Time-varying effects of FOXA1 on breast cancer prognosis

Abstract

Purpose

Results of previous studies on the associations between Forkhead box A1 (FOXA1) expression in breast cancer tissues and the prognosis varied depending on the follow-up durations. The present study would investigate whether there is a time-varying effect of FOXA1 in breast cancer tissues on the prognosis.

Methods

FOXA1 expressions were evaluated in 1041 primary invasive breast tumors with tissue microarrays by immunohistochemistry. Cox models with restricted cubic splines and Kaplan–Meier survival analysis were used to examine the associations between FOXA1 and the prognosis. Flexible parametric models were applied to explore the time-varying effect of FOXA1.

Results

Overall, the association between FOXA1 expression and the prognosis was not significant but varied on the time of follow-up. Compared to FOXA1 ≤ 270 of H-score, the hazard ratios (HRs) of death for those with 271–285 of FOXA1 expression increased from 0.35 (95% CI 0.14–0.86) at 6 months after diagnosis to 2.88 (95% CI 1.35–6.15) at 120 months with a crossover at around 36 months. Similar patterns were also observed for FOXA1 > 285 of H-score and for progression free survival (PFS). Moreover, when allowed both FOXA1 and estrogen receptor (ER) to change over time in the model (considering that ER had a similar time-varying effect), these time-varying effects remained for FOXA1 on both overall survival (OS) (P < 0.01) and PFS (P = 0.01) but were attenuated for ER (P = 0.13 for OS).

Conclusions

This study revealed an independent time-varying effect of FOXA1 on breast cancer prognosis, which would provide an insight into the roles of FOXA1 as a marker of breast cancer prognosis and may help optimize the medication strategies.

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Abbreviations

CI:

Confidence interval

DAB:

Diaminobenzidine

ER:

Estrogen receptor

EMT:

Epithelial to mesenchymal transition

FOXA1:

Forkhead box A1

HE:

Hematoxylin and eosin

HER-2:

Human epidermal growth factor receptor 2

HR:

Hazard ratio

IHC:

Immunohistochemistry

Ki-67:

Proliferation index factor Ki-67

OS:

Overall survival

PFS:

Progression free survival

PR:

Progesterone receptor

TMA:

Tissue microarray

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Acknowledgements

We sincerely thank the patients who participated in this study, the staff who conducted the baseline and the follow‐up data collection, and the medical staff in the breast departments of the First Affiliated Hospital, and the Cancer Center of Sun Yat‐Sen University.

Funding

This research was funded by National Natural Science Foundation of China (81773515 and 81973115) and Science and Technology Planning Project of Guangdong Province, China (2019B030316002). The founders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors

Contributions

QC, ZR, and JY designed and directed the study, wrote and/or revise the manuscript. YY and YL constructed the TMAs. YY contributed to the IHC. ZW, XZ, JG, and LT contributed to digital imaging of IHC-stained sections and the assessment of immunohistochemical expression. QC, ZL, ZH, JC and YL contributed to clinical data collection and curation. QC, ZL, and ZH participated in the statistical analysis plan and interpretation of results. ZR, and JY provided administrative support and supervision for the study. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jing-ping Yun or Ze-fang Ren.

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The authors declare that they have no competing interests.

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The study was approved by the ethics committee of School of Public Health, Sun Yat-sen University.

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All participants provided written informed consent.

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Cite this article

Chen, Qx., Yang, Yz., Liang, Zz. et al. Time-varying effects of FOXA1 on breast cancer prognosis. Breast Cancer Res Treat (2021). https://doi.org/10.1007/s10549-021-06125-7

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Keywords

  • FOXA1
  • Breast cancer
  • Prognosis
  • Time-varying effects
  • Tissue microarray