SpringerLink
Log in

Circulating tumor cell phenotype detection based on epithelial-mesenchymal transition markers combined with clinicopathological risk has potential to better predict recurrence in stage III breast cancer treated with neoadjuvant chemotherapy: a pilot study

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Background

The potential value of detecting epithelial–mesenchymal transition (EMT) CTCs in early breast cancer, especially during the neoadjuvant therapy period, requires further investigation. We analyzed dynamic CTC phenotype status, to improve recurrence risk stratification for patients with stage III breast cancers.

Methods

We enrolled 45 patients with stage III breast cancers from 2 clinical trials undergoing neoadjuvant chemotherapy and utilized the CanPatrol CTC enrichment technique pre- and post-chemotherapy to identify CTC phenotypes, including epithelial CTCs, biphenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs, in peripheral blood samples. Kaplan–Meier analyses were conducted to explore the prognostic value of dynamic change of CTC count and the proportion of CTCs with different phenotypes. Then, redefine the risk stratification based on CTC status and clinicopathological risk in combination.

Results

Increased proportion of M + CTCs was a high-risk CTC status that was associated with decreased DFS (HR, 3.584; 95% CI, 1.057–12.15). In a combined analysis with clinicopathological risk, patients with high-risk tumors had an elevated risk of recurrence compared to patients with low-risk tumors (HR, 4.482; 95% CI, 1.246–16.12). The recurrence risk could be effectively stratified by newly defined risk stratification criteria, with 5-year DFS of 100.0%, 77.3%, and 50.0%, respectively, for low-risk, mid-risk, and high-risk patients (P = 0.0077). Finally, in the ROC analysis, the redefined risk stratification demonstrated higher predictive significance with an AUC of 0.7727, compared to CTC status alone (AUC of 0.6751) or clinicopathological risk alone (AUC of 0.6858).

Conclusion

The proportion of M + CTCs increased after neoadjuvant chemotherapy indicating a higher risk of tumor recurrence. Combining CTC status with clinicopathological risk has potential to redefine the risk stratification of stage III breast cancers and provide improved predictions of relapse.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Data availability

Enquiries about data availability should be directed to the authors.

Abbreviations

EMT:

Epithelial–mesenchymal transition

CTC:

Circulating tumor cell

E + :

Epithelial markers positive

EM + :

Biphenotypic epithelial/mesenchymal markers positive

M + :

Mesenchymal markers positive

DFS:

Disease-free survival

AJCC:

The American Joint Committee on Cancer

HER2:

Human epidermal growth factor receptor 2

LVI:

Lymphatic vessel invasion

AUC:

Area under the curve

ROC:

Receiver operating characteristic

HR:

Hazard ratio

References

  1. Sung H et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249

    Article  PubMed  Google Scholar 

  2. Afifi AM et al (2020) Causes of death after breast cancer diagnosis: a US population-based analysis. Cancer 126(7):1559–1567

    Article  PubMed  Google Scholar 

  3. Leone JP et al (2021) Twenty-year risks of breast cancer-specific mortality for stage III breast cancer in the surveillance, epidemiology, and end results registry. Breast Cancer Res Treat 187(3):843–852

    Article  PubMed  Google Scholar 

  4. Aebi S, Karlsson P, Wapnir IL (2022) Locally advanced breast cancer. Breast. https://doi.org/10.1016/j.breast.2021.12.011

    Article  PubMed  Google Scholar 

  5. Mittendorf EA et al (2016) The Neo-Bioscore update for staging breast cancer treated with neoadjuvant chemotherapy: incorporation of prognostic biologic factors into staging after treatment. JAMA Oncol 2(7):929–936

    Article  PubMed  PubMed Central  Google Scholar 

  6. Yau C et al (2022) Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients. Lancet Oncol 23(1):149–160

    Article  CAS  PubMed  Google Scholar 

  7. Laas E et al (2021) Determination of breast cancer prognosis after neoadjuvant chemotherapy: comparison of Residual Cancer Burden (RCB) and Neo-Bioscore. Br J Cancer 124(8):1421–1427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Masuda N et al (2017) Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376(22):2147–2159

    Article  CAS  PubMed  Google Scholar 

  9. von Minckwitz G et al (2019) Trastuzumab Emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 380(7):617–628

    Article  Google Scholar 

  10. Sundling KE, Lowe AC (2019) Circulating tumor cells: overview and opportunities in cytology. Adv Anat Pathol 26(1):56–63

    Article  CAS  PubMed  Google Scholar 

  11. Li Y et al (2022) Postoperative circulating tumor DNA combined with consensus molecular subtypes can better predict outcomes in stage III colon cancers: a prospective cohort study. Eur J Cancer 169:198–209

    Article  CAS  PubMed  Google Scholar 

  12. Rack B et al (2014) Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. https://doi.org/10.1093/jnci/dju066

    Article  PubMed  PubMed Central  Google Scholar 

  13. Guan X et al (2019) The prognostic and therapeutic implications of circulating tumor cell phenotype detection based on epithelial-mesenchymal transition markers in the first-line chemotherapy of HER2-negative metastatic breast cancer. Cancer Commun (Lond) 39(1):1

    Article  PubMed  Google Scholar 

  14. Radovich M et al (2020) Association of circulating tumor DNA and circulating tumor cells after neoadjuvant chemotherapy with disease recurrence in patients with triple-negative breast cancer: preplanned secondary analysis of the BRE12-158 randomized clinical trial. JAMA Oncol 6(9):1410–1415

    Article  PubMed  Google Scholar 

  15. Yu M et al (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339(6119):580–584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Horimoto Y et al (2018) Analysis of circulating tumour cell and the epithelial mesenchymal transition (EMT) status during eribulin-based treatment in 22 patients with metastatic breast cancer: a pilot study. J Transl Med 16(1):287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Agnoletto C et al (2019) Heterogeneity in circulating tumor cells: the relevance of the stem-cell subset. Cancers (Basel). https://doi.org/10.3390/cancers11040483

    Article  PubMed  Google Scholar 

  18. Zhang S et al (2017) Mesenchymal phenotype of circulating tumor cells is associated with distant metastasis in breast cancer patients. Cancer Manag Res 9:691–700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang X et al (2020) A randomized parallel controlled phase II trial of recombinant human endostatin added to neoadjuvant chemotherapy for stage III breast cancer. Clin Breast Cancer. https://doi.org/10.1016/j.clbc.2020.04.009

    Article  PubMed  Google Scholar 

  20. Wang L et al (2020) Combination of pegylated liposomal doxorubicin and docetaxel as neoadjuvant therapy for breast cancer with axillary lymph node metastasis. J Int Med Res 48(8):300060520944310

    Article  CAS  PubMed  Google Scholar 

  21. Xu L et al (2021) Assessment of CPS + EG, Neo-Bioscore and modified Neo-Bioscore in breast cancer patients treated with preoperative systemic therapy: a multicenter cohort study. Front Oncol 11:606477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wu S et al (2015) Classification of circulating tumor cells by epithelial-mesenchymal transition markers. PLoS ONE 10(4):e0123976

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lin D et al (2021) Circulating tumor cells: biology and clinical significance. Signal Transduct Target Ther 6(1):404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Alix-Panabieres C, Pantel K (2014) Challenges in circulating tumour cell research. Nat Rev Cancer 14(9):623–631

    Article  CAS  PubMed  Google Scholar 

  25. Barriere G et al (2012) Mesenchymal and stemness circulating tumor cells in early breast cancer diagnosis. BMC Cancer 12:114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bidard FC et al (2018) Circulating tumor cells in breast cancer patients treated by neoadjuvant chemotherapy: a meta-analysis. J Natl Cancer Inst 110(6):560–567

    Article  PubMed  Google Scholar 

  27. Graf RP et al (2020) Clinical utility of the nuclear-localized AR-v7 biomarker in circulating tumor cells in improving physician treatment choice in castration-resistant prostate cancer. Eur Urol 77(2):170–177

    Article  CAS  PubMed  Google Scholar 

  28. Wei T et al (2019) Vimentin-positive circulating tumor cells as a biomarker for diagnosis and treatment monitoring in patients with pancreatic cancer. Cancer Lett 452:237–243

    Article  CAS  PubMed  Google Scholar 

  29. Economos C, Morrissey C, Vessella RL (2012) Circulating tumor cells as a marker of response: implications for determining treatment efficacy and evaluating new agents. Curr Opin Urol 22(3):190–196

    Article  PubMed  Google Scholar 

  30. Li Y, Wu S, Bai F (2018) Molecular characterization of circulating tumor cells-from bench to bedside. Semin Cell Dev Biol 75:88–97

    Article  PubMed  Google Scholar 

  31. Sloane JP, Ormerod MG, Neville AM (1980) Potential pathological application of immunocytochemical methods to the detection of micrometastases. Cancer Res 40(8 Pt 2):3079–3082

    CAS  PubMed  Google Scholar 

  32. Mansi J et al (2016) Bone marrow micrometastases in early breast cancer-30-year outcome. Br J Cancer 114(3):243–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cristofanilli M et al (2005) Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 23(7):1420–1430

    Article  PubMed  Google Scholar 

  34. Janni WJ et al (2016) Pooled analysis of the prognostic relevance of circulating tumor cells in primary breast cancer. Clin Cancer Res 22(10):2583–2593

    Article  CAS  PubMed  Google Scholar 

  35. Pierga JY et al (2017) Circulating tumour cells and pathological complete response: independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phase II trials (BEVERLY-1 and -2) of neoadjuvant chemotherapy combined with bevacizumab. Ann Oncol 28(1):103–109

    Article  PubMed  Google Scholar 

  36. Semaan A et al (2021) Characterisation of circulating tumour cell phenotypes identifies a partial-EMT sub-population for clinical stratification of pancreatic cancer. Br J Cancer 124(12):1970–1977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Paoletti C et al (2019) Circulating Tumor Cell Clusters in Patients with Metastatic Breast Cancer: a SWOG S0500 Translational Medicine Study. Clin Cancer Res 25(20):6089–6097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hepp P et al (2016) Association of CA27.29 and circulating tumor cells before and at different times after adjuvant chemotherapy in patients with early-stage breast cancer—the SUCCESS trial. Anticancer Res. https://doi.org/10.21873/anticanres.11034

    Article  PubMed  Google Scholar 

  39. Goodman CR et al (2018) Association of circulating tumor cell status with benefit of radiotherapy and survival in early-stage breast cancer. JAMA Oncol 4(8):e180163

    Article  PubMed  PubMed Central  Google Scholar 

  40. Bidard FC et al (2021) Efficacy of circulating tumor cell count-driven vs clinician-driven first-line therapy choice in hormone receptor-positive, ERBB2-negative metastatic breast cancer: the STIC CTC randomized clinical trial. JAMA Oncol 7(1):34–41

    Article  PubMed  Google Scholar 

  41. Jacot W et al (2019) Actionability of HER2-amplified circulating tumor cells in HER2-negative metastatic breast cancer: the CirCe T-DM1 trial. Breast Cancer Res 21(1):121

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank the patients and family members who gave their consent to presenting the data in this study, as well as the investigators and research staff involved in this study.

Funding

This work was supported by Project of “100 Foreign Experts Plan of Hebei Province”, China (2022001).

Author information

Authors and Affiliations

  1. Radiotherapy Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, People’s Republic of China

    Kai-Ye Du

  2. Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Shijiazhuang, 050011, People’s Republic of China

    Kai-Ye Du, Shang Wu, **ndi Ma & Yunjiang Liu

  3. Breast Center, The Fourth Hospital of Hebei Medical University, 169 Tianshan Street, Shijiazhuang, 050011, Hebei, People’s Republic of China

    Shang Wu, **ndi Ma & Yunjiang Liu

Authors
  1. Kai-Ye Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. **ndi Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yunjiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Clinical research and data collection were performed by Shang Wu and **ndi Ma. Data analysis was performed by Kai-Ye Du. The first draft of the manuscript was written by Kai-Ye Du and Yunjiang Liu. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yunjiang Liu.

Ethics declarations

Competing interests

The authors declare that they have no conflicts of interest.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of The Fourth Hospital of Hebei Medical University.

Consent to participate

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

Consent for publication

Informed consent was signed by every patient before entering the research trial.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 2178 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Du, KY., Wu, S., Ma, X. et al. Circulating tumor cell phenotype detection based on epithelial-mesenchymal transition markers combined with clinicopathological risk has potential to better predict recurrence in stage III breast cancer treated with neoadjuvant chemotherapy: a pilot study. Breast Cancer Res Treat (2024). https://doi.org/10.1007/s10549-024-07430-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10549-024-07430-7

Keywords

Search

Navigation