1 Introduction
1.1 Background
1.2 HER2/HER3 pathway
1.3 HER2 and HER3 determination
0+ (negative) | 1+ (weak; negative) | 2+ (moderate; equivocal) | 3+ (strong; positive) | |
---|---|---|---|---|
HER2 expression (IHC) | ||||
Breast cancer | No staining observed or membrane staining that is incomplete and is faint/barely perceptible and within ≤10 % of the invasive tumor cells | Incomplete membrane staining that is faint/barely perceptible and within >10 % of the invasive tumor cells | Circumferential membrane staining that is incomplete and/or weak/moderate and within >10 % of the invasive tumor cells or complete and circumferential membrane staining that is intense and within ≤10 % of the invasive tumor cells | Circumferential membrane staining that is complete and intense in >10 % of the cancerous cells |
Gastric cancer; surgical specimens | No reactivity or membranous reactivity in <10 % of cells | Faint⁄barely perceptible membranous reactivity in >10 % of cells; cells are reactive only in part of their membrane | Weak to moderate complete or basolateral membranous reactivity in >10 % of tumor cells | Moderate to strong complete or basolateral membranous reactivity in >10 % of tumor cells |
Gastric cancer; biopsy specimens | No reactivity or no membranous reactivity in any tumor cell | Faint/barely perceptible membranous reactivity irrespective of percentage of tumor cells | Weak to moderate complete, basolateral or lateral membranous reactivity irrespective of percentage of tumor cells | Strong complete, basolateral or lateral membranous reactivity irrespective of percentage of tumor cells |
HER2 amplification (ISH) | ||||
Breast cancer | HER2 FISH testing (gene copy number and HER2-to-CEP17 ratio) positive: HER2 gene copy number is greater than 6.0 (single probe) and in case of HER2 2+ if either HER2/CEP17 ratio is ≥2.0 regardless gene copy number or if HER2/CEP17 ratio is <2.0 with an average HER2 copy number ≥6.0 (dual probe) | |||
Gastric cancer | FISH amplified (positive): IHC/HER2 2+ tumor samples are considered FISH amplified if HER2/CEP17 ratio is ≥2 |
2 Methods
2.1 Study selection criteria
2.2 Search strategy
2.3 Primary and secondary objectives
2.4 Data collection
2.5 Statistical analysis
3 Results
3.1 Eligible studies
3.2 Patient population
Study | Country |
N
| Primary | HER2/IHC | HER2/ISH | HER3/IHC | HER3/ISH | ||||
---|---|---|---|---|---|---|---|---|---|---|---|
N
| % |
N
| % |
N
| % |
N
| % | ||||
Brunt EM | USA (Western) | 6 | CC | 4/6 | 66.7 | NR | NR | NR | |||
Collier JD 1992 | UK (Western) | 10 | CC | 0/10 | 0 | NR | NR | NR | |||
Lei S 1995 | USA (Western) | 6 | AC | 2/6 | 33.3 | NR | NR | NR | |||
Chow NH 1995 | Taiwan (China) (Asian) | 18 | IHCC | 5/18 | 27.8 | NR | NR | NR | |||
18 | AC | 5/18 | 27.8 | NR | NR | NR | |||||
11 | GBC | 7/11 | 63.6 | NR | NR | NR | |||||
Vaidya P 1996 | Japan (Asian) | 14 | EHCC | 10/14 | 71.4 | NR | 4/14 | 28.6 | NR | ||
13 | AC | 9/13 | 69.2 | NR | 4/13 | 30.8 | NR | ||||
Terada T 1998 | Japan (Asian) | 47 | CC | 33/47 | 70 | NR | NR | NR | |||
Kim YW 2001 | Not specified | 71 | GBC | 33/71 | 46.5 | NR | NR | NR | |||
Ajiki T 2001 | Japan (Asian) | 30 | AC | 7/30 | 23 | NR | NR | NR | |||
Ukita Y 2002 | Japan (Asian) | 22 | IHCC | 18/22 | 82 | 22/22 | 100 | NR | NR | ||
Endo K 2002 | Japan, Thailand, USA (n/a) | 71 | CC | 21/71 | 29.6 | NR | NR | NR | |||
Altimari A 2003 | Italy (Western) | 48 | IHCC | 2/48 | 4 | 2/48 | 4 | NR | NR | ||
Matsuyama S 2004 | Japan (Asian) | 43 | GBC | 4/43 | 9.4 | NR | NR | NR | |||
KIM HJ 2005 | South Korea (Asian) | 20 | CC | 5/20 | 25 | NR | NR | NR | |||
Nakazawa K 2005 | Japan (Asian) | 28 | IHCC | 0/28 | 0 | NR | NR | NR | |||
78 | EHCC | 4/78 | 5.1 | NR | NR | NR | |||||
89 | GBC | 14/89 | 15.7 | NR | NR | NR | |||||
26 | AV | 3/26 | 11.5 | NR | NR | NR | |||||
71 | BTC | – | 15/71 | 21.1 | – | – | |||||
19 | BTC | – | 15/19 | 79 | – | – | |||||
Settakorn J 2005 | Australia/Thailand (n/a) | 31 | IHCC | 10/31 | 32.3 | NR | NR | NR | |||
Ogo Y 2006 | Japan (Asian) | 72 | BTCs | 47/72 | 65 | NR | NR | NR | |||
Kim JH 2007 | South Korea (Asian) | 55 | EHCC | 16/55 | 29.1 | 10/55 | 18.1 | NR | NR | ||
Kawamoto T 2007 | USA/Chile (Western) | 21 | IHCC | 7/21 | 33.3 | 0/14 | 0 | NR | NR | ||
16 | EHCC | 5/16 | 33.3 | 3/14 | 21.4 | NR | NR | ||||
77 | GBC | 24/77 | 31.2 | 14/67 | 20.9 | NR | NR | ||||
Yoshikawa D 2008 | Japan (Asian) | 106 | IHCC | 1/106 | 0.9 | NR | NR | NR | |||
130 | EHCC | 11/130 | 8.5 | NR | NR | NR | |||||
Miyahara n 2008 | Japan (Asian) | 51 | GBC | 16/51 | 31 | 4/16 | 25 | NR | NR | ||
Joo HH 2007 | South Korea (Asian) | 112 | BTCs | 5/112 | 4.5 | NR | NR | NR | |||
Puhalla H 2007 | Austria (Western) | 55 | GBC | 7/55 | 13 | NR | NR | NR | |||
Kaufmann M 2008 | USA (Western) | 16 | GBC | 1/16 | 6.3 | NR | NR | NR | |||
Baumhoer D 2008 | Switzerland, Germany, Italy (Western) | 82 | AV | NR | 5/82 | 6 | NR | NR | |||
Choi HJ 2009 | Not specified | 50 | IHCC | 36/50 | 72 | NR | NR | NR | |||
Aloysius MM 2009 | UK (Western) | 29 | EHCC | 0/29 | 0 | NR | NR | NR | |||
22 | AV | 0/22 | 0 | NR | NR | NR | |||||
Harder J 2009 | Germany (Western) | 124 | BTCs | 25/124 | 20.2 | 6/25 | 24 | NR | NR | ||
Shafizadeh N 2010 | USA (Western) | 26 | IHCC | 0/26 | 0 | NR | NR | NR | |||
19 | EHCC | 2/19 | 10.5 | NR | NR | NR | |||||
6 | GBC | 0/6 | 0 | NR | NR | NR | |||||
Pignochino Y 2010 | Italy (Western) | 17 | IHCC | 0/10 | 0 | NR | NR | NR | |||
19 | EHCC | 4/19 | 21 | 2/4 | 50 | NR | NR | ||||
13 | GBC | 1/10 | 10 | 1/1 | 100 | NR | NR | ||||
Toledo C 2012 | Chile (Western) | 12 | GBC | 4/12 | 33 | 0/12 | 0 | NR | NR | ||
Kumari N 2012 | India (Asian) | 104 | GBC | 14/104 | 13.4 | NR | NR | NR | |||
Lee HJ 2012 | South Korea (Asian) | 230 | EHCC | 13/224 | 6 | NR | 90/230 | 39 | NR | ||
Roa Iván 2013 | Chile (Western) | 187 | GBC | 62/187 | 31.11 | NR | NR | NR | |||
Wang W 2014 | China (Asian) | 58 | IHCC | 0/90 | 0 | 0/90 | 0 | NR | NR | ||
94 | EHCC | 4/90 | 4.4 | 3/94 | 3.5 | NR | NR | ||||
Graham RP 2014 | USA (Western) | 100 | BTCs | 3/100 | 3 | 3/3 | 100 | NR | NR | ||
Yang X 2014 | China (Asian) | 65 | IHCC | 0/65 | 0 | 0/65 | 0 | 8/65 | 12.3 | NR | |
110 | EHCC | 5/110 | 4.5 | 8/108 | 7.4 | 13/110 | 11.8 | NR | |||
Kawamoto T 2015 | USA | 47 | GBC | 15/47 | 32 | 8/47 | 17 | 16/47 | 34 | 12/47 | 26 |
Japan (n/a) | 66 | CC | 15/66 | 23 | 15/66 | 23 | 19/66 | 29 | 18/66 | 27 | |
Hechtman J 2015 | USA (Western) | 106 | AC | 27/106 | 25.5 | 13/100 | 13 | NR | NR | ||
Oliveira Fernandes VT 2015 | Brazil (Western) | 38 | CC | 11/38 | 30 | NR | NR | NR | |||
Holcombe RF 2015 | USA (Western) | 126 | EHCC | NR | NR | 18 | NR | NR | |||
434 | IHCC | NR | NR | 1.5 | NR | NR | |||||
244 | GBC | NR | NR | 15 | NR | NR |
3.3 HER2 expression (IHC)
Study | HER2 | HER3 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Platform | IHC scoring | Qualitative/semiquantitative | LQ/HQ assessment | ISH | Selection of patients for ISH | Platform | IHC scoring | Qualitative/semiquantitative | LQ/HQ assessment | ISH | |
Brunt EM 1992 | MAb (Triton Biosciences Inc., USA) | Weak (1+), moderate (2+) or strong (3+), and focal or diffuse | Semiquantitative | LQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Collier JD 1992 | MAb NCL-CB11 | Negative and positive | Qualitative | LQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Lei S 1995 | MAb CB11 | Negative, weak, moderate, or strong | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Chow NH 1995 | MAb-1 (Triton Biosciences Inc., USA) | Focal staining (+) and diffuse staining (++) | Qualitative | LQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Vaidya P 1996 | PolyAb (Dakopatts, Denmark) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | Novocastra Lab. Ltd., UK | A 4r-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a |
Terada T 1998 | MAb 3B5 (Immunotech, France) | A 5-point scale: –, +, ++, +++, and ++++ | Semiquantitative | LQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Kim YW 2001 | PolyAb (Dako, USA) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | LQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Ajiki T 2001 | PolyAb (Dako, Denmark) | Immunoreactivity present in more than 10 % of tumor cells | Semiquantitative | LQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Ukita Y 2002 | MAb 3B5 (Immunotech, France) | A 5-point scale: –, +, ++, +++, and ++++ | Semiquantitative | LQ | FISH | Unselected | n/a | n/a | n/a | n/a | n/a |
Endo K 2002 | Mab F-11 (Dako, USA) | A 5-point scale: 0, ±, +, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Altimari A 2003 | PolyAb HercepTest (Dako, Denmark) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | CISH | Unselected | n/a | n/a | n/a | n/a | n/a |
Matsuyama S 2004 | PolyAb HercepTest (Dako, Denmark) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Kim HJ 2005 | MAb (Oncogene, USA) | Negative or positive | Qualitative | LQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Nakazawa 2005 | PolyAb (Nichirei, Japan) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | FISH | Unselected and selected | n/a | n/a | n/a | n/a | n/a |
Settakorn J 2005 | PolyAb (HercepTest, Dako) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Ogo Y 2006 | PolyAb (HercepTest Dako, A0485) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Kim HJ 2007 | PolyAb (Zymed Lab, USA) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | CISH | Unselected | n/a | n/a | n/a | n/a | n/a |
Kawamoto T 2007 | PolyAb HercepTest (Dako, Denmark) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | FISH | Unselected | n/a | n/a | n/a | n/a | n/a |
Yoshikawa D 2008 | Polyab HercepTest (Dako, Denmark) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Baumhoer D 2008 | n/a | n/a | n/a | LQ | FISH | Unselected | n/a | n/a | n/a | n/a | n/a |
Miyahara N 2008 | PolyAb HercepTest (Dako) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | FISH | Selected | n/a | n/a | n/a | n/a | n/a |
Joo HH 2007 | PolyAb (Zymed) | A distinctive membrane staining was referred as positive | Qualitative | LQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Puhalla H 2007 | PolyAb HercepTest (Dako) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Kaufmann M 2008 | MAb CB11 (Carpinteria, USA) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Aloysius MM 2009 | PolyAb HercepTest (Dako) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Harder J 2009 | PolyAb (Dako REAL™, Denmark) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | FISH | Selected | n/a | n/a | n/a | n/a | n/a |
Choi 2009 | NR | NR | NR | LQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Shafizadeh N 2010 | MAb CB11, (Ventana, USA) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Pignochino Y 2010 | PolyAb HercepTest (Dako) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | FISH | Selected | n/a | n/a | n/a | n/a | n/a |
Toledo C 2012 | MAb NCL-CBE-356 (Novocastra) | Positive or negative | Qualitative | LQ | FISH | Unselected | n/a | n/a | n/a | n/a | n/a |
Kumari N 2012 | PolyAb (Dako) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Lee HJ 2012 | PolyAb A0485 (Dako, Denmark) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | MAb RTJ.2 (Santa Cruz, USA) | Staining intensity and percentage of positive cellsa
| Semiquantitative | HQ | n/a |
Roa I 2013 | MAb NCL-CB11 (Novocastra) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Wang W 2014 | PolyAb (Dako, USA) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | FISH | Unselected | n/a | n/a | n/a | n/a | n/a |
Graham 2014 | PolyAb HercepTest (Dako, USA) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | FISH | Selected | n/a | n/a | n/a | n/a | n/a |
Yang X 2014 | PolyAb (Dako) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | FISH | Unselected | sc-415 (Santa Cruz Biotechnology, USA) | Rajikumar scoreb
| Semiquantitative | HQ | n/a |
Kawamoto T 2015 | PolyAb HercepTest II (Dako A/S, Denmark) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | FISH | Unselected | Spring Bioscience, USA | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | FISH |
Hechtman J 2015 | MAb 4B5 (Ventana Medical Systems, USA) | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | CISH | Unselected | n/a | n/a | n/a | n/a | n/a |
Oliveira Fernandes VT 2015 | NR | A 4-point scale: 0, 1+, 2+, and 3+ | Semiquantitative | HQ | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
Holcombe RF 2015 | n/a | n/a | n/a | LQ | FISH | Unselected | n/a | n/a | n/a | n/a | n/a |
HER2 status | No. of studies | Expression rate mean (95 % CI, %) |
p value | |
---|---|---|---|---|
Overall expression by IHC | All | 38 | 26.5 % (18.9–34.1 %) | |
By ethnicity | Asian | 17 | 28.4 % (14.5–42.3 %) | Ref |
Western | 16 | 19.7 % (10.1–29.2 %) | 0.4936 | |
By IHC assessment (quality) | Low quality (LQ) | 11 | 41.7 % (22.9–60.5 %) | Ref |
High quality (HQ) | 27 | 20.3 % (13.2–27.5 %) |
0.0336
| |
By site of primary (HQ studies only) | IHCC | 8 | 4.8 % (0–14.5 %) | Ref |
EH-BTC | 28 | 19.9 % (12.8–27.1 %) |
0.0049
| |
EHCC | 11 | 17.4 % (3.4–31.4 %) |
0.0134
| |
GBC | 12 | 19.1 % (11.2–26.8 %) |
0.0123
| |
AC | 5 | 27.9 % (0–60.7 %) | 0.0642 | |
Overall amplification by ISH | All | 16 | 30.1 % (11.7–48.5 %) | |
By site of primary | IHCC | 6 | 17.6 % (0–60.1 %) | Ref |
EH-BTC | 14 | 22.5 % (7.9 %–37.2 %) |
0.0468
| |
By patient selection | Unselected | 12 | 17.9 % (0.1–35.4 %) | Ref |
Selected | 5 | 57.6 % (16.2–99 %) |
0.0072
|