Abstract Background: Triple negative breast cancer is defined by lack of expression of ER/PR (immunohistochemistry expression <1%) and absence of HER2 gene amplification. However, data regarding endocrine therapy benefit in patients with low levels (1-10%) of ER/PR expression are lacking. Furthermore, gene expression studies show tremendous similarities between HER2 negative tumors with low and negative ER/PR status. Accordingly, the 2020 ASCO/CAP guideline designates that ER expression of 1-10% be reported as a distinct “ER low positive” category. Utilizing data from a prospective registry, the aim of this study was to determine the impact of low versus negative ER/PR status on clinico-pathologic characteristics and survival outcomes in patients with HER2 negative breast cancers. Methods: 516 subjects with stage I-III HER2 negative breast cancer and ER/PR IHC ≤10% were enrolled in an IRB-approved multisite prospective registry between 2011 and 2019. Demographic, clinical, pathologic, and treatment information was collected, and patients were followed for recurrence and survival. Patients were categorized according to ER/PR expression into two groups: TNBC (ER and PR <1%) and Low-ER (ER and/or PR 1-10%). Recurrence free survival (RFS) and overall survival (OS) were estimated according to the Kaplan-Meier method and compared among groups by log-rank test, followed by Cox regression analysis. Results: TNBC and Low-ER groups comprised 451/516 (87.4%) and 65/516 (12.6%) patients, respectively. Demographic, clinical, pathologic, and treatment characteristics of the two groups are described in Table 1. Median follow-up was 39 months. Three-year RFS was 82% for both TNBC and Low-ER groups (p=0.70). Three-year OS was 88% and 83% for TNBC and Low-ER groups, respectively (p=0.63). Twenty percent of patients in the Low-ER group received adjuvant endocrine therapy, and endocrine therapy use did not impact outcomes in the Low-ER group (RFS: p=0.32; OS: p=0.88). On multivariate analysis, T stage, nodal status, and age significantly impacted RFS (T stage 3/4 vs 1/2, HR=2.7, p<0.001; nodal status positive vs negative, HR=2.4, p<0.001; age above vs below median, HR=1.8, p=0.006) and OS (T stage 3/4 vs 1/2, HR=3.6, p<0.001; nodal status positive vs negative, HR=2.8, p<0.001; age above vs below median, HR=1.026, p=0.01). For patients who received neoadjuvant chemotherapy, achievement of pathological complete response (pCR) was associated with superior RFS (3-year RFS of 95% and 67% in those with and without pCR, respectively, HR=0.18, p<0.001). Conclusions: Patients with TNBC and Low-ER HER2 negative breast cancer present with similar clinico-pathologic characteristics, including prevalence of germline BRCA1/2 mutation. Prognosis and rate of pCR (with neo-adjuvant chemotherapy) in patients with Low-ER HER2 negative breast cancer is similar to those with TNBC. The role and efficacy of adjuvant endocrine therapy in patients with Low-ER breast cancer is unclear. These findings support consideration for inclusion of patients with Low-ER disease along with TNBC for future clinical trial eligibility and planning. Table 1. Demographic, clinical, pathologic, and treatment characteristicsCharacteristics - N (%)All N=516TNBC (ER & PR <1%) n=451Low-ER (ER or PR 1-10%) n=65pAge at diagnosis, years - median (range)53 (23-97)54 (23-97)51 (28-76)0.61RaceWhite386 (75%)335 (74%)51 (79%)0.69Black101 (20%)89 (20%)12 (19%)Asian8 (2%)8 (2%)0 (0%)Menopausal statusPre214 (42%)181 (41%)33 (51%)0.25Post295 (58%)263 (59%)32 (49%)Histological gradeI2 (0.4%)2 (0.4%)0 (0%)0.82II86 (17%)76 (17%)10 (15%)III428 (83%)373 (83%)55 (85%)T stageT1-2446 (87%)388 (87%)58 (89%)0.56T3-467 (13%)60 (13%)7 (11%)N statusPositive177 (34%)158 (35%)19 (29%)0.36Negative339 (66%)293 (65%)46 (71%)TNM stageI179 (35%)150 (33%)29 (44%)0.10II263 (51%)232 (52%)31 (48%)III74 (14%)69 (15%)5 (8%)Germline BRCA1/2 mutationYes70 (14%)64 (14%)6 (9%)0.53No357 (69%)309 (69%)48 (74%)Unknown89 (17%)78 (17%)11 (17%)ChemotherapyNeoadjuvant357 (69%)318 (71%)39 (60%)0.23Adjuvant147 (29%)123 (27%)24 (37%)None12 (2%)10 (2%)2 (3%)Surgery typeMastectomy308 (60%)275 (61%)33 (51%)0.10Lumpectomy205 (40%)173 (39%)32 (49%)Adjuvant endocrine therapyYes20 (4%)7 (2%)13 (20%)<0.001No496 (96%)444 (98%)52 (80%)pCR (in patients with neoadjuvant chemotherapy, n=357)176 (49%)157 (49%)19 (49%)0.94 Citation Format: Rachel Yoder, Bruce F Kimler, Joshua M Staley, Kelsey Schwensen, Yen Y Wang, Karissa Finke, Anne O'Dea, Lauren Nye, Manana Elia, Gregory Crane, Richard McKittrick, Robert Pluenneke, Sheshadri Madhusudhana, Larry Beck, Roberto Rodriguez, Anuj Shrestha, Larry Corum, Mark Marsico, Andrew K Godwin, Qamar Khan, Priyanka Sharma. Impact of low versus negative estrogen/progesterone receptor status on clinico-pathologic characteristics and survival outcomes in HER2 negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-04.