Improved survival of HER2+ breast cancer patients treated with trastuzumab and chemotherapy is associated with host antibody immunity against the HER2 intracellular domain

Keith L Knutson, Raphael Clynes, Barath Shreeder, Patrick Yeramian, Kathleen P. Kemp, Karla Ballman, Kathleen S. Tenner, Courtney L. Erskine, Nadine Norton, Donald W Northfelt, Winston Tan, Carmen Calfa, Mark Pegram, Elizabeth A. Mittendorf, Edith A. Perez

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3702-3710
Number of pages9
JournalCancer Research
Volume76
Issue number13
DOIs
StatePublished - Jul 1 2016

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Immunity
Breast Neoplasms
Drug Therapy
Survival
Antibodies
Antibody Formation
Tetanus Toxin
Therapeutics
Tetanus Toxoid
Serum
Disease-Free Survival
Trastuzumab
Epitopes
Immune System
Immunoglobulin G
Clinical Trials

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Improved survival of HER2+ breast cancer patients treated with trastuzumab and chemotherapy is associated with host antibody immunity against the HER2 intracellular domain. / Knutson, Keith L; Clynes, Raphael; Shreeder, Barath; Yeramian, Patrick; Kemp, Kathleen P.; Ballman, Karla; Tenner, Kathleen S.; Erskine, Courtney L.; Norton, Nadine; Northfelt, Donald W; Tan, Winston; Calfa, Carmen; Pegram, Mark; Mittendorf, Elizabeth A.; Perez, Edith A.

In: Cancer Research, Vol. 76, No. 13, 01.07.2016, p. 3702-3710.

Research output: Contribution to journalArticle

Knutson, Keith L ; Clynes, Raphael ; Shreeder, Barath ; Yeramian, Patrick ; Kemp, Kathleen P. ; Ballman, Karla ; Tenner, Kathleen S. ; Erskine, Courtney L. ; Norton, Nadine ; Northfelt, Donald W ; Tan, Winston ; Calfa, Carmen ; Pegram, Mark ; Mittendorf, Elizabeth A. ; Perez, Edith A. / Improved survival of HER2+ breast cancer patients treated with trastuzumab and chemotherapy is associated with host antibody immunity against the HER2 intracellular domain. In: Cancer Research. 2016 ; Vol. 76, No. 13. pp. 3702-3710.
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AU - Kemp, Kathleen P.

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AU - Tenner, Kathleen S.

AU - Erskine, Courtney L.

AU - Norton, Nadine

AU - Northfelt, Donald W

AU - Tan, Winston

AU - Calfa, Carmen

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