Table 11Hierarchy of evidence, KQ3a

Level of EvidenceStudynSettingTreatmentsOutcome Results
Adjuvant chemotherapy for resected early breast cancer
HER2 stratified or HER2-guided RCT
RCT prespecified MV SGA Martin 20051262adjuvantTAC vs. FACDFSCox regression treatment by FISH
HER2 interaction, p=NS  FISH+ TAC > FAC, FISH- TAC > FAC
RCT post-hoc MV SGA Gusterson 20031506adjuvantLN-: no tx vs. CMFOSLN- adjusted Cox regression IHC
HER2+, tx < cx p=NSLN+: periop CMF vs. prolonged CMFLN- adjusted Cox regression IHC
HER2-, tx ≈ cx p=NSLN+ adjusted Cox regression IHC
HER2+, tx < cx p=NSLN+ adjusted Cox regression IHC
HER2-, tx > cx p<0.05DFSLN- adjusted Cox regression IHC
HER2+, tx < cx p=NSLN- adjusted Cox regression IHC
HER2-, tx > cx p=NSLN+ adjusted Cox regression IHC
HER2+, tx > cx p=NSLN+ adjusted Cox regression IHC
HER2-, tx > cx p<0.05
Moliterni 2003506adjuvantCMF→A vs. CMFOSCox regression treatment by IHC
HER2 interaction p=0.052 HER2+ tx > cx p= NS, HER2- tx < cx p=NS
RFSCox regression treatment by IHC
HER2 interaction p=NS HER2+ tx > cx p= NS, HER2- tx < cx p=NS
Colozza 2005266adjuvantCMF vs. epirubOSCox regression treatment by IHC
HER2 interaction p=NS cx HER2+ < HER2- p=0.024, tx
HER2+ < HER2- p=NS
HER2 interaction p=NSRFSCox regression treatment by IHC
HER2+ < HER2-p=NS cx HER2+ HER2- p=NS, tx
Pritchard 2006628adjuvantCMF vs. CEFOSCox regression treatment by FISH
HER2 interaction p=0.02
 HER2+ tx > cx p=0.06, HER2- tx ≈ cx p=NS
RFSCox regression treatment by FISH
HER2 interaction p=0.02 HER2+ tx > cx p=0.003, HER2- tx ≈ cx p=NS
Knoop 2005805adjuvantCMF vs. CEFOSCox regression HER2+ tx > cx p=0.09, HER2- tx > cx p=0.23
RFSCox regression HER2+ tx > cx p=0.10, HER2- tx > cx p=0.10
Dressler 2005521adjuvantCAF: high vs. mode-DFSCox regression FISH HER2 by CAF
dose interaction, p=0.033rate vs. low doseCox regression IHC HER2 by CAF
dose interaction, p=0.0003Cox regression PCR HER2 by CAF
dose interaction, p=0.043 FISH+/PCR+/IHC+ high > moderate ≈ low dose
 FISH-/PCR-/IHC- high ≈ moderate ≈ low dose
Del Mastro 2004731adjuvantFEC q2wk vs. q3wkDFSCox regression IHC HER2 by Tx
schedule interaction, p=0.12 FEC q2wk HER2 + ≈ HER2-, FEC
q3wk HER2+ < HER2-OSCox regression IHC HER2 by Tx
schedule interaction, p=0.38 FEC q2wk HER2 + ≈ HER2-, FEC
q3wk HER2+ < HER2-
Hayes 20071500adjuvantAC vs. AC→POSCox regression treatment by FISH
HER2 interaction p=0.01DFS HER2+ tx > cx, HER2- tx ≈ cx
Cox regression treatment by FISH
HER2 interaction p=0.01HER2+ tx > cx, HER2- tx ≈ cx
RCT treatment by HER2 SGA
1-arm prespecified MV analysis
1-arm post-hoc MV analysis
1-arm UV analysis Yang 200394adjuvantCMFDFSIHC HER2+ ↓ vs. HER2- p=0.002
Tanner 2006180adjuvantFECOSCISH HER2+ < HER2- but not statistical tests described
RFSCISH HER2+ < HER2- but not statistical tests described
Neoadjuvant (preoperative) chemotherapy for locally advanced breast cancer
HER2 stratified or HER2-guided RCT
RCT prespecified MV SGA
RCT post-hoc MV SGA Learn 2005104neoadjuvantAC vs. AC+DpCRIHC HER2+, AC vs. AC+D, p=NS
IHC HER2-, AC vs. AC+D, p=NS
cORRIHC HER2+, AC vs. AC+D, p=NS
(CR+PR)IHC HER2-, AC vs. AC+ D, p<0.05
RCT treatment by HER2 SGA
1-arm prespecified MV analysis
1-arm post-hocPark 200367neoadjuvantdoxorubpRespCISH HER2+ > HER2- p=0.013
MV analysis Zhang 200397neoadjuvantFACDFSCISH HER2+ ≈ HER2- p=NS
ORRIHC HER2+ > HER2- p=NS
pRespIHC HER2+ > HER2- p=NS
1-arm UV analysis Arriola 2006229neoadjuvantdoxorubpRespCISH HER2+ > HER2- p=0.03
Tulbah 200252neoadjuvantpaclit+cisplpRespIHC HER2+ ≈ HER2- p=NS
OSIHC HER2+ (3+) ≈ HER2- p=NS
OSIHC HER2+ (2+/3+) ≈ HER2- p=0.051
DFSIHC HER2+ (3+) ≈ HER2- p=NS
DFSIHC HER2+ (2+/3+) ≈ HER2- p=0.09
Tinari 200677neoadjuvantFECpResp (pCR+MRD)IHC 3+ or IHC2+/FISH+ HER2+ vs. HER2-, p=0.008
First- or second-line chemotherapy for advanced or metastatic breast cancer
HER2 stratified or HER2-guided RCT
RCT prespecified MV SGA
RCT post-hoc MV SGA Di Leo 2004149metastaticdoxorub vs. docetaxOSCox regression treatment by IHC HER2 interaction p=.10
 IHC/FISH HER2+ tx < cx p=NS, HER2- tx > cx p=.07
TTPCox regression treatment by IHC HER2 interaction p=NS
 IHC/FISH HER2+ tx > cx p=NS, HER2- tx > cx p=NS
Resplogistic regression treatment by IHC HER2 interaction p=.01
 IHC/FISH HER2+ tx > cx p=.04, HER2- tx > cx p=NS, HER2? tx ≈ cx p=NS
Konecny 2004275metastaticepirub+cyclophosph vs. epirub+paclitaxelOSCox regression treatment by IHC HER2 interaction p=NS
 IFISH HER2+ tx > cx p=.059, HER2- tx ≈ cx p=NS
PFSCox regression treatment by IHC HER2 interaction p=.109
 IFISH HER2+ tx > cx p=.062, HER2- tx ≈ cx p=NS
ORRlogistic regression treatment by IHC HER2 interaction p=NS
 IFISH HER2+ tx > cx p=.005, HER2- tx > cx p=.046
RCT treatment by HER2 SGA
1-arm prespecified MV analysis
1-arm post-hoc MV analysis
1-arm UV analysisHarris 2006156metastaticpaclitaxelOSIHC CB11 HER2+ < HER2- p=NS
OSFISH HER2+ < HER2- p=NS
OSIHC HercepTest HER2+ ≈ HER2- p=NS
ORRIHC CB11 HER2+ ≈ HER2- p=NS
ORRFISH HER2+ ≈ HER2- p=NS
ORRIHC HercepTest HER2+ > HER2- p=.026

Abbreviations: Please refer to the text or list of abbreviations at the end of the report for definition of specific chemotherapy regimens/agents. cx: control; DFS: disease-free survival; HR: hazard ratio; MV: multivariate; ORR: overall response rate; OS: overall survival; q2wk: every 2 weeks; q3wk: every 3 weeks; RCT: randomized, controlled trial; RFS: recurrence-free survival; SGA: subgroup analysis; TTP: time to progression; tx: treatment; UV: univariate analysis;

From: 3, Results and Conclusions

Cover of HER2 Testing to Manage Patients With Breast Cancer or Other Solid Tumors
HER2 Testing to Manage Patients With Breast Cancer or Other Solid Tumors.
Evidence Reports/Technology Assessments, No. 172.
Seidenfeld J, Samson DJ, Rothenberg BM, et al.

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