Abstract Background: We proposed adjunctive statistical standardization of quantitated ER and PgR to improve inter-laboratory comparability of biomarker results and therapeutic management of breast cancer. Adjunctive statistical standardization of quantitated HER2 is used here; we also examined the effects on outcome of ultra-low HER2 and very low statistically standardized HER2. Methods: We utilized CCTG MA.27 (NCT00066573), an adjuvant phase III trial of exemestane versus anastrozole in postmenopausal women with ER+ and/or PgR+ tumors. IHC HER2 HSCORE and % positivity (%+) were centrally assessed by machine image quantitation, and statistically standardized to mean of 0, standard deviationn (SD) of 1 followig Box-Cox variance stabilization transformations of 1.) natural logarithm (ln with addition of 0.1 to 0 HSCOREs and 0 %+), 2. square root. Additionally, centrally assessed FISH HER2 and CEP17 values were used to define ASCO/CAP categorizatiion. Post hoc, the effects of ultra-low HER2 , IHC 0 with (0,10%] 1+ stain, were examined. The primary endpoint was distant disease-free survival (DDFS) at the longest trial follow-up of median 4.1 years. Survival was described with Kaplan-Meier plots and tested with the univariate Wilcoxon (Peto-Prentice) test statistic. We examined cut-points at standard deviations about mean of 0 (<-1; (-1,0]; (0,1]; >1). Cox multivariant regressions were adjusted for age, T and N stage, grade, lymphovascular invasion, treatment, baseline patient demographics, ER and PgR; 2-sided Wald tests had nominal significance if p<0.05. Results: Of 7576 women accrued to MA.27, 2900 women had ER, 2726 had PgR, and 2680 had HER2 results; 2325 had all three biomarkers for multivariant investigations. Twenty-five women received received herceptin with only one experiencng a DDFS event. ASCO/CAP categorization significantly differentiated univariate DDFS (p=0.01). Image analysis identified 57% of IHC 0 to have ultra-low HER2. Five-year DDFS for IHC 0 without stain was 92% [95% CI (90,95); N=864] which was similar to that for ultra-low HER2 of 96% [95% CI (94,97); N=1143]. Statistical standardization did not significantly differentiate univariate DDFS (p=0.08-0.27). DDFS for ln standardized values <-1.0 (HSCORE, or %+ <0.1) was similar to that with standardized values >1.0 (HSCORE >19, or %+ >14): for HSCORE <1.0, 5-year DDFS was 92% [95% CI (85.98); N=88] vs for >1.0, 92% [95% CI (89,95); N=577]; for %+, 5-year DDFS was 91% [95% CI (85,98); N=102] vs >1.0, 92% [95% CI (89,95); N=613].In multivariant assessments with ASCO/CAP guideline and statistically standardized data, both ER (p=0.65-0.94) and HER2 (p=0.20-0.97) were not significantly associated with the DDFS primary endpoint in models with PgR; while higher PgR had significantly better DDFS (p<.003) in models with ER and HER2. Conclusions: ASCO/CAP HER2 guidelines significantly differentiated univariate DDFS although not values of IHC 0 and ultra-low HER2, with <10% weak stain. Statistical standardization did not differentiate univariate DDFS. Image quantitation identified very small numbers of 1+/2+/3+ intensity stained nuclei. DDFS was similar for any intensity of low ln(HER2) stain (<1 SD below the mean) compared to any intensity of higher HER2 stain (>1 SD above the mean), although we offer caution in assessment of ultra-low, or very low, HER2 stain due to the dynamic range of the HER2 assay. Neither ASCO/CAP nor standardized HER2 had multivariant significance in these hormone receptor rich patient tumors. The adjunctive statistical standardization of ER, PgR, and HER2 performed here is similar to that mandated for clinical practice by the World Health Organization for BMD. Citation Format: Judith-Anne Chapman, Jane Bayani, Sandip SenGupta, John M.S. Bartlett, Tammy Piper, Mary Anne Quintayo, Shakeel Virk, Paul E. Goss, James N. Ingle, Matthew J. Ellis, George W. Sledge, G. Thomas Budd, Manuela Rabaglio, Rafat H. Ansari, Richard Tozer, David P. D'Souza, Haji Chalchal, Silvana Spadafora, Vered Stearns, Edith A. Perez, Karen A. Gelmon, Timothy J. Whelan, Catherine Elliott, Lois E. Shepherd, Bingshu E. Chen, Karen J. Taylor. Adjunctive statistical standardization of quantitated adjuvant HER2 and very low statistically standardized HER2 in CCTG MA.27 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-07-06.