Background: Although the addition of trastuzumab to neoadjuvant CT for O/LABC have dramatically increased pCR, clinical research is moving forward to further improve the overall outcome. In this regard, the DUAL inhibition of the HER-2 pathway and the choice of the best CT backbone may represent an issue to be addressed. Methods: Phase II randomized/Phase III trials were considered. pCR events/rates were extracted from papers/presentation and cumulated (R[pCR]) according to a random-effect model; 95% confidence intervals (CI) were derived. A sensitivity analysis according to SINGLE/DUAL HER-2 inhibition and to administered CT (anthracyclines-taxanes: anthra-TAX; TAX alone) was accomplished, in order to test for interaction. Results: 7 trials (2155 pts) were gathered; 1855 pts were enrolled in arms where anti-HER-2 targeted therapy was administered. HER-2 inhibition was obtained with trastuzumab, lapatinib and pertuzumab (alone or combined). Results according to HER-2 inhibition follow in the table below. With regard to CT, a significant interaction (p=0.0001) in favour of the addition of Anthra to TAX was found in the context of SINGLE HER-2 inhibition subgroup (R[pCR] 46.5%, 95% CI 37-51, vs 26.9%, 95% CI 23-31), while no significant interaction was determined in the context of the DUAL subgroup (R[pCR] 49.0%, 95% CI 26-72, vs 49.0%, 95% CI 43-55). A significant interaction (p=0.0001) in favour of the addition of Anthra to TAX was found for pts receiving trastuzumab (R[pCR] 45.5%, 95% CI 37-53, vs 26.5%, 95% CI 21-32) as well. Conclusions: Although biases in the pCR definition, the DUAL inhibition of HER-2 pathway may significantly increase pCR, regardless of the CT backbone; if confirmed, this strategy allows to reduce toxicities by sparing Anthra. For pts receiving SINGLE HER-2 inhibition, Anthra-TAX-based CT should be still considered the best treatment option.

	Anthra-TAX		TAX
	Single	Dual	Single	Dual
pCR (n°)/pts	259/591	139/390	136/506	127/259
R[pCR] (95% CI)	46.5% (37-51)	49.0% (26-72)	26.9% (23-31)	49.0% (43-55)
Interaction test	p=0.67		p=0.0001