Breast Cancer Research and Treatment

, Volume 157, Issue 1, pp 55–63 | Cite as

Protective effect of naturally occurring anti-HER2 autoantibodies on breast cancer

  • Yukiko Tabuchi
  • Masafumi Shimoda
  • Naofumi Kagara
  • Yasuto Naoi
  • Tomonori Tanei
  • Atsushi Shimomura
  • Kenzo Shimazu
  • Seung Jin Kim
  • Shinzaburo Noguchi
Preclinical Study


Anti-HER2-autoantibodies (HER2-AAbs) are found in breast cancer patients as well as healthy individuals. However, the clinical relevance of the antibodies is unknown. We established an enzyme-linked immunosorbent assay with high sensitivity and quantified serum HER2-AAbs in 100 healthy women, 100 untreated patients with ductal carcinoma in situ (DCIS), and 500 untreated patients with invasive breast carcinoma (IBC). The associations between the levels of HER2-AAbs and breast cancer risk, and recurrence-free survival, were examined. High levels of HER2-AAbs were significantly associated with a reduced risk of DCIS (odds ratio [OR] 0.19, P = 4.6 × 10−7) or IBC (OR 0.31, P = 3.7 × 10−7). Subgroup analysis of IBC revealed a stronger association of HER2-AAbs with a reduced risk of the hormone receptor (HR)/HER2+ subtype (OR 0.12) than the other subtypes (HR+/HER2 [OR = 0.32], HR+/HER2+ [OR 0.38], and HR/HER2 [OR 0.29]). When we set the cutoff of HER2-AAbs at 20 ng/mL, recurrence-free survival of HER2-AAb-positive patients (N = 74) was significantly better than that of HER2-AAb-negative patients (N = 426) (P = 0.015). Univariate and multivariate analyses demonstrated that HER2-AAbs, as well as histological grade, were independently and significantly (P = 0.0065 and 0.049, respectively) associated with recurrence-free survival. Our exploratory study suggests a protective effect of naturally occurring HER2-AAbs on the development of primary and recurrent breast cancer. Further studies on HER2-AAbs are warranted.


HER2 Autoantibodies Humoral immunity Enzyme-linked immunosorbent assay Immunotherapy 



This study was supported, in part, by a research grant from AstraZeneca (Grant ID: 201500400) and Novartis Pharma. We are grateful to Dr. Junichiro Ikeda and Dr. Tsutomu Kasugai for a help with the pathological evaluations. We thank Dr. Yoshiaki Sota for valuable comments on the statistical analyses and Dr. Koji Morimoto for administrative works.

Compliance with ethical standards

Conflicts of Interest

Masafumi Shimoda has received research grants from AstraZeneca. Shinzaburo Noguchi received honoraria from Chugai Pharmaceutical, and has received research grants from AstraZeneca, Novartis Pharma, and Chugai Pharmaceutical.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional research ethics committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

10549_2016_3801_MOESM1_ESM.eps (932 kb)
Supplementary material 1 (EPS 931 kb) Supplementary Fig. S1 Evaluation of serum backgrounds. Absorbance at 450 nm (A450) of patient serum samples loaded on both wells coated with HER2-ECD and wells left uncoated. (a) Comparison of absorbance of coated wells (Coated) with absorbance of uncoated wells (Uncoated). (b) The concentrations of HER2-AAbs in each serum was calculated using only A450 of coated wells (Coated), and using A450 of coated wells from which A450 of uncoated wells were subtracted (Coated–Uncoated). Two values from each sample were compared in order to evaluate the effect of serum backgrounds
10549_2016_3801_MOESM2_ESM.eps (761 kb)
Supplementary material 2 (EPS 760 kb) Supplementary Fig. S2 Spike-in test. A450 of trastuzumab serially diluted with fetal bovine serum (FBS) or with human serum containing a low level of HER2-AAbs are shown
10549_2016_3801_MOESM3_ESM.eps (789 kb)
Supplementary material 3 (EPS 789 kb) Supplementary Fig. S3 Competition assay. Influence of HER2-ECD preincubation with serum samples from two patients on the ELISA signals was evaluated
10549_2016_3801_MOESM4_ESM.doc (32 kb)
Supplementary material 4 (DOC 31 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Yukiko Tabuchi
    • 1
  • Masafumi Shimoda
    • 1
  • Naofumi Kagara
    • 1
  • Yasuto Naoi
    • 1
  • Tomonori Tanei
    • 1
  • Atsushi Shimomura
    • 1
  • Kenzo Shimazu
    • 1
  • Seung Jin Kim
    • 1
  • Shinzaburo Noguchi
    • 1
  1. 1.Department of Breast and Endocrine SurgeryOsaka University Graduate School of MedicineSuitaJapan

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