxane and/or anthracycline based CT. The impact of HER2 low status and other baseline clinicopathological features on clinical outcomes were evaluated using covariates in Cox regression analysis. HER2 IHC status was per local testing. HER2 low was defined as IHC 1+ or IHC 2+ without HER2 gene amplification, and HER2 zero was defined as IHC 0. The primary endpoint was IDFS, defined as the time from the date of randomization to the date of a first invasive recurrence (local, regional, or distant), a new invasive primary cancer (breast cancer or another type of cancer), or death from any cause. Secondary objectives included distant-relapse free survival (DRFS). Results: Among the 4,983 eligible participants, 4,588 had IHC HER2 status available. 52% of 2,052 pre-menopausal women had HER2 low BC and 57% of 3,042 post-menopausal women had HER2 low BC. There was a small, but statistically significant (p=0.03) difference, in RS between HER2 low (mean 14.5) and HER2 zero (mean 14.1) status. The proportion of participants with HER2 low and zero were balanced between treatment group assignment (CET vs ET). Among pre-menopausal women adjusting for RS, CET led to an observed improvement in IDFS among both HER2 low (HR=0.67; 95% CI 0.43-1.04) and HER2 zero subgroups (HR=0.57; 95% CI 0.36-0.89) (interaction p=0.55). Similarly, among post-menopausal women, there was no difference in IDFS between CET vs ET among both HER2 low (HR=0.98; 95% CI 0.75-1.29) and HER2 zero (HR=1.12; 95% CI 0.80-1.56) subgroups (interaction p=0.57). In multivariable analysis, adjusting for treatment arm, RS, and menopausal status, HER2 low status was not associated with worse IDFS compared to HER2 zero status (HR=0.93; 95% CI 0.78-1.11). Additionally, no differences were noted in DRFS. Conclusion: HER2 low or zero status had no impact on clinical outcomes with CET vs ET among pre-menopausal or post-menopausal women with HR+/HER- BC with 1-3+ LNs and RS </25. HER2 low evaluation should not be currently used for CET vs ET clinical decision making among patients with HR+/HER2- breast cancer with 1-3+ LN and RS </25. Further research on the role of HER2 low status in other settings may be warranted. Citation Format: Laura M. Spring, William E. Barlow, Aditya Bardia, Priyanka Sharma, Lajos Pusztai, Gabriel N. Hortobagyi, Kevin Kalinsky. HER2-19 Impact of HER2 low status on clinical outcomes in participants with 1-3 positive lymph nodes, HR+/HER2- breast cancer with recurrence score </25 randomized to endocrine therapy +/- chemotherapy: results from SWOG S1007 (RxPONDER) [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 HER2-19.