Abstract
BackgroundMucin-1 (MUC1, CD227), more widely known as CA15-3, is an abundantly expressed epithelial cell surface antigen and has evolved to be the most predictive serum tumour marker in breast cancer. PankoMab-GEX™, which is currently being evaluated for its therapeutic efficacy in a phase IIb clinical trial, is a glyco-optimized anti-MUC1 antibody specifically recognizing a tumour-associated MUC1 epitope (TA-MUC1). The current study aimed to analyse the immunoreactivity of PankoMabGEX™ and its correlation with established clinico-pathological variables including 10-year and overall survival in a large cohort of breast cancer patients.MethodsBreast cancer tissue sections (n = 227) underwent a standardized immunohistochemical staining protocol for TA-MUC1 by using PankoMab-GEX™ as a primary antibody. The staining was evaluated by two independent observers and quantified by applying the IR-score.ResultsTA-MUC1 as detected by PankoMab-GEX™ was identified in 74.9% of breast cancer tissue sections. Patients were subdivided according to the subcellular localisation of TA-MUC1 and cases classified as mem-PankoMab-GEX™ (solely membranous) positive, cyt-PankoMab-GEX™ (solely cytoplasmic) positive, double positive or as completely negative were compared regarding their survival. Herein mem-PankoMab-GEX™-positive patients performed best, while double-negative ones presented with a significantly shortened survival. Positivity for mem-PankoMab-GEX™ as well as a double-negative immunophenotype turned out to be independent prognosticators for survival.ConclusionsThis is the first study to report on PankoMab-GEX™ in a large panel of breast cancer patients. The PankoMab-GEX™ epitope TA-MUC1 could be identified in the majority of cases and was found to be an independent prognosticator depending on its subcellular localisation. Since TA-MUC1 is known to be highly immunogenic cancers staining positive for PankoMab-GEX™ might be more compromised by host anti-tumour immune defence. Further, the observations reported here might be fundamental for selecting patients to undergo PankoMab-GEX™-containing chemotherapy protocols.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0152-7) contains supplementary material, which is available to authorized users.
Highlights
Mucin-1 (MUC1, CD227), more widely known as CA15-3, is an abundantly expressed epithelial cell surface antigen and has evolved to be the most predictive serum tumour marker in breast cancer
tumour-associated MUC1 epitope (TA-MUC1) as detected by PankoMab-GEXTM was identified in 74.9% (170/227) of breast cancer tissue sections
Univariate analysis revealed significant differences regarding overall survival of the four subgroups studied (A). mem-PankoMab-GEXTM positivity turned out to be related to more favourable (B) survival, while a double negative immunophenotype was associated with worse prognosis (D)
Summary
Mucin-1 (MUC1, CD227), more widely known as CA15-3, is an abundantly expressed epithelial cell surface antigen and has evolved to be the most predictive serum tumour marker in breast cancer. TA-MUC1 has been characterized as a carbohydrate-induced conformational epitope [6,7] Structure wise it comprises a PDTRP (Pro-Asp-ThrArg-Pro) motif containing a glyco-modified threonine residue (T) [3,6,7,8]. Glycans linked to this threonine by O-glycosylation are tumour specific carbohydrate modifications themselves. Presence of this glyco-modified PDTRP motif is regarded to be an absolute requirement for binding of PankoMab-GEXTM [6]. To the best of our knowledge there are only few publications having studied TA-MUC1 in breast cancer tissue and none of them included specific information on PankoMab-GEXTM in healthy breast tissue [10,11,12]
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