© 2007 European Society for Medical Oncology
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Does triple-negative phenotype accurately identify basal-like tumour? An immunohistochemical analysis based on 143 ‘triple-negative’ breast cancers
Basal-like cancer has been identified as a breast cancer molecular subclass by genomic analysis [1]. Immunohistochemically, these tumours are characterized by the absence of estrogen receptor (ER), progesterone receptor (PR) and HER2 expression, together with expression of EGF-R and/or CK 5/6 [2], whereas Bcl2 and CK 8/18 expression characterizes a luminal phenotype. This molecular subclass bears a high rate of p53 mutations and is common among BRCA1 germline mutation carriers [3]. In daily practice, tumours exhibiting a triple negativity for PR, ER and HER2 are commonly referred to as basal-like tumours, although the level of evidence for such a definition is low. In the present study, we analysed by immunohistochemistry (IHC) whether the triple-negative phenotype accurately identified basal-like tumours. Out of 823 tumours from localized breast cancer patients included in two prospective randomized trials included in a tissue microarray [4], 150 were triple negative for ER, PR and Her2 expression. EGFR, CK5/6, CK8/18, p53 and Bcl2 expression were assessed on 143 of these 150 samples by IHC (Table 1). In addition, ER and PR positivity evaluated by a ligand-binding assay were determined in the past for most of the patients. The cut-off for positivity was 10% tumour cells for ER, PR, Her2 (strong and continuous staining), p53, CK 8/18 and Bcl2, while EGF-R and CK5/6 staining were considered positive when at least one tumour cell was stained. A basal-like phenotype was defined as a Her2–/ER–/EGFR+ and/or CK5/6+ expression [2]. Ninety-five (66%) out of the 143 triple-negative assessable tumours presented a basal-like phenotype, while 48 did not (34%). Table 1 reports patient and tumour characteristics of these two entities. The ‘true’ basal-like tumours exhibited a significantly higher tumour grade. Interestingly, a high proportion of ER–/PR–/Her2–/non-basal tumours expressed luminal-associated biomarkers as ER expression by ligand-binding assay (82%), PR expression by ligand-binding assay (61%), and CK18 expression (76%), and could actually be considered as luminal-B tumours. Basal-like cancers exhibited features of apoptosis deregulation with lower Bcl2 and higher p53 expressions when compared with ER–/PR–/Her2–/non-basal cancers. Finally, there was no difference in disease-free survival nor overall survival between the 95 basal-like and the 48 Her2–/ER–/PR–/non-basal tumours [hazard ratio for relapse or death adjusted for tumour grade and stage, and age of the patient: : HR = 1.17, IC95% = (0.62 – 2.20), adjusted HR for death = 1.38, IC95% = (0.68 – 2.78)].
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In conclusion, this study suggests that the triple-negative phenotype, when defined by IHC using a 10% cut-off for the three biomarkers, is not optimal to define basal-like breast cancer. This phenotype indeed includes a mixture of basal-like tumours together with some luminal-B tumours characterized by a decreased ER expression. The triple-negative phenotype should therefore be used with caution to select patients for clinical trials.
1 Department of Medical Oncology
2 Department of Translational Research UPRES EA03535
3 Department of Biostatistics, Institut Gustave Roussy, 94805 Villejuif, France
* (E-mail: fabrice.andre{at}igr.fr)
References
1. Perou CM, Sorlie T, Elsen MB, et al. Molecular portraits of human breast tumours. Nature (2000) 406:747–752.[CrossRef][Medline]
2. Livasy CA, Karaca G, Nanda R, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol (2006) 19:264–271.[CrossRef][ISI][Medline]
3. Brenton JD, Carey LA, Ahmed AA, et al. Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol (2005) 23:7350–7360.
4. Conforti R, Boulet T, Tomasic G, et al. Breast cancer molecular subclassification and estrogen receptor expression to predict efficacy of adjuvant anthracyclines-based chemotherapy: a biomarker study from two randomized trials. Ann Oncol 2007; doi:10.1093/annonc/mdm209.
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