Quantitative proteomic analysis of HER2 expression in the selection of gastric cancer patients for trastuzumab treatment.
A wide range of response rates have been reported in HER2-positive gastric cancer (GC) patients treated with trastuzumab. Other HER2-targeted therapies for GC have yet to show efficacy in clinical trials. These findings raise question about the ability of standard HER2 diagnostics to accurately distinguish between GC patients who would and would not benefit from anti-HER2 therapies.



GC patients (n = 237), including a subset from the Trastuzumab in GC (ToGA) trial were divided into three groups based on HER2 status and history of treatment with standard chemotherapy or chemotherapy plus trastuzumab. We applied mass spectrometry-based proteomic analysis to quantify HER2 protein expression in formalin-fixed tumor samples. Using HER2 expression as a continuous variable, we defined a predictive protein level cutoff to identify which patients would benefit from trastuzumab. We compared quantitated protein level with clinical outcome and HER2 status as determined by conventional HER2 diagnostics.



Quantitative proteomics detected a 115-fold range of HER2 protein expression among patients diagnosed as HER2 positive by standard methods. A protein level of 1825 amol/µg was predicted to determine benefit from the addition of trastuzumab to chemotherapy. Trastuzumab treated patients with HER2 protein levels above this cutoff had twice the median overall survival (OS) of their counterparts below the cutoff (35.0 versus 17.5 months, P = 0.011). Conversely, trastuzumab-treated patients with HER2 levels below the cutoff had outcomes similar to HER2-positive patients treated with chemotherapy. (Progression-free survival = 7.0 versus 6.5 months: P = 0.504; OS = 17.5 versus 12.6 months: P = 0.520). HER2 levels were not prognostic for response to chemotherapy.



Proteomic analysis of HER2 expression demonstrated a quantitative cutoff that improves selection of GC patients for trastuzumab as compared with current diagnostic methods.
NantOmics, Rockville, USA|Oncoplex Diagnostics, Rockville, USA.
E
E
An
Department of Internal Medicine, Seoul National University Hospital, Seoul,  Seoul, Korea.
C-Y
CY
Ock
Department of Internal Medicine, Seoul National University Hospital, Seoul,  Seoul, Korea.
T-Y
TY
Kim
Department of Internal Medicine, Seoul National University Hospital, Seoul,  Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul,  Seoul, Korea.
K-H
KH
Lee
Department of Internal Medicine, Seoul National University Hospital, Seoul,  Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul,  Seoul, Korea.
S-W
SW
Han
Department of Internal Medicine, Seoul National University Hospital, Seoul,  Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul,  Seoul, Korea.
S-A
SA
Im
Department of Internal Medicine, Seoul National University Hospital, Seoul,  Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul,  Seoul, Korea.
T-Y
TY
Kim
NantOmics, Rockville, USA|Oncoplex Diagnostics, Rockville, USA.
W-L
WL
Liao
NantOmics, Rockville, USA|Oncoplex Diagnostics, Rockville, USA.
F
F
Cecchi
NantOmics, Rockville, USA|Oncoplex Diagnostics, Rockville, USA.
A
A
Blackler
NantOmics, Rockville, USA|Oncoplex Diagnostics, Rockville, USA.
S
S
Thyparambil
Department of Pathology, Seoul National University Hospital, Seoul, Korea.
W H
WH
Kim
Oncoplex Diagnostics, Rockville, USA.
J
J
Burrows
NantOmics, Rockville, USA|Oncoplex Diagnostics, Rockville, USA.
T
T
Hembrough
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, USA.
D V T
DVT
Catenacci
Department of Internal Medicine, Seoul National University Hospital, Seoul,  Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul,  Seoul, Korea.
D-Y
DY
Oh
Department of Internal Medicine, Seoul National University Hospital, Seoul,  Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul,  Seoul, Korea.
Y-J
YJ
Bang
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D018579:Patient Selection; D016016:Proportional Hazards Models; D040901:Proteomics / Q000379:methods; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000096:biosynthesis; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D000068878:Trastuzumab / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
HER2; gastric cancer; molecular characterization; proteomics; trastuzumab
J Clin Oncol. 2016 Feb 10;34(5):443-51
26628478
Clin Cancer Res. 2015 Jun 1;21(11):2520-9
25712681
J Mol Diagn. 2013 Jul;15(4):454-65
23672976
Clin Proteomics. 2012 May 03;9(1):5
22554165
Mol Cell Proteomics. 2015 Oct;14 (10 ):2786-99
26149442
Clin Transl Oncol. 2011 Mar;13(3):179-84
21421462
Cancer Cell. 2016 Mar 14;29(3):255-69
26977878
J Clin Oncol. 2013 Dec 10;31(35):4445-52
24127447
CA Cancer J Clin. 2015 Mar;65(2):87-108
25651787
Br J Cancer. 2014 Mar 4;110(5):1163-8
24473399
Cancer Cell. 2007 Oct;12 (4):395-402
17936563
Gastric Cancer. 2016 Oct;19(4):1066-79
26581548
Nature. 2007 Jan 25;445(7126):437-41
17206155
Mol Oncol. 2016 Jan;10 (1):138-147
26422389
J Clin Oncol. 2014 Jul 1;32(19):2039-49
24868024
Ann Oncol. 2013 Mar;24(3):725-33
23139264
Lancet. 2010 Aug 28;376(9742):687-97
20728210