title: Membranous Nectin-4 expression is a risk factor for distant relapse of T1-T2, N0 luminal-A early breast cancer.
abstract: Nectins are Ca(2+)-independent immunoglobulin-like cell adhesion molecules that compose a family of four members that regulate several cellular activities such as movement, proliferation, survival, differentiation, polarization, and the entry of viruses. Nectin-4 has recently emerged as a metastatis-associated protein in several cancers. Here, we have evaluated the association between the expression of Nectin-4 and the clinical outcome of patients with node-negative, T1/T2 breast cancers.The study group consisted of 197 patients presenting with primary unilateral breast carcinoma (T1/T2), with no evidence of nodal involvement and distant metastases. Nectin-4 protein expression was assessed by immunohistochemistry on tissue microarrays, and the results correlated with the clinical data using Kaplan-Meier curves and multivariate Cox regression analysis. Thirty-four out of 197 tumors (17.3%) exhibited Nectin-4 expression on cell membrane (m-Nectin-4) and 122 out of the 163m-Nectin-4 negative tumors (74.8%) showed high cytoplasmic expression of Nectin-4 (c-Nectin-4(High)). At Kaplan-Meier analysis, m-Nectin-4 positivity was significantly associated with a lower disease-free survival (DFS) and distant relapse-free survival (DRFS) rate in patients with a luminal-A phenotype (P=0.030 and P=0.002, respectively). Multivariate analysis showed that in luminal-A tumors m-Nectin-4 positivity is an independent prognostic factor for DFS (P=0.018) and DRFS (P=0.004), but not for local relapse-free survival (LRFS). On the other hand, c-Nectin-4(High) was significantly associated with higher rates of DFS and LRFS, but not DRFS, in the whole population (P=0.008 and P=0.004, respectively) and in patients with luminal-A tumors (P=0.022 and P=0.018, respectively). In patients with luminal-A tumors, multivariate analysis showed that the prognostic value of c-Nectin-4(Low/Negative) is limited to DFS (P=0.012) and LRFS (P=0.022). We suggest that Nectin-4 represents a prognostic factor and a therapeutic target in luminal-A early stage breast cancer.
authors.affiliation: 1] Department of Experimental and Clinical Sciences, Chieti, Italy [2] Center of Excellence for Research on Aging, Chieti, Italy [3] MediaPharma s.r.l., Chieti, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Lattanzio
authors.affiliation: 1] Department of Experimental and Clinical Sciences, Chieti, Italy [2] Center of Excellence for Research on Aging, Chieti, Italy [3] Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
authors.forename: R
authors.initials: R
authors.lastname: Ghasemi
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Brancati
authors.affiliation: 1] Department of Experimental and Clinical Sciences, Chieti, Italy [2] Center of Excellence for Research on Aging, Chieti, Italy [3] MediaPharma s.r.l., Chieti, Italy.
authors.forename: R L
authors.initials: RL
authors.lastname: Sorda
authors.affiliation: 1] Department of Experimental and Clinical Sciences, Chieti, Italy [2] Center of Excellence for Research on Aging, Chieti, Italy [3] MediaPharma s.r.l., Chieti, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Tinari
authors.affiliation: Department of Pathology, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Perracchio
authors.affiliation: 1] Department of Experimental and Clinical Sciences, Chieti, Italy [2] Center of Excellence for Research on Aging, Chieti, Italy [3] MediaPharma s.r.l., Chieti, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Iacobelli
authors.affiliation: Department of Pathology, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: CINBO Laboratories, University 'G. D'Annunzio', Chieti, Italy.
authors.forename: P G
authors.initials: PG
authors.lastname: Natali
authors.affiliation: 1] Department of Experimental and Clinical Sciences, Chieti, Italy [2] Center of Excellence for Research on Aging, Chieti, Italy [3] MediaPharma s.r.l., Chieti, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Piantelli