Table 1.

Summary of Characteristics and Limitations of all Included Randomized Controlled Trials.

Study	Type	Design	Country	Clinical Stage	Cases (n)	Neoadjuvant treatment	Age	Arm	HER2+ %	HR+ %	Limitations of the Study	Ref
MD Anderson, 2005 & 2007	Peer reviewed	Open-label	United States	II-IIIA	42	CT C	52 48	23 19	100 100	56 58	Small sample size, unoptimal imaging modalities or cancer markers used, unclear description about building of outcome assessment, premature termination	[40, 41]
Pierga, 2010	Peer reviewed	Multicentre, open-label, phase II	France	II-III	120	CT C	47 47	62 58	100 100	55 63	Absence of long-term outcome	[42]
NOAH, 2010 & 2014	Peer reviewed	Multicentre, open-label, phase III	Europe and North America 6 counties	T3N1 or T4 or any T N2-3	235	CT C	NR	117 118	100	35 35	Unclear description about building of outcome assessment.	[43, 44]
H2269s, 2010	Peer reviewed	Open-label	United States	T2-4	29	CT C	50	15 14	100	NR	Small sample size, absence of HR status data, unclear description about building of outcome assessment, different pCR definition used, absence of long-term outcome	[45, 46]
LPT 109096 2011	Abstract	Multicentre, open-label, phase II	United States	T2-4, N0-2	100	CTL CT CL	49 51 51	33 33 34	100	NR	Full-text unavailable, small sample size.	[47]
GeparQuinto–GBG44 2012	Peer reviewed	Multicentre, open-label, phase III	Germany	T1 pNSLN+, T2cN+, T3-4,	615	CT CL	50 50	309 311	100 100	55 56	Unmasked allocation concealment, absence of long-term outcome	[48]
NeoALTTO, 2012 & 2014	Peer reviewed	Multicentre, open-label, phase III	International 25 countries	T2-4	455	CTL CT CL	50 49 50	152 149 154	100 100 100	51 50 52	More patients had to stop treatment due to side-effects in the lapatinib-containing groups	[49, 50]
CHER-LOB, 2012	Peer reviewed	Multicentre, open-label phase IIb	Italy	II-IIIA	121	CTL CT CL	49 50 49	46 36 39	100 100 100	61 58 62	Small sample size, absence of HR status data, absence of long-term outcome	[51]
NeoSphere, 2012 & 2016	Peer reviewed	Multicentre, open-label, phase II	International 19 countries	T2-4	417	CTL TP CT CP	50 49 50 49	107 107 107 96	100 100 100 100	47 47 47 48	Not been identified	[52, 53]
NSABP B41, 2013	Peer reviewed	Muticentre open-label, phase III	North America 3 countries	T2-T3, N0-N2a	519	CTP CT CL	NR	174 181 174	100 100 100	62 67 58	Unmasked allocation concealment, unclear description about building of outcome assessment,	[54]
TRIO-US B07, 2013	Abstract	Multicentre, open-label, phase II	United States	I-III	106	CTL CT CL	NR	58 34 36	100 100 100	NR	Unbalanced baseline characteristic, small sample size, absence of HR status data, absence of long-term outcome	[55]
ABCSG-24, 2013	Peer reviewed	Multicentre open-label, phase III	Austria	T1-4	93	CT C	50 48	44 49	100 100	41 38	Small sample size, key regimen is not used internationally, absence of long-term outcome	[56]
GEICAM, 2014	Peer reviewed	Multicentre, open-label, phase II	Spain	I-III or inflammatory	99	CT CL	49 48	50 52	100 100	60 56	Absence of long-term outcome, small sample size	[57]
EORTC 10054, 2014	Peer reviewed	Multicentre, open-label, phase IIb	Europe 5 countries	IIA-IIC	122	CTL CT CL	49 47 50	52 53 23	100 100 100	52 52 68	Unbalanced baseline characteristic, small sample size, premature termination, absence of long-term outcome	[58]
KRISTINE, 2016	Abstract	Multicentre, open-label, phase III	International, 11 countries	II-IIIC	444	MP CTP	NR	223 221	100 100	51 49	Full-text unavailable	[59, 60]
CALGB 40601, 2016	Peer reviewed	Multicentre, open-label, phase III	United States	II-III	295	CTL CT CL	48 50 50	118 120 67	100 100 100	59 59 58	Premature termination, absence of long-term outcome	[61]

Note. C indicates chemotherapy alone; CL, chemotherapy plus lapatinib; CP, chemotherapy plus pertuzumab; CT, chemotherapy plus trastuzumab; CTL, chemotherapy plus trastuzumab plus lapatinib; CTP, chemotherapy plus trastuzumab plus pertuzumab; HER2, human epidermal growth factor receptor-2; HR, hormone receptor; MP, trastuzumab emtansine plus pertuzumab; NR, not reported; TP, trastuzumab plus pertuzumab.