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Expression of ER, PgR, HER-2, and Ki-67 in core biopsies and in definitive histological specimens in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy

  • Luigi Rossi
  • Monica VerricoEmail author
  • Silverio Tomao
  • Fabio Ricci
  • Antonella Fontana
  • Gian Paolo Spinelli
  • Maria Colonna
  • Patrizia Vici
  • Federica Tomao
Original Article
  • 24 Downloads

Abstract

Purpose

Many studies have indicated that the response to therapy and the prognostic impact of a pathologic complete response after neoadjuvant treatment differ among breast cancer subtypes.

Methods

The aim of our study is to evaluate the effect of this treatment on the expression of estrogen and progesterone receptors, human epidermal growth hormone receptor 2 and Ki67 in breast cancer. We identified 125 patients.

Results

The estrogen receptor modified its expression from positive to negative in 8% patients and from negative to positive in 22%; progesterone in 21% and in 37% cases. Median Ki-67 value was 20.9% at biopsy and 18% after, HER-2 status did not show a remarkable change before or after neoadjuvant chemotherapy (NACT). We have identified a significant reduction in Ki-67 expression levels after chemotherapy in patients with a pathologic response. Detection of pretreatment Ki-67 could identify patients most likely to benefit from NACT.

Conclusions

NACT can change the status of ER, PgR, and Ki-67 expression in patients with breast adenocarcinoma, but it did not exert a significant effect on HER-2 status; HER-2 amplification appears to be more stable. We have identified a prognostic role for a decreased expression of PgR and Ki-67 after preoperative chemotherapy in breast cancer patients.

Keywords

Breast cancer Neoadjuvant chemotherapy Estrogen receptor Progesterone receptor Human epidermal growth factor receptor 2 Ki67 

Notes

Acknowledgements

We thank the CINBO Istitution (Consorzio interuniversitario per la Bio-Oncologia) for support and contribution to our study.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    DeSantis C, Ma J, Bryan L, Jemal A (2014) Breast cancer statistics 2013 CA. Cancer J Clin. 64:52–62.  https://doi.org/10.3322/caac.21203 CrossRefGoogle Scholar
  2. 2.
    American Cancer Society (2009) Breast cancer facts and figures 2007–2008 Atlanta: American Cancer Society. http://www.cancer.org/downloads/stt/bcff-final.pdf
  3. 3.
    Kaufmann M, von Minckwitz G, Mamounas EP et al (2012) Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 19:1508–1516.  https://doi.org/10.1245/s10434-011-2108-2 CrossRefPubMedGoogle Scholar
  4. 4.
    Chavez Mac Gregor M, Gonzalez-Angulo AM (2010) Breast cancer, neoadjuvant and residual disease. Clin Trans Oncol 12:461–467.  https://doi.org/10.1007/s12094-010-0538-0 CrossRefGoogle Scholar
  5. 5.
    Hennessy BT, Hortobagy GN, Rouzier RN et al (2005) Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol 23:9304–9311.  https://doi.org/10.1200/JCO.2005.02.5023 CrossRefPubMedGoogle Scholar
  6. 6.
    Romero A, Garcia-Saenz JA, Fuentes-Ferrer M et al (2013) Correlation between response to neoadjuvant chemotherapy and survival in locally advanced breast cancer patients. Ann Oncol 24:655–661.  https://doi.org/10.1093/annonc/mds493 CrossRefPubMedGoogle Scholar
  7. 7.
    Symmans WF, Peintinger F, Hatzis C et al (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 25:4414–4422.  https://doi.org/10.1200/JCO.2007.10.6823 CrossRefGoogle Scholar
  8. 8.
    Ge W, Yang B, Zuo W et al (2015) Evaluation of hormone receptor, human epidermal growth factor receptor-2 and Ki 67 with core needle biopsy and neoadjuvant chemotherapy effects in breast cancer patients. Thoracic Cancer.  https://doi.org/10.1111/1759-7714.12133 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Zhou X, Zhang J, Yun H et al. (2015) Alterations of biomarker profiles after neoadjuvant chemotherapy in breast cancer: tumor heterogeneity should be taken into consideration. Oncotarget 6: 36894–36902. 10.18632/oncotarget.5050.Google Scholar
  10. 10.
    Chen S, Chen CM, Yu KD, Zhou RJ, Shao ZM (2012) Prognostic value of a positive-to-negative change in hormone receptor status after NCT in patients with hormone receptor-positive breast cancer. Ann Surg Oncol 19:3002–3011.  https://doi.org/10.1245/s10434-012-2318-2 CrossRefPubMedGoogle Scholar
  11. 11.
    Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA (2010) Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol 11:174–183.  https://doi.org/10.1016/S1470-2045(09)70262-1 CrossRefPubMedGoogle Scholar
  12. 12.
    Bottini A, Berruti A, Bersiga A et al (2001) Relationship between tumour shrinkage and reduction in Ki67 expression after primary chemotherapy in human breast cancer. Br J Cancer 85:1106–1112.  https://doi.org/10.1054/bjoc.2001.2048 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Makris A, Powles TJ, Allred DC et al (1999) Quantitative changes in cytological molecular markers during primary medical treatment of breast cancer: a pilot study. Breast Cancer Res Treat 53:51–59CrossRefGoogle Scholar
  14. 14.
    Zhang N, Moran MS, Huo Q, Haffty BG, Yang Q. (2001) The hormonal receptor status in breast cancer can be altered by neoadjuvant chemotherapy: a meta-analysis. Cancer Investig 29: 594–598.  https://doi.org/10.3109/07357907.2011.621913.CrossRefGoogle Scholar
  15. 15.
    Tagliabue E, Agresti R, Carcangiu ML et al (2003) Role of HER2 in wound-induced breast carcinoma proliferation. Lancet 362(9383):527–533.  https://doi.org/10.1016/S0140-6736(03)14112-8 CrossRefPubMedGoogle Scholar
  16. 16.
    Chen X, Zhu S, Fei X et al (2015) Surgery time interval and molecular subtype may influence Ki67 change after core needle biopsy in breast cancer patients. BMC Cancer 15:822.  https://doi.org/10.1186/s12885-015-1853-1 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kim HS, Park S, Koo JS (2016) Risk factors associated with discordant Ki-67 levels between preoperative biopsy and postoperative surgical specimens in breast cancers. PLoS One 11(3):0151054.  https://doi.org/10.1371/journal.pone.0151054.eCollection2016 CrossRefGoogle Scholar
  18. 18.
    Criscitiello C, Disalvatore D, De Laurentiis M et al (2014) High Ki-67 score is indicative of a greater benefit from adjuvant chemotherapy when added to endocrine therapy in luminal-B HER2 negative and node-positive breast cancer. Breast 23:69–75.  https://doi.org/10.1016/j.breast.2013.11.007 CrossRefGoogle Scholar
  19. 19.
    Andre F, Arnedos M, Goubar A, Ghouadni A, Delaloge S (2015) Ki67—no evidence for its use in node-positive breast cancer. Nat Rev Clin Oncol. 12:296–301.  https://doi.org/10.1038/nrclinonc.2015.46 CrossRefPubMedGoogle Scholar
  20. 20.
    Jones RL, Salter J, A’Hern R et al (2009) The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 116:53–68.  https://doi.org/10.1007/s10549-008-0081-7 CrossRefPubMedGoogle Scholar
  21. 21.
    Miglietta L, Morabito F, Provinciali N (2013) A prognostic model based on combining estrogen receptor expression and Ki-67 value after neoadjuvant chemotherapy predicts clinical outcome in locally advanced breast cancer: extension and analysis of a previously reported cohort of patients. Eur J Surg Oncol 39(10):1046–1052.  https://doi.org/10.1016/j.ejso.2013.06.024 CrossRefPubMedGoogle Scholar
  22. 22.
    von Minckwiz G, Schmitt WD, Loibl S et al (2013) Ki67 measured after neoadjuvant chemotherapy for primary breast cancer. Clin Cancer Res 15:4521–4531.  https://doi.org/10.1158/1078-0432.CCR-12-3628 CrossRefGoogle Scholar
  23. 23.
    Gianni L, Eiermann W, Semiglazov V et al (2010) Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2 negative cohort. Lancet 375:377–384.  https://doi.org/10.1016/S0140-6736(09)61964-4 CrossRefPubMedGoogle Scholar
  24. 24.
    Untch M, Von MG (2009) Recent advances in systemic therapy: advances in neoadjuvant (primary) systemic therapy with cytotoxic agents. Breast Cancer Res 11:203.  https://doi.org/10.1186/bcr2227 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Untch M, Rezai M, Loibl S et al (2010) Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol 28:2024–2031.  https://doi.org/10.1200/JCO.2009.23.8451 CrossRefPubMedGoogle Scholar
  26. 26.
    Mittendorf EA, Wu Y, Scaltriti M et al (2009) Loss of HER2 amplification following Trastuzumab based neoadjuvant systemic therapy and survival outcomes. Clin Cancer ResClin Cancer Res 15:7381–7388.  https://doi.org/10.1158/1078-0432.CCR-09-1735 CrossRefGoogle Scholar
  27. 27.
    Goldhirsch A, Winer EP, Coates AS et al (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 24:2206–2223.  https://doi.org/10.1093/annonc/mdt303 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Prat A, Cheang MC, Martin M et al (2013) Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer. J Clin Oncol 31:203–209.  https://doi.org/10.1200/JCO.2012.43.4134 CrossRefPubMedGoogle Scholar
  29. 29.
    Bossuyt V, Provenzano E, Symmans WF et al (2015) Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration. Ann Oncol 26:1280–1291.  https://doi.org/10.1200/JCO.2012.43.4134 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Provenzano E, Bossuyt V, Viale G et al (2015) Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: recommendations from an international working group. Mod Pathol 28:1185–1201.  https://doi.org/10.1038/modpathol.2015.74 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Guarneri V, Broglio K, Kau SW et al (2006) Prognostic Value of Pathologic Complete Response After Primary Chemotherapy in Relation to Hormone Receptor Status and Other Factors. J Clin Oncol 24:1037–1044.  https://doi.org/10.1200/JCO.2005.02.6914 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Balmativola D, Marchio C, Maule M et al (2014) Pathological nonresponse to chemotherapy in a neoadjuvant setting of breast cancer: an inter-institutional study. Breast Cancer Res Treat 148:511–523CrossRefGoogle Scholar
  33. 33.
    Montagna E, Bagnardi V, Viale G et al (2015) Changes in PgR and Ki-67 in residual tumour and outcome of breast cancer patients treated with neoadjuvant chemotherapy. Ann Oncol 26(2):307–313.  https://doi.org/10.1093/annonc/mdu528 CrossRefPubMedGoogle Scholar
  34. 34.
    Kurozumi S, Inoue K, Takei H et al (2015) ER, PgR, Ki67, p27(Kip1), and histological grade as predictors of pathological complete response in patients with HER2-positive breast cancer receiving neoadjuvant chemotherapy using taxanes followed by fluorouracil, epirubicin, and cyclophosphamide concomitant with trastuzumab. BMC Cancer 15:622.  https://doi.org/10.1186/s12885-015-1641-y CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Valachis A, Mauri D, Polyzos NP, Chlouverakis G, Mavroudis D, Georgoulias V (2011) Trastuzumab combined to neoadjuvant chemotherapy in patients with HER2-positive breast cancer: a systematic review and meta-analysis. Breast 20(6):485–490.  https://doi.org/10.1016/j.breast.2011.06.009 CrossRefPubMedGoogle Scholar
  36. 36.
    Nishimura R, Arima N (2008) Is triple negative a prognostic factor in breast cancer? Breast Cancer 15(4):303–308.  https://doi.org/10.1007/s12282-008-0042-3 CrossRefPubMedGoogle Scholar
  37. 37.
    Cancello G, Maisonneuve P, Rotmensz N et al (2013) Progesterone receptor loss identifies Luminal B breast cancer subgroups at higher risk of relapse. Ann Oncol 24:661–668.  https://doi.org/10.1093/annonc/mds430 CrossRefPubMedGoogle Scholar
  38. 38.
    Gahlaut R, Bennett A, Fatayer H et al (2016) Effect of neoadjuvant chemotherapy on breast cancer phenotype, ER/PR and HER2 expression – Implications for the practising oncologist. Eur J Cancer 60:40–48.  https://doi.org/10.1016/j.ejca.2016.03.006 CrossRefPubMedGoogle Scholar
  39. 39.
    van de Ven S, Smit VT, Dekker TJ, Nortier JW, Kroep JR (2011) Discordances in ER, PR and HER2 receptors after neoadjuvant chemotherapy in breast cancer. Cancer Treat Rev 37(6):422–430.  https://doi.org/10.1016/j.ctrv.2010.11.006 CrossRefPubMedGoogle Scholar
  40. 40.
    kai Ge W, Yang B, Zuo W et al (2015) Evaluation of hormone receptor, human epidermal growth factor receptor-2 and Ki-67 with core needle biopsy and neoadjuvant chemotherapy effects in breast cancer patients. Thoracic Cancer 6:64–69.  https://doi.org/10.1111/1759-7714.12133 CrossRefGoogle Scholar
  41. 41.
    Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ (2011) Strategies for subtypes–dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer. Ann Oncol 2011 22:1736–1747.  https://doi.org/10.1093/annonc/mdr304.CrossRefGoogle Scholar
  42. 42.
    Cserni G, Voros A, Liepniece-Karele I et al (2014) Distribution pattern of the Ki67 labelling index in breast cancer and its implications for choosing cut-off values. Breast 23:259–263.  https://doi.org/10.1016/j.breast.2014.02.003 CrossRefPubMedGoogle Scholar
  43. 43.
    Faneyte IF, Schrama JG, Peterse JL, Remijnse PL, Rodenhuis S, van de Vijver MJ (2003) Breast cancer response to neoadjuvant chemotherapy: predictive markers and relation with outcome. Br J Cancer 88:406–412.  https://doi.org/10.1038/sj.bjc.6600749 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Penault-Llorca F, Andre F, Sagan C et al (2009) Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27(17):2809–2815.  https://doi.org/10.1200/JCO.2008.18.2808 CrossRefPubMedGoogle Scholar
  45. 45.
    Viale G, Giobbie-Hurder A, Regan MM et al (2008) Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1–98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol 26(34):5569–5575.  https://doi.org/10.1200/JCO.2008.17.0829 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Oncology Unit, Department of Medico-Surgical Sciences and BiotechnologiesSapienza University of RomeApriliaItaly
  2. 2.Division of Medical Oncology A, Policlinico Umberto ISapienza University of RomeRomeItaly
  3. 3.Consorzio Interuniversitario per la Bio-Oncologia (CINBO)ChietiItaly
  4. 4.Department of SurgerySanta Maria Goretti HospitalLatinaItaly
  5. 5.Department of RadiotherapySanta Maria Goretti HospitalLatinaItaly
  6. 6.Oncology UnitA. Fiorini HospitalTerracinaItaly
  7. 7.Division of Medical Oncology 2Regina Elena National Cancer InstituteRomeItaly
  8. 8.Department of Gynaecology and Obstetrics, Policlinico Umberto ISapienza University of RomeRomeItaly

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