The impact of HER2/neu expression level on response to the E75 vaccine: from U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02.
OBJECTIVE
HER2/neu, a source of immunogenic peptides, is expressed in >75% of breast cancer patients. We have conducted clinical trials with the HER2/neu E75 peptide vaccine in breast cancer patients with varying levels of HER2/neu expression. Vaccine response based on HER2/neu expression level was analyzed.


METHODS
Patients were stratified by HER2/neu expression. Low expressors (n = 100) were defined as HER2/neu immunohistochemistry (IHC) 1(+) to 2(+) or fluorescence in situ hybridization < 2.0. Overexpressors (n = 51) were defined as IHC 3(+) or fluorescence in situ hybridization > or = 2.0. Additional analyses were done stratifying by IHC status (0-3(+)). Standard clinocopathlogic factors, immunologic response (in vivo delayed-type hypersensitivity reactions; ex vivo human leukocyte antigen A2:immunoglobulin G dimer assay), and clinical responses (recurrence; mortality) were assessed.


RESULTS
Low-expressor (control, 44; vaccinated, 56) versus overexpressor patients (control, 22; vaccinated, 29) were assessed. Low expressors, overexpressors, and most IHC-status vaccinated groups responded immunologically. Vaccinated low-expressor patients had larger maximum immunologic responses compared with overexpressor patients (P = 0.04), and vaccinated IHC 1(+) patients had increased long-term immune response (P = 0.08). More importantly, compared with controls, low-expressor patients had a mortality reduction (P = 0.08). The largest decrease in mortality was seen in IHC 1(+) patients (P = 0.05). In addition, a subset of overexpressor patients (n = 7) received trastuzumab before vaccination, and this combination seems safe and immunologically beneficial.


CONCLUSIONS
Most patients with various levels of HER2/neu expression responded immunologically and seemed to benefit from vaccination. The low expressors, specifically IHC 1(+) patients, had more robust immunologic responses and may derive the greatest clinical benefit from the E75 vaccine.
Department of Surgery, General Surgery Service, Brooke Army Medical Center, Houston, Texas 78234, USA.
Linda C
LC
Benavides
Jeremy D
JD
Gates
Mark G
MG
Carmichael
Ritesh
R
Patil
Ritesh
R
Patel
Jarrod P
JP
Holmes
Matthew T
MT
Hueman
Elizabeth A
EA
Mittendorf
Dianna
D
Craig
Alexander
A
Stojadinovic
Sathibalan
S
Ponniah
George E
GE
Peoples
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000401:mortality / Q000628:therapy*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000276:immunology; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019496:Cancer Vaccines; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C474513:HER-2 peptide E75 (369-377), human