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Therapeutic predictors of neoadjuvant endocrine therapy response in estrogen receptor-positive breast cancer with reference to optimal gene expression profiling

  • Preclinical study
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Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Neoadjuvant endocrine therapy (NAET) for estrogen receptor-positive primary breast cancer causes adequate tumor shrinkage, and is expected to be helpful for breast-conserving surgery, but the adaptation criteria, especially in regard to treatment duration, have never been elucidated. Re-visiting past gene expression profiles, we explored the data for specialized pre-therapeutic predictors and validated the results using our in-house clinical cohorts.

Methods

We sorted the genes related to a > 30% tumor volume reduction through NAET from a cDNA microarray data-set of GSE20181, then selected the top 40 genes. We validated these gene expression levels using pre-therapeutic biopsy samples obtained from patients treated with long-term NAET (over 4 months; N = 40). A short-term (2–8 weeks; N = 37) NAET cohort was also validated to clarify whether expression of these genes is also related to a rapid response of Ki67 and PEPI score.

Results

In the long-term group, higher expression of KRAS, CUL2, FAM13A, ADCK2, and LILRA2 was significantly associated with tumor shrinkage, and KRAS, MMS19, and IVD were related to lower PEPI score (≤ 3). Meanwhile in the short-term group, none of these genes except CUL2 showed a direct correlation with Ki67 reduction or PEPI score. This suggested that tumor shrinkage by NAET might be induced by response to the hypoxic environment (CUL2, FAM13A, KRAS) and activation of tumor immune system (LILRA2), without involving inhibition of proliferation.

Conclusion

Expression of specific genes may allow selection of the most responsive patients for maximum tumor shrinkage with NAET.

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Funding

This study was founded by a Grant in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (M. Ibusuki-Yamamoto, 25870539 and 15K21237).

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Authors and Affiliations

  1. The Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

    Lisa Goto-Yamaguchi, Mutsuko Yamamoto-Ibusuki, Yutaka Yamamoto, Yoshitaka Fujiki, Mai Tomiguchi, Aiko Sueta, Takashi Takeshita & Hirotaka Iwase

Authors
  1. Lisa Goto-Yamaguchi
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  2. Mutsuko Yamamoto-Ibusuki
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  3. Yutaka Yamamoto
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  4. Yoshitaka Fujiki
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  5. Mai Tomiguchi
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  6. Aiko Sueta
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  7. Takashi Takeshita
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  8. Hirotaka Iwase
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Corresponding author

Correspondence to Yutaka Yamamoto.

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Conflict of interest

Y.Y has received fees for serving on advisory boards and a speaker honorarium from Astra Zeneca, Novartis, and Pfizer. L.G-Y, M.Y-I, Y.F, M.T, A.S, T.T and H.I declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Goto-Yamaguchi, L., Yamamoto-Ibusuki, M., Yamamoto, Y. et al. Therapeutic predictors of neoadjuvant endocrine therapy response in estrogen receptor-positive breast cancer with reference to optimal gene expression profiling. Breast Cancer Res Treat 172, 353–362 (2018). https://doi.org/10.1007/s10549-018-4933-5

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  • DOI: https://doi.org/10.1007/s10549-018-4933-5

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