Table 3.

Summary of studies where all patients received anthracycline (compared different doses/frequency)—outcome based on HER2.

Study (Year)	Ref	Regimens	Dz Setting	HER2 evaluable N	Outcomes	Interaction HER2 and outcome	HER2 test assay/definition
CALGB 8541 88691 Muss 1994 Thor 1998 Dressler 2005	91–93	FAC High dose (H) (HFAC) (A = 60 mg/m2 × 4 = 240 mg/m2 total) Standard (S) (FAC) (A = 40 mg/m2 × 6 = 240 mg/m2 total) Low dose (L) (LFAC) (30 mg/m2 × 4 = 120 mg/m2 total)	ADJ	992	5-year DFS H-S-L (based on IHC) HER2+ 71% - 52% - 50% HER2- 65% - 66% - 60% p interaction = 0.001 5-year OS H-S-L HER2+ 87% - 66% - 63% HER2- 77% - 82% - 78% p interaction <0.001	Yes Significant DFS and OS benefit with anthracycline in HER2+ only	IHC CB11 Positive >50% Dressler tested HER2 by IHC/FISH/PCR-all showed benefit of higher dose anthracyclines in HER2+
HE10/97 Kostopoulos 2006	99	E x 3→Tx 3→CMF x 3 E x 4→CMFx4	ADJ	394	OS p int = 0.73 DFS p int = 0.57	No	HercepTest 3+FISH >2
French series Petit 2001	97	FEC50 vs FEC100	NAC	79	Retrospective series Clinical response to six cycles Hi dose anthracycline and HER2+ predicted high objective response ORR HER2+ FEC50 12.5% FEC100 100% ORR HER2− FEC50 74% FEC100 70%	Maybe Non-significant trend toward ORR benefit with high dose anthracycline in HER2+ only	CB11 IHC 2+ or 3+
Belgian1 Di Leo 2001 and 2002	77, 78	EC (E: 60 mg/m2) vs HEC (E: 100 mg/m2) (vs CMF, see Table 2A)	ADJ	481 by IHC 236 FISH (117 HEC, 119 EC)	Predictive value of HER2 may vary according to the Abs used EFS HEC vs EC by IHC HER2+ (CB11/4D5): HR 0.58 HER2 neg: HR = 0.73; p int = 0.49 EFS HEC vs EC by FISH HER2+: HR = 0.90 HER2-: HR = 1.33, p int = 0.53	Maybe Non-significant trend toward better EFS with high dose anthracycline, in HER2+	IHC CB11 and 4D5 And cocktail of TAB-250 and p-Ab HER2+ if >1% cells stained-High (8/21, 38%) false positive with cocktail
FASG-052 Arnould 2003	95	FEC50 vs FEC100	ADJ	332	10-year DFS HER2+ FEC100 55% FEC50 37% HER2- FEC100 39% FEC50 36% p int NR	Maybe Non-significant trend toward better DFS with high dose anthracycline in HER2+	IHC, Ab not stated IHC 2+ or 3+ on 0–3 scale
Dutch Rodenhuis 2006	100	FECx5 vs FECx4-HD chemo and ASCT Analysis of extra doses of anthracycline confounded by fact that FECx4 received high dose chemo/stem cell rescue	ADJ	801	621 HER2 neg-benefitted from less anthracycline and high dose chemo ASCT; HER2+ did not (resistant to alkylating agents); RFS FEC vs FEC-HD/ASCT HER2+ HR = 1.26 HER2− HR = 0.68 p interaction = 0.006	No Significant benefit with less anthracycline and HD chemo/ASCT if HER2 negative	IHC and CISH. IHC 3+ by 3B5 Ab Amplif >5 copies
GONO-MIG-11,2 Del Mastro 2005	96	FEC21 v FEC14	ADJ	731	EFS FEC14 vs FEC21 HER2+ HR = 0.54 HER2− HR = 0.91; p int = 0.12 OS FEC14 vs FEC21 HER2+ HR = 0.59 HER2− HR = 0.79; p int = 0.38	Maybe Non-significant trend toward better EFS/OS with increased frequency anthracycline if HER2+	IHC CB11 IHC 3+ = positive (strong complete membrane staining >10% of tumor cells)
CALGB 9344 Hayes 2007	94	AC +/ pac (A at 60, 75, or 90 mg/m2) × 4	ADJ	1322	No anthracycline dose-response relationship with HER2: 5-year DFS by dose anthracycl. HER2+ 60 mg/m2 63% 90 mg/m2: 63% HER2−: 60 mg/m2 72% 90 mg/m2 69%	No (taxane does better with HER2+)	IHC CB11 >50% staining = positive Or Herceptest 3+ Or FISH >2.0
Dhesy-Thind Meta-analysis 2007	90	Included CALGB 8541 (HFAC/FAC, N = 670), Belgian (HEC/EC by FISH, N = 236), GONO-MIG-1, N = 731)	ADJ	1637	HER2+ had significant DFS benefit with more intense anthracycline regimen HR = 0.54 (95% CI 0.38–0.79) HER2− no signif DFS benefit HR = 0.98
ASG1–3 Fasching 2019	98	EC-Pac q3 weekly (E:90 mg/m2) vs E+Pac q2 weekly (E:120 mg/m2)	ADJ	906	HER2+ significant DFS benefit with ddET vs EC-P: HR = 0.24 (95% CI: 0.10–0.60) HER2− no significant benefit with dose-dense: HR = 1.45 (95% CI 0.86–2.45)	Yes	Not reported