Prognostic and predictive value of Ki-67 in triple-negative breast cancer

This study was to investigate the prognostic role of Ki-67 in further classification of triple negative breast cancer (TNBC), and to test whether high expression level of Ki67 can predict benefit from carboplatin. From January 2004 to December 2012, 363 patients operated for TNBC were identified through the institutional clinical database. After a median follow-up time of 34 months (5.2–120.0 months), 62 patients (17.1%) had relapses and 33 patients (9.1%) died of breast cancer. In univariate analysis, high Ki-67 index as well as larger tumor size and lymph node involvement was associated with shorter disease-free survival (DFS) and overall survival (OS). In multivariate analysis, high Ki-67 is an independent risk factor for DFS (Risk Ratio, RR: 2.835, 95% confidence interval, 95% CI: 1.586–5.068, P < 0.001) and OS (RR: 3.180, 95% CI: 1.488–6.793, P = 0.003). When analyzing the 3-year DFS by Ki-67 distribution, Subpopulation Treatment Effect Pattern Plot analysis showed a beneficial effect of carboplatin in patients with high Ki-67 index. In conclusion, TNBC is probably a heterogeneous disease with different characteristics and prognosis, and may be further subdivided according to the Ki-67 expression levels. Patients in the high Ki- 67 group seem to benefit more from treatment with carboplatin, but this needs to be further verified.

[1]  C. Gomez-Fernandez,et al.  The use of neoadjuvant platinum-based chemotherapy in locally advanced breast cancer that is triple negative: retrospective analysis of 144 patients , 2013, Breast Cancer Research and Treatment.

[2]  M. Bonetti,et al.  A graphical method to assess treatment-covariate interactions using the Cox model on subsets of the data. , 2000, Statistics in medicine.

[3]  G. Hortobagyi,et al.  Nodal status and clinical outcomes in a large cohort of patients with triple-negative breast cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  Päivi Heikkilä,et al.  Subtyping of Breast Cancer by Immunohistochemistry to Investigate a Relationship between Subtype and Short and Long Term Survival: A Collaborative Analysis of Data for 10,159 Cases from 12 Studies , 2010, PLoS medicine.

[5]  Sally Hunsberger,et al.  Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  John M S Bartlett,et al.  Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. , 2014, Archives of pathology & laboratory medicine.

[7]  N Harbeck,et al.  Triple-negative breast cancer--current status and future directions. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[8]  C. Perou,et al.  Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. , 2006, JAMA.

[9]  A. Luini,et al.  Prognostic value of Ki-67 labeling index in patients with node-negative, triple-negative breast cancer , 2012, Breast Cancer Research and Treatment.

[10]  H. Sasano,et al.  Histopathological subclassification of triple negative breast cancer using prognostic scoring system: five variables as candidates , 2010, Virchows Archiv.

[11]  K. Shen,et al.  Progesterone Receptor Status and Ki-67 Index May Predict Early Relapse in Luminal B/HER2 Negative Breast Cancer Patients: A Retrospective Study , 2014, PloS one.

[12]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. , 2002, Histopathology.

[13]  M. Daidone,et al.  Prognostic and predictive role of proliferation indices in adjuvant therapy of breast cancer. , 2001, Journal of the National Cancer Institute. Monographs.

[14]  K. Hess,et al.  Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  K. Gelmon,et al.  Ki67 in breast cancer: prognostic and predictive potential. , 2010, The Lancet. Oncology.

[16]  Peter Devilee,et al.  Pathology and Genetics of Tumours of the Breast and Female Genital Organs , 2003 .

[17]  V. Čapkun,et al.  Prognostic value of Ki-67 proliferating index in triple negative breast carcinomas. , 2013, Pathology, research and practice.

[18]  Jack Cuzick,et al.  Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. , 2011, Journal of the National Cancer Institute.

[19]  Vandana G. Abramson,et al.  New Strategies for Triple-Negative Breast Cancer—Deciphering the Heterogeneity , 2014, Clinical Cancer Research.

[20]  M. Nardi,et al.  Carboplatin and Gemcitabine Combination in Metastatic Triple-Negative Anthracycline- and Taxane-Pretreated Breast Cancer Patients: A Phase II Study , 2011, Journal of chemotherapy.

[21]  W. Han,et al.  Ki-67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis , 2011, Breast Cancer Research.

[22]  R. Elashoff,et al.  Differential response of triple‐negative breast cancer to a docetaxel and carboplatin‐based neoadjuvant treatment , 2010, Cancer.

[23]  M. Rezai,et al.  Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. , 2014, The Lancet. Oncology.

[24]  X. Chen,et al.  Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. , 2011, The Journal of clinical investigation.

[25]  J. Lubiński,et al.  Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  Anthony Rhodes,et al.  American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. , 2010, Archives of pathology & laboratory medicine.

[27]  R. Gelber,et al.  Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. , 2008, Journal of the National Cancer Institute.

[28]  I. Ellis,et al.  Prognostic value of proliferation assay in the luminal, HER2-positive, and triple-negative biologic classes of breast cancer , 2012, Breast Cancer Research.

[29]  C. Perou,et al.  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 , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[30]  B. Pockaj,et al.  Triple-Negative Breast Cancers: Unique Clinical Presentations and Outcomes , 2010, Annals of Surgical Oncology.

[31]  S. Narod,et al.  Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence , 2007, Clinical Cancer Research.

[32]  Anastasia Ivanova,et al.  TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  D. Berry,et al.  Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  Mitch Dowsett,et al.  Proliferation marker Ki-67 in early breast cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.