title: Improved Survival of HER2+ Breast Cancer Patients Treated with Trastuzumab and Chemotherapy Is Associated with Host Antibody Immunity against the HER2 Intracellular Domain.
abstract: The addition of trastuzumab to chemotherapy extends survival among patients with HER2(+) breast cancer. Prior work showed that trastuzumab and chemotherapy augments HER2 extracellular domain (ECD)-specific antibodies. The current study investigated whether combination therapy induced immune responses beyond HER2-ECD and, importantly, whether those immune responses were associated with survival. Pretreatment and posttreatment sera were obtained from 48 women with metastatic HER2(+) breast cancer on NCCTG (now Alliance for Clinical Trials in Oncology) studies, N0337 and N983252. IgG to HER2 intracellular domain (ICD), HER2-ECD, p53, IGFBP2, CEA, and tetanus toxoid were examined. Sera from 25 age-matched controls and 26 surgically resected HER2(+) patients were also examined. Prior to therapy, some patients with metastatic disease had elevated antibodies to IGFBP2, p53, HER2-ICD, HER2-ECD, and CEA, but not to tetanus toxin, relative to controls and surgically resected patients. Treatment augmented antibody responses to HER2-ICD in 69% of metastatic patients, which was highly associated with improved progression-free survival (PFS; HR = 0.5, P = 0.0042) and overall survival (OS; HR = 0.7, P = 0.038). Augmented antibody responses to HER2-ICD also correlated (P = 0.03) with increased antibody responses to CEA, IGFBP2, and p53, indicating that treatment induces epitope spreading. Paradoxically, patients who already had high preexisting immunity to HER2-ICD did not respond to therapy with increased antibodies to HER2-ICD and demonstrated poorer PFS (HR = 1.6, P < 0.0001) and OS (HR = 1.4, P = 0.0006). Overall, the findings further demonstrate the importance of the adaptive immune system in the efficacy of trastuzumab-containing regimens. Cancer Res; 76(13); 3702-10. ©2016 AACR.
authors.affiliation: Department of Immunology, Mayo Clinic, Jacksonville, Florida. knutson.keith@mayo.edu.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
authors.affiliation: Division of Hematology and Oncology, Columbia University, New York, New York.
authors.forename: Raphael
authors.initials: R
authors.lastname: Clynes
authors.affiliation: Department of Immunology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Barath
authors.initials: B
authors.lastname: Shreeder
authors.affiliation: Cancer Vaccines and Immune Therapies Program, Center for Diseases of Aging, Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Patrick
authors.initials: P
authors.lastname: Yeramian
authors.affiliation: Cancer Vaccines and Immune Therapies Program, Center for Diseases of Aging, Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Kathleen P
authors.initials: KP
authors.lastname: Kemp
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Karla
authors.initials: K
authors.lastname: Ballman
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Tenner
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Erskine
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Nadine
authors.initials: N
authors.lastname: Norton
authors.affiliation: Division of Hematology and Oncology, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Donald
authors.initials: D
authors.lastname: Northfelt
authors.affiliation: Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Winston
authors.initials: W
authors.lastname: Tan
authors.affiliation: Memorial Hospital, Hollywood, Florida.
authors.forename: Carmen
authors.initials: C
authors.lastname: Calfa
authors.affiliation: Stanford University, Stanford, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Pegram
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mittendorf
authors.affiliation: Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000401:mortality*; D000069287:Capecitabine / Q000008:administration & dosage; D016190:Carboplatin / Q000008:administration & dosage; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007114:Immunization; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D015996:Survival Rate; D000068878:Trastuzumab / Q000008:administration & dosage; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D014408:Biomarkers, Tumor; D000069287:Capecitabine; D016190:Carboplatin; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D014747:Vinblastine; D000077235:Vinorelbine