Therapeutic options for HER-2 positive breast cancer: Perspectives and future directions

Table 1 Selected clinical trials in the adjuvant setting for human epidermal growth factor receptor-2 positive breast cancer

Drug or studyname	Populationincluded	No. ofpatients	Comparison	Medianfollow-up	DFS	OS	CHF/Drop LVEF	Ref.
Trastuzumab (H)
NCCTG N9831	LN (+) or	1087	AC → T vs		71.8% (5-yr)	88.4% (5-yr)	0%/0%	Perez et al[14]
	high risk LN (-)	949	AC → T → H (52 wk) vs AC	72 mo	80.1% (5-yr)	89.7% (5-yr)	2.2%/7%
		954	→ TH (H then 40 wk)		84.4% (5-yr)	91.9% (5-yr)	1.5%/3.6%
HERA	LN (+) or	1552	Std QT → H (52 wk) vs	96 mo	75.9% (5-yr)	86.9% (5-yr)	1%/7.2%	Goldhirsch et al[16]
	high risk LN (-)	1553	Std QT → H (104 wk) vs		76.5% (5-yr)	88.7% (5-yr)	0.8%/4.1%
		1697	Std QT → Observation		70.0% (5-yr)	84.5% (5-yr)	0.1%/0.9%
FINHER	LN (+) or	58	Docetaxel → FEC vs	62 mo	74.1% (5-yr)	82.0% (5-yr)	1.7%/10.5%	Joensuu et al[18]
	high risk LN (-)	58	Vinorelbine → FEC vs		72.0% (5-yr)	82.8% (5-yr)	(QT only)
		54	Docetaxel + H → FEC vs		92.5% (5-yr)	94.4% (5-yr)	0.9%/6.8%
		61	Vinorelbine + H → FEC		75.2% (5-yr)	88.4% (5-yr)	(QT + H)
BCIRG 006	LN (+) or	1073	AC → Docetaxel vs	65 mo	75% (5-yr)	87% (5-yr)	0.7%/11.2%	Slamon et al[19]
	high risk LN (-)	1074	AC → Docetaxel + H vs		84% (5-yr)	92% (5-yr)	2.0%/18.6%
		1075	TCH		81% (5-yr)	91% (5-yr)	0.4%/9.4%
PACS 04	LN (+)	260	FE100C or ED75 → Obser vs	62 mo	77.9% (3-yr)	96% (3-yr)	0.3%/14.2%	Spielmann et al[20]
		268	FE100C or ED75 → H		80.9% (3-yr)	95% (3-yr)	1.5%/35.4%
PHARE	HER-2 (+) early breast cancer	1690	Std QT → H (26 wk) vs	42.5 mo	91.1% (2-yr)	96.1% (2-yr)	5.7% (both)	Pivot et al[21]
		1690	Std QT → H (52 wk)		93.8% (2-yr)	94.5% (2-yr)	1.9% (both)
Lapatinib (L)
TEACH	Stage I-IIIc – H naïve	1230 (HER-2 +)	Std QT → L (52 wk) vs	47.4 mo	87% (4-yr)	94% (4-yr)	3.0% (both)	Goss et al[22]
		1260 (HER-2 +)	Std QT → Observation	48.3 mo	83% (4-yr)	94% (4-yr	3.0% (both)

LN: Lymph nodes; AC → T: Adriamycin cyclophosphamide paclitaxel; FEC: 5-FU epirubicin cyclophosphamide; ED: Epirubicin docetaxel; Std QT: Standard chemotherapy; OS: Overall survival; DFS: Disease free survival; CHF: Cardiac heart failure; LVEF: Left ventricular ejection fraction.

Table 2 Selected clinical trials in the neo-adjuvant setting for human epidermal growth factor receptor-2 positive breast cancer

Study	Neo-adjuvant chemotherapy	No. of patients	Pathological completeresponse (%)	Comments	Ref.
Trastuzumab (H)
MD Anderson Group	T → FEC vs T → FEC + H	19 vs 23	26% (95%CI: 9%-51%) vs 65% (95%CI: 43%-84%)	Probably the first study to emphasize better pCR with H	Buzdar et al[24]
The NOAH Trial	A + T → T → CMF vs A + T → T → CMF + H	117 HER-2 (+) vs 118 HER-2 (+)	22% (95%CI: not reported) vs 43% (95%CI: not reported)	Not originally designed to test the effects of neoadjuvance	Gianni et al[26]
The TECHNO Trial	EC → TH	217	38.7% (95%CI: 32%-45%)	Suggest pCR correlate with DFS	Untch et al[27]
The Z1041 Trial	FEC → TH vs T + H → FEC + H	138 vs 142	56.5% (95%CI: 48%-65%) vs 54.2% (95%CI: 46%-62%)	Concurrent use of H with anthracyclines is not better	Buzdar et al[28]
The HannaH Trial	Doc + H (SQ) → FEC + H vs Doc + H (IV) → FEC + H	260 vs 263	45.4% (95%CI: 39%-52%) vs 40.7% (95%CI: 35%-47%)	H can be administered subcutaneously	Ismael et al[30]
Lapatinib(L) +/- (H)
The GeparQuinto Trial	ECH → TH vs ECL → TL	309 vs 311	30.3% (95%CI: 25%-36%) vs 22.7% (95%CI: 18%-28%)	Lapatinib is less effective that H	Untch et al[31]
The NeoALLTO Trial	TH vs TL vs THL	149 vs 154 vs 152	29.5% (22%–37%) vs 24.7% (22% -37%) vs 51.3% (43%-59%)	Suggested that combination H + L could be quite effective	Baselga et al[32]
The NSABP B-41 Trial	AC → TH or TL or THL	181 vs 174 vs 174	52.5% (50%-59.5%) vs 53.2% (45%-60%) vs 62.0% (54%-69%)	H + L no better. All patients received anthracyclines	Robidoux et al[33]
Pertuzumab (P)
The NeoSphere Trial	Do + H vs Do + P + H vs Do + P vs P + H	107 vs 107 vs 107 vs 96	29.0% (21%-38.5%) vs 45.8% (36%-56%) vs 24.0% (16%-34%) vs 16.8% (10%-25%).	Combination P + H result in better pCR.	Gianni et al[34]
The Tryphaena Trial (Abstract Only)	FEC + HP → Do + HP vs FEC → Do + HP vs TCHP	223 patients in total	62% vs 57% vs 66%	TCH + P is an active combination	N/A

T: Paclitaxel; F: 5-FU; E: Epirubicin; C: Cyclophosphamide; A: Adriamycin; M; Methotrexate; Do: Docetaxel; TC: Docetaxel carboplatin.

Table 3 Selected clinical trials in metastatic human epidermal growth factor receptor-2 positive breast cancer

Drug or study name	Population included	No. ofpatients	Comparison	MedianOS (mo)	MedianTTP (mo)	ORR	1-yr Survival	Ref.
Single agents
Trastuzumab (H)	Phase II, first line, MBC	114	None-2 doses of H used	24.4	3.8	26% (18%-34%)	N/A (approximat- ely 65%)	Vogel et al[45]
Ado-trastuzumab	Phase II, refractory MBC	110	None	N/A	6.9 (4.2–8.4)	34% (26%-44%)	N/A	Krop et al[48]
Anti-HER-2 + QT
H + Paclitaxel (T)	Phase III, first line, MBC	469	QT (AC or T) + H vs QT	25.1 vs 20.3	7.4 vs 4.6	50% vs 32%	78% vs 67%	Slamon et al[44]
Cont. Anti-HER-2 after failing 1st line
Lapatinib (L)	Phase III, failed to H	324	Cape + L vs Cape alone	N/A	8.4 vs 4.4	22% vs 14%	N/A (approximat- ely 60%)	Geyer et al[54]
EMILIA Trial (Ado-trastuzumab)	Phase III, MBC who failed TH	991	Ado-T vs Cape + L	30.9 vs 25.1	9.6 vs 6.4	43.6% vs 30.8%	85% vs 78%	Verma et al[55]
Dual Anti-HER-2
CLEOPATRA	Phase III, first line, MBC	808	Do + H + P vs Do + H	Not reached	18.5 vs 12.4	80% vs 69%	N/A (approximat- ely 90%-95%)	Baselga et al[57]
Lap + Trastuzumab	Phase III, failed to H	296	L + H vs L alone	11.8 vs 8.9	2.75 vs 1.85	10% vs 7%	70% vs 36%	Blackwell et al[59]
H + Pertuzumab (P)	Phase II, failed to H	66	None-H + P single arm	N/A	5.5	24.20%	N/A	Baselga et al[61]
Anti-HER-2 + AI
Anastrozole + H	Phase III, HR and HER-2 positive, 1st line in MBC	207	Anastrozole + H vs Anastrozole alone	28.5 vs 23.9	4.8 vs 2.4	20% vs 6.8%	N/A (approximat- ely 78%)	Kaufman et al[63]
Letrozole + L	Same	219	Letrozole + L vs Letrozole alone	33.3 vs 32.3	8.2 vs 3.0	28% vs 15%	N/A	Johnston et al[64]

QT: Chemotherapy; AI: Aromatase Inhibitor; MBC: Metastatic breast cancer; HR: Hormones receptor; Do: Docetaxel; AC: Adriamycin cyclophosphamide; T: Paclitaxel; OS: Overall survival; TTP: Time to progression; N/A: Not available or not reported.