Background: HER2 low is defined by HER2 immunohistochemistry (IHC) score 1+ or 2+ with negative florescent in situ hybridization (FISH-). In metastatic BC the HER2 directing antibody drug conjugates (ACDs) had shown significant efficacy; however, its curative role in early BC has not defined yet. Here we aimed to study the clinical and molecular features of HER Low in 3850 cases of early BC and its response to NACT; Anthracycline/Taxane with/without Trastuzumab to optimize its clinical utility. Methods: Paired sections from pre and post NACT samples of 1250 early BCs (NACT cohort) were profiled for HER2 and SPAG5 using IHC and FISH. A novel triple coloured SPAG5 HER2 Ch17 probe was used as well HER2 Ch17 probe. ASCO guidelines were followed. Pre therapy samples of 400 BC were profiled for 450 customised genes using the Nano String nCounter platform. Moreover, 2600 cases of early BC who received adjuvant non-HER2 targeted therapies (ADJ cohort) were studied. The primary end point was pathological complete response (pCR). The Secondary endpoints were relapse free survival and bookmarks changes. Results: HER2 low was expressed in 31% (800/2600) of ADJ and 39% (490/1250) of NACT cohorts whereas HER2 overexpression (+) (HER2 IHC+3 or IHC+2/FISH+) was detected in 21% (540/2600) and 32% (401/1250) of ADJ and NACT cohorts; respectively. Compared to those with HER2 IHC 0 expression, HER2 low was associated with more aggressive features: ER-, PR-, Ki67+, SPAG5+, high grade, and p53 mutation and enriched in ERBB2 and its related genes EGFR, ERBB4, GRB7, SPAG5 and FGRF4; p < 0.0001. After NACT, HER2 low had the lowest pCR rate (16%; 57/348) compared to HER2 IHC+3 (54%; 120/223), HER2 IHC+2/FISH+ (23%; 14/60) and HER2 IHC 0 (25% (66/264); p < 0.0001. Compared to either HER2+ or HER2 IHC 0 cases; HER2 low had higher risk of 5 relapse [(HR (95% CI) = 2.04 (3.05-1.36); p = 0.001) and (HR (95% CI) = 1.45 (1.001-2.09); p = 0.05); respectively] after NACT. SPAG5 overexpression (+) determined the response for NCAT. None of HER2 IHC +2 with negative SPAG5 (-) expression (0/170) either with FISH+ (0/112) or FISH- (0/58) achieved pCR whereas 47% (31/66) of those of HER IHC+2 with SPAG5+ achieved pCR after NACT (p < 0.0001). Similarly 73% (78/107) of HER2 IHC+3 with SPAG5+ achieved pCR after NACT+ Trastuzumab compared to 11% (10/95) of those with SPAG5- ; p < 0.0001. Changes of HER2 expression after NACT was common (50%); 31% (106/348) of the resituate HER2 low tumours were HER2 IHC 0 and 7% were HER2+. Meanwhile 28% (17/60) of HER2 IHC+2/FISH+, 7% (15/223) of HER2 IHC+3 and 14% of HER2 IHC 0 changed into HER2 low. Conclusions: HER2 low is common in early BC and is associated with resistance to the anthracycline/Taxane NACT. Significant change of HER2 expression in the residual tumour is common after NACT. SPAG5 expression could help to optimize the use of NACT and ACDs in early BC.