Br J Surg. 2013 Mar;100(4):490-6.

c-Kit expression as a prognostic molecular marker in patients with basal-like breast cancer.

S. Kashiwagi1, M. Yashiro1,2, T. Takashima1, N. Aomatsu1, H. Kawajiri1, Y. Ogawa4, N. Onoda1, T. Ishikawa1, K. Wakasa3 and K. Hirakawa1

1Department of Surgical Oncology, 2Oncology Institute of Geriatrics and Medical Science and 3Department of Diagnostic Pathology, Osaka City University Graduate School of Medicine, and 4Department of Breast Surgical Oncology, Osaka City General Hospital, Osaka, Japan

Abstract

Background: As patients with basal-like breast cancer (BLBC) have a poor prognosis and have no specifically tailored therapy, molecular biological characterization of BLBC is necessary. c-Kit is a transmembrane receptor tyrosine kinase known to play important roles in various solid cancers. Therefore, this study classified BLBCs from patients with breast carcinoma, and addressed the significance of c-Kit expression in these tumours.

Methods: Primary breast tumours were stained with antibodies against oestrogen receptor, progesterone receptor, human epidermal growth factor receptor (HER) 2, epidermal growth factor receptor (EGFR), cytokeratin 5/6 and c-Kit. The association between c-Kit, BLBC and survival was analysed.

Results: A total of 667 patients with breast cancer were followed up for a median of 39 (range 6–72) months. Some 190 tumours (28.5 per cent) were classified as triple-negative for breast cancer (negative for oestrogen receptor, progesterone receptor and HER2), and 149 (78.4 per cent) had characteristics of BLBC (positive for CK5/6 and/or EGFR). c-Kit expression was detected in 111 (16.6 per cent) of 667 tumours. c-Kit-positive tumours were more commonly found among patients with BLBC (42 of 149, 28.2 per cent; P < 0.001) and in patients with nodal metastasis (47 of 216, 21.8 per cent; P = 0.014) than in those without. In patients with BLBC, the prognosis was significantly worse in those with c-Kit expression (P < 0.001). Multivariable logistic regression analysis revealed c-Kit as an independent negative prognostic factor for cancer-specific survival in patients with BLBC (hazard ratio 2.29, 95 per cent confidence interval 1.11 to 4.72).

Conclusion: c-Kit might be a prognostic marker and possible molecular target for therapy in patients with BLBC.

Copyright © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

PMID: 23319435

 

Supplement

The mortality of breast carcinoma is decreasing because of recent developments in diagnostic techniques and therapies. However, the prognosis of BLBC remains poor. Because there are no specifically tailored therapies for BLBC, molecular biological characterization of this subtype may be important for evaluating outcomes and developing treatment strategies.

c-Kit is a proto-oncogene located at 4q12, which spans 21 exons and encodes Kit (CD117), a 145–160-kDa transmembrane receptor tyrosine kinase that plays an important role in the development of gastrointestinal stromal cell tumours, small-cell lung cancer and breast cancer. Studies of several malignant tumours have shown a variable effect of c-Kit positivity on survival. In breast cancer, the significance of c-Kit expression is controversial. It has been reported that the c-Kit protein is highly expressed in normal epithelium, and at decreased levels in invasive breast cancers. Littleis known about c-Kit expression in BLBC. This study classified BLBCs from patients with breast carcinoma, and examined the impact of c-Kit expression on outcome.

Expression of c-Kit has been reported in 25 per cent of all breast cancers, and overexpression of c-Kit has been identified in approximately 30 per cent of BLBCs. c-Kit-positive BLBC had a significantly worse prognosis than c-Kit-negative BLBC. Multivariable logistic regression analysis identified c-Kit as an independent predictor of poor cancer-specific survival in patients with BLBC.

The BLBC subtype showed a high frequency of lymph node metastasis. c-Kit expression was also associated with lymphatic spread of the disease. These observations suggest that c-Kit expression might be associated with lymph node metastasis in BLBC. It could therefore be hypothesized that c-Kit might be one of the potential target molecules for the treatment of BLBC. c-Kit phosphorylation inhibitors, such as imatinib or sunitinib, may have potential as targeted therapeutic agents for patients with BLBC. c-Kit mutations in gastrointestinal stromal cell tumours have been reported to be associated with differential treatment responses to these inhibitors.

The results of the present study suggest that c-Kit might be a prognostic marker and possible molecular target for therapy in patients with breast cancer, particularly those with BLBC.

Shinichiro Kashiwagi-1Figure 1. Cancer-specific and disease-free survival in relation to c-Kit expression in all patients with breast cancer and patients with basal-like breast cancer (BLBC).

Table 1. Univariable and multivariable Cox proportional hazards analysis with respect to cancer-specific survival in 149 patients with basal-like breast cancer

 Shinichiro Kashiwagi-tab1

References

1.Kashiwagi S, Yashiro M, Takashima T, Aomatsu N, Ikeda K, Ogawa Y et al. Advantages of adjuvant chemotherapy for patients with triple-negative breast cancer at Stage II: usefulness of prognostic markers E-cadherin and Ki67. Breast Cancer Res 2011; 13: R122.

2.Kashiwagi S, Yashiro M, Takashima T, Nomura S, Noda S, Kawajiri H et al. Significance of E-cadherin expression in triple-negative breast cancer. Br J Cancer 2010; 103: 249–255.

 

Contact:

Shinichiro Kashiwagi, MD, Ph D

Assistant Professor

Department of Surgical Oncology, Osaka CityUniversityGraduateSchool of Medicine,

1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan

http://www.med.osaka-cu.ac.jp/surgical-oncology/

 

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