Background: HER2+ breast cancer (BC) is a well characterized subtype of BC, due to the predictive value of HER2 overexpression for anti-HER2 targeted therapies. Nevertheless, around 50% of HER2+ BC are ER+ and clasiffied as luminal B/HER2+, but their biological and clinical behaviour may be different from HER2+/ER- tumors. Methods: We retrospectively reviewed 347 HER2+ (Herceptest +++ or FISH+) early BC patients (see Table) diagnosed at our institution in 1997-2007, and were divided into two study groups: HER2+/ER+ (group A) and HER2+/ER- (group B). ER+ was defined if expressed in > 10% tumor cells. Results: See table below. Mean age: 54.7 y (44.6 – 65). Mean Ki 67 was higher in B (37,2 vs 22,4%, p<0.0001). At the current FU, n¼ of events were insufficient to reach median DFS/OS. Mean DFS was 6.9 y (3.5 – 10.2); recurrent disease was higher (p 0.003) for B (54 pts, 43%) vs A (62 pts, 28%). 5-year DFS estimates: 78.4 % (95% CI 72.3 – 83.3) and 62.3 % (95% CI 53 – 70.27) for A and B, and 10-year DFS was 73.4% (95% CI 66.6 – 79) and 52.5% (95% CI 42.4 – 61.6) for A and B, respectively (p 0.0006). Most common recurrent sites were local (18) and bone (9) for HER2+/ER+ and liver (8) and lung (8) for HER2+/ER-. Mean OS was 8.03y (5.4 – 10.8); 28 (12,6%) pts died in A, vs 26 (21%) in B (p 0.043). 5-year OS estimates: 93.9 % (95% CI 89.7 – 96.4) and 87.6 % (95% CI 80.3 – 92.3) for A and B, and 10-year DFS was 84.2% (95% CI 77.5 – 89.0) and 74.1% (95% CI 63.4 – 82.2) for A and B, respectively (p 0.01). Conclusions: ER expression in HER2+ early BC defines two clinically distinct diseases with different long-term prognosis. These data may help to better individualize adjuvant therapies and future clinical trial designs.

	A N (%)	B N (%)
N	222	125
T1	104 (47)	44 (35,2)
T2	94 (92,5)	63 (50,4)
T3	9 (4)	13 (10,4)
T4	14 (6)	5 (4)
Missing	1
N0	120 (58,5)	60 (51,2)
N1	46 (22,4)	26 (22,2)
N2	28 (13,6)	22 (18,8)
N3	11 (5,3)	9 (7,7)
Missing	17	8
Neoadjuvant CT	50 (22,5)	30 (24)
Adjuvant CT	126 (57)	88 (70,4)
Type of CT No A, no T A, no T A and T Other	44 (25) 74 (42) 34 (19,3) 24 (13,6)	30 (25,4) 57 (48,3) 27 (23) 4 (3,3)
Adjuvant RT	172 (77,4)	96 (77)
Adjuvant trastuzumab	33 (14,8)	28 (22,4)
Adjuvant HT	213 (96)	16 (13)
Tam +/- LHRHa	77 (36)	8 (50)
Aromatase inh.	136 (64)	8 (50)