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Impact of Topoisomerase IIα, PTEN, ABCC1/MRP1, and KI67 on triple-negative breast cancer patients treated with neoadjuvant chemotherapy

  • Fouzia Guestini
  • Katsuhiko Ono
  • Minoru Miyashita
  • Takanori Ishida
  • Noriaki Ohuchi
  • Saki Nakagawa
  • Hisashi Hirakawa
  • Kentaro Tamaki
  • Yasuyo Ohi
  • Yoshiaki Rai
  • Yasuaki Sagara
  • Hironobu Sasano
  • Keely May McNamara
Preclinical study
  • 193 Downloads

Abstract

Purpose

Triple-negative breast cancer (TNBC) patients with residual disease following neoadjuvant chemotherapy (NAC) harbor higher risk of relapse, and eventual demise compared to those who achieve pathologic complete response. Therefore, in this study, we assessed a panel of molecules involved in key pathways of drug resistance and tumor progression before and after NAC in TNBC patients, in order to clarify the underlying mechanisms.

Methods

We studied 148 TNBC Japanese patients treated with anthracycline/taxane-based NAC. KI67, Topoisomerase IIα (TopoIIα), PTEN, p53, Bcl2, vimentin, ABCG2/BCRP1, ABCB1/MDR1, and ABCC1/MRP1 were immunolocalized in surgical pathology materials before and after NAC.

Results

The status of vimentin and increasing labeling index (LI) of TopoIIα and KI67 in biopsy specimens were significantly associated with those who responded to NAC treatment. The abundance of p53 (p = 0.003), ABCC1/MRP1 (p = 0.033), ABCB1/MDR1 (p = 0.022), and a loss of PTEN (p < 0.0001) in surgery specimens following treatment were associated with pathologic parameters. TopoIIα, PTEN, and ABCC1/MRP1 status predicted pathologic response. In addition, the status of PTEN, ABCC1/MRP1, ABCB1/MDR1, Bcl2, and vimentin in surgical specimens was also significantly associated with adverse clinicopathological factors in surgery specimens, suggesting that these alterations could be responsible for tumor relapse in TNBC patients.

Conclusion

KI67, TopoIIα, PTEN, and ABCC1/MRP1 status could predict treatment response and/or eventual clinical outcomes. These results could also provide an insight into the mechanisms of drug resistance and relapse of TNBC patients receiving NAC.

Keywords

Triple-negative breast cancer Neoadjuvant chemotherapy Mechanistic markers Drug resistance Residual disease Outcomes 

Abbreviations

ABCB1/MDR1

Multidrug resistance 1 encoded by the gene ABCB1

ABCC1/MRP1

Multidrug resistance protein 1 encoded by the gene ABCC1

ABCG2/BCRP1

Breast cancer resistance protein encoded by the gene ABCG2

Bcl2

B-cell lymphoma 2

CI

Confidence interval

CR

Complete response

DFS

Disease-free survival

LI

Labeling index

NAC

Neoadjuvant chemotherapy

OR

Odd ratio

OS

Overall survival

p53

Tumor protein 53

pCR

Pathologic complete response

PD

Progressive disease

PR

Partial response

PTEN

Phosphatase and tensin homolog

RD

Residual disease

SD

Stable disease

TNBC

Triple-negative breast cancer

TNM

Tumor, node, metastasis

TopoIIα

Topoisomerase IIα

Notes

Acknowledgements

The author Fouzia Guestini work was supported by the Japanese Government Ministry of Education, Culture, Sports, Science, and Technology (MEXT). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Supplementary material

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Supplementary material 1 (DOCX 167 KB)
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10549_2018_4985_MOESM5_ESM.docx (851 kb)
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10549_2018_4985_MOESM6_ESM.docx (238 kb)
Supplementary material 6 (DOCX 238 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Fouzia Guestini
    • 1
  • Katsuhiko Ono
    • 1
  • Minoru Miyashita
    • 1
  • Takanori Ishida
    • 1
  • Noriaki Ohuchi
    • 1
  • Saki Nakagawa
    • 1
  • Hisashi Hirakawa
    • 2
  • Kentaro Tamaki
    • 3
  • Yasuyo Ohi
    • 4
  • Yoshiaki Rai
    • 4
  • Yasuaki Sagara
    • 4
  • Hironobu Sasano
    • 1
  • Keely May McNamara
    • 1
  1. 1.Tohoku UniversitySendaiJapan
  2. 2.Tohoku Kousai HospitalSendaiJapan
  3. 3.Nahanishi ClinicOkinawaJapan
  4. 4.Sagara HospitalKagoshimaJapan

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