Follow-up periods ranged from 8 to 56 months (median 41 months). The overall survival and tumor recurrence were expressed as the number of months from diagnosis to the occurrence of disease-related death or local recurrence, respectively. Follow-up information was available for all studied patients; during their follow-up period, 40 (55.6%) patients died of disease and the recurrence was 24 out of 72 (33.3%) and the median time to recurrence was 15.5 months (4.1–18.2) months. The patients alive were 32 out of 72 (44.4%), and the recurrence free was 48 out of 72 (66.7%).
Regarding the relation between c-KIT expression and overall survival, 34 out of 40 (85%) dead patients were c-KIT positive compared with 20 out of 32 (62.5%) of the surviving patients; this difference in life span was statistically insignificant (P=0.06). In addition, c-KIT-positive staining was detected in 32 out of 48 (66.7%) patients who had been recurrence free during their follow-up compared with 22 out of 24 (91.7%) patients with recurrence; this difference was statistically insignificant (P=0.174).
We then analyzed the relationship between c-KIT expression and the clinicopathological parameters of TNBC. Increased expression was more frequent in TNBC with positive LNM (89.7%) than in negative cases (14.3%), showing a statistically significant relationship (P<0.0001). As shown in Table 1, 22 out of 25 grade III tumors (88%) had positive c-KIT expression, whereas 10 out of 22 (45.5s%) grade II tumors were positive; the relationship between c-KIT expression and tumor grade was statistically significant (P<0.0001). With regard to c-KIT expression in cases with LVSI, there were statistically significant differences between c-KIT-positive and c-KIT-negative cases (P<0.0001). However, no significant differences were found between c-KIT immunoreactivity, age, and DCISC as well as tumor stage (P=0.7, 0.4, and 0.48, respectively) (Table 1).
Breast cancer patients fall into three main groups: (a) those with hormone receptor-positive tumors who are managed with a number of ER-targeted therapy options±chemotherapy; (b) those with HER2+ tumors, who will, in addition, receive HER2-directed therapy; and (c) those with hormone receptor (ER) and progesterone receptor-negative and HER2- negative breast cancers, for whom chemotherapy is the only modality of systemic therapy available. On the basis of the above, it is clear that the interest in triple-negative cancers stems from the lack of tailored therapies for this group of breast cancer patients (Reis-Filho and Tutt, 2008).
Also, triple-negative tumors more frequently affect younger patients (<50 years) (Haffty et al., 2006; Bauer et al., 2007; Dent et al., 2007; Morris et al., 2007; Tischkowitz et al., 2007); as shown in our results, 58.3% of our patients were below 53 years of age and they also had significantly more aggressive tumors compare with the other molecular subgroups (Harris et al., 2006; Bauer et al., 2007; Tischkowitz et al., 2007). This aggressiveness is best illustrated by the fact that the peak risk of recurrence is between the first and the third years and the majority of deaths occur in the first 5 years, following therapy (Dent et al., 2007; Tischkowitz et al., 2007). This is consistent with our results that 55.6 and 33.3% of our studied patients died and were positive for recurrence, respectively.
From a pathologist’s point of view, the differences between triple-negative and non-TNBC are not surprising, given that the majority of triple-negative cancers are of histological grade III (Dent et al., 2007; Rakha et al., 2007); there was a higher prevalence of LNM in triple-negative cancers compared with controls (Dent et al., 2007), which is in agreement with our results, wherein 69.4 and 80.65% of the studied cases were high grade and positive for nodal metastasis, respectively.
Although triple-negative cancers are reported to respond to neoadjuvant chemotherapy (Carey et al., 2007), the survival of patients with such tumors is still poor and their management may therefore require a more aggressive alternative intervention. Thus, the development of biologically informed systemic therapies and targeted therapies for triple-negative cancers is of paramount importance.
In this study, we used the antibody A4502 (DAKO) as it was found to be optimal in staining property, because it had the highest frequency of positivity in arrayed gastrointestinal stromal tumors and because reagents are available for preabsorption control experiments to ensure maximum specificity of the system (Simon et al., 2004).
To our knowledge, at the time of drafting this paper, no immunohistochemical analysis of c-KIT in TNBC has been reported. According to the current study, c-KIT was detected in 75% of the studied cases. Patients with c-KIT-positive tumors were younger than the c-KIT-negative patients but the difference is not statistically significant. Our study revealed a significant association between tumor grade and c-KIT positivity (88.0% at GIII vs. 45.5% at GII, P<0.0001); we also reported a statistically significant relation between c-KIT expression and LNM and LVSI, with a P-value less than <0.0001 for both. The possible association between the expression of c-KIT and DCISC and tumor stage remains unclear; no significant correlation was demonstrated in this study.
The role of c-KIT expression and prognosis was evaluated in other tumors rather than TNBC; one of these studies showed a significant association with poor survival (Micke et al., 2003) and others revealed a significant association (Potti et al., 2003; Pan et al., 2005). In the current study, although a trend toward poor survival and high local tumor recurrence was seen for c-KIT positive patients, it did not reach statistical significance; it had not been clearly defined and needs further studies in large series.
Triple-negative cancer constitutes one of the most challenging groups of breast cancer; it is associated with a high expression of c-KIT immunohistochemically, high grade, high recurrence rate, and increased LNM. It has been hypothesized that imatinib mesylate could be used as a tailored therapy for triple-negative cancers, on the basis of its inhibition of c-KIT. We recommend further studies to determine whether c-KIT expression is correlated with c-KIT DNA mutations and to test the possibility of treatment with imatinib mesylate (Gleevec).
There are no conflicts of interest.
Andre C, Martin E, Cornu F, Hu WX, Wang XP, Galibert F. Genomic organization of the human c-kit gene: Evolution of the receptor tyrosine kinase subclass III. Oncogene. 1992;7:685–691
Aydin O, Yildiz L, Kefeli M, Kandemir B. CD117 expression in normal, neoplastic, inflammatory and reactive lesions of the thyroid. Pathol Res Pract. 2008;204:359–365
Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of Estrogen Receptor (ER)-negative, Progesterone Receptor (PR)-negative and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California Cancer Registry. Cancer. 2007;109:1721–1728
Besmer P, Murphy JE, George PC, Qiu FH, Bergold PJ, Lederman L, et al. A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. Nature. 1986;320:415–421
Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13:2329–2334
Chui X, Egami H, Yamashita J, Kurizaki T, Ohmachi H, Yamamoto S, et al. Immunohistochemical expression of the c-kit proto-oncogene product in human malignant and non-malignant breast tissues. Br J Cancer. 1996;73:1233–1236
Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13:4429–4434
Frierson HF Jr, Wolber RA, Berean KW, Franquemont DW, Gaffey MJ, Boyd JC, et al. Interobserver reproducibility of the Nottingham modification of the Bloom and Richardson histologic grading scheme for infiltrating ductal carcinoma. Am J Clin Pathol. 1995;103:195–198
Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol. 2006;24:5652–5657
Harris LN, Broadwater G, Lin NU, Miron A, Schnitt SJ, Cowan D, et al. Molecular subtypes of breast cancer in relation to paclitaxel response and outcomes in women with metastatic disease: results from CALGB 9342. Breast Cancer Res. 2006;8:R66
Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti Passerini C, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645–652
Micke P, Basrai M, Faldum A, Bittinger F, Ronnstrand L, Blaukat A, et al. Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications. Clin Cancer Res. 2003;9:188–194
Miettinen M, Furlong M, Sarlomo Rikala M, Burke A, Sobin LH, Lasota J. Gastrointestinal stromal tumors, intramural leiomyomas and leiomyosarcomas in the rectum and anus: A clinicopathologic, immunohistochemical and molecular genetic study of 144 cases. Am J Surg Pathol. 2001;25:1121–1133
Morris GJ, Naidu S, Topham AK, Guiles F, Xu Y, McCue P, et al. Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: a single-institution compilation compared with the National Cancer Institute’s Surveillance, Epidemiology and End Results database. Cancer. 2007;110:876–884
Natali PG, Nicotra MR, Sures I, Mottolese M, Botti C, Ullrich A. Breast cancer is associated with loss of the c-kit oncogene product. Int J Cancer. 1992;52:713–717
Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10:5367–5374
Pan CX, Yang XJ, Lopez Beltran A, MacLennan GT, Eble JN, Koch MO, et al. c-kit Expression in small cell carcinoma of the urinary bladder: prognostic and therapeutic implications. Mod Pathol. 2005;18:320–323
Potti A, Moazzam N, Ramar K, Hanekom DS, Kargas S, Koch M. CD117 (c-KIT) overexpression in patients with extensive-stage small-cell lung carcinoma. Ann Oncol. 2003;14:894–897
Qiu FH, Ray P, Brown K, Barker PE, Jhanwar S, Ruddle FH, et al. Primary structure of c-kit: Relationship with the CSF-1/PDGF receptor kinase family–oncogenic activation of v-kit involves deletion of extracellular domain and C terminus. EMBO J. 1988;7:1003–1011
Rakha EA, El Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO. Prognostic markers in triple-negative breast cancer. Cancer. 2007;109:25–32
Reis-Filho JS, Tutt ANJ. Triple negative tumours: a critical review. Histopathology. 2008;52:108–118
Savage DG, Antman KH. Imatinib mesylate–a new oral targeted therapy. N Engl J Med. 2002;346:683–693
Sawyers CL. Imatinib GIST keeps finding new indications: successful treatment of dermatofibrosarcoma protuberans by targeted inhibition of the platelet-derived growth factor receptor. J Clin Oncol. 2002;20:3568–3569
Sihto H, Sarlomo Rikala M, Tynninen O, Tanner M, Andersson LC, Franssila K, et al. KIT and platelet-derived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human solid tumors. J Clin Oncol. 2005;23:49–57
Simon R, Panussis S, Maurer R, Spichtin H, Glatz K, Tapia C, et al. KIT (CD117)-positive breast cancers are infrequent and lack KIT gene mutations. Clin Cancer Res. 2004;10(1 Pt 1):178–183
Spritz RA, Strunk KM, Lee ST, Lu Kuo JM, Ward DC, Le Paslier D, et al. A YAC contig spanning a cluster of human type III receptor protein tyrosine kinase genes (PDGFRA-KIT-KDR) in chromosome segment 4q12. Genomics. 1994;22:431–436
Tischkowitz M, Brunet JS, Begin LR, Huntsman DG, Cheang MC, Akslen LA, et al. Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer. 2007;7:134
Tsuura Y, Suzuki T, Honma K, Sano M. Expression of c-kit protein in proliferative lesions of human breast: sexual difference and close association with phosphotyrosine status. J Cancer Res Clin Oncol. 2002;128:239–246
Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990;61:203–212
Went PT, Dirnhofer S, Bundi M, Mirlacher M, Schraml P, Mangialaio S, et al. Prevalence of KIT expression in human tumors. J Clin Oncol. 2004;22:4514–4522