title: Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer.
abstract: Triple-negative breast cancers (TNBCs) are associated with a poor prognosis. In contrast to other molecular subtypes, they have no identified specific target and chemotherapy remains the only available systemic treatment. The adhesion molecule nectin-4 represents a new potential therapeutic target in different cancer models. Here, we have tested the prognostic value of nectin-4 expression and assessed the therapeutic efficiency of an anti-nectin 4 antibody drug conjugate (ADC) on localised and metastatic TNBC in vitro and in vivo.
  
  
  
  We analysed nectin-4/PVRL4 mRNA expression in 5673 invasive breast cancers and searched for correlations with clinicopathological features including metastasis-free survival (MFS). Immunohistochemistry was carried out in 61 TNBCs and in samples of primary TNBC Patient-Derived Xenografts (PDXs). An anti-nectin-4 antibody eligible for ADC was produced and tested in vitro and in vivo in localised and metastatic TNBC PDXs.
  
  
  
  High nectin-4/PVRL4 mRNA expression was associated with poor-prognosis features including the TN and basal subtypes. High PVRL4 mRNA expression showed independent negative prognostic value for MFS in multivariate analysis in TNBCs. Nectin-4 protein expression was not detected in adult healthy tissues including mammary tissue. Membranous protein expression was found in 62% of TNBCs, with strong correlation with mRNA expression. We developed an ADC (N41mab-vcMMAE) comprising a human anti-nectin-4 monoclonal antibody conjugated to monomethyl auristatin-E (MMAE). In vitro, this ADC bound to nectin-4 with high affinity and specificity and induced its internalisation as well as dose-dependent cytotoxicity on nectin-4-expressing breast cancer cell lines. In vivo, this ADC induced rapid, complete and durable responses on nectin-4-positive xenograft TNBC samples including primary tumours, metastatic lesions, and local relapses; efficiency was dependent on both the dose and the nectin-4 tumour expression level.
  
  
  
  Nectin-4 is both a new promising prognostic biomarker and specific therapeutic target for ADC in the very limited armamentarium against TNBC.
authors.affiliation: Centre de Cancérologie de Marseille, INSERM U1068, Equipe Immunité et Cancer, Institut Paoli-Calmettes, Aix-Marseille Université, CNRS, UMR7258, Marseille, France.
authors.forename: M
authors.initials: M
authors.lastname: M-Rabet
authors.affiliation: Molecular Oncology "Equipe labellisée Ligue Contre le Cancer," Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, 13273 Marseille, France.
authors.forename: O
authors.initials: O
authors.lastname: Cabaud
authors.affiliation: CRCM, INSERM, U1068; Institut Paoli-Calmettes; Aix-Marseille Université; CNRS, UMR 7258, Marseille, France.
authors.forename: E
authors.initials: E
authors.lastname: Josselin
authors.affiliation: Aix Marseille Université, CNRS, INSERM , Institut Paoli-Calmettes, CRCM, Equipe Oncologie Moléculaire labellisée 'Ligue contre le cancer' , Marseille , France.
authors.forename: P
authors.initials: P
authors.lastname: Finetti
authors.affiliation: TrGET Platform, Inserm, U1068, Marseille F-13009, France.
authors.forename: R
authors.initials: R
authors.lastname: Castellano
authors.affiliation: ICEP Platform, Inserm, U1068, CRCM, Institut Paoli Calmettes, Aix-Marseille Université, UM 105, CNRS, UMR7258.
authors.forename: A
authors.initials: A
authors.lastname: Farina
authors.affiliation: ICEP Platform, Inserm, U1068, CRCM, Institut Paoli Calmettes, Aix-Marseille Université, UM 105, CNRS, UMR7258.
authors.forename: E
authors.initials: E
authors.lastname: Agavnian-Couquiaud
authors.affiliation: Aix Marseille Université, CNRS, INSERM , Institut Paoli-Calmettes, CRCM, Equipe Oncologie Moléculaire labellisée 'Ligue contre le cancer' , Marseille , France.
authors.forename: G
authors.initials: G
authors.lastname: Saviane
authors.affiliation: TrGET Platform, Inserm, U1068, Marseille F-13009, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Collette
authors.affiliation: Département d'Oncologie Médicale, Institut Paoli Calmettes, Aix-Marseille Université, UM 105, Marseille, France.
authors.forename: P
authors.initials: P
authors.lastname: Viens
authors.affiliation: Département d'Oncologie Médicale, Institut Paoli Calmettes, Aix-Marseille Université, UM 105, Marseille, France.
authors.forename: A
authors.initials: A
authors.lastname: Gonçalves
authors.affiliation: Aix Marseille Université, CNRS, INSERM , Institut Paoli-Calmettes, CRCM, Equipe Oncologie Moléculaire labellisée 'Ligue contre le cancer' , Marseille , France.
authors.forename: C
authors.initials: C
authors.lastname: Ginestier
authors.affiliation: Aix Marseille Université, CNRS, INSERM , Institut Paoli-Calmettes, CRCM, Equipe Oncologie Moléculaire labellisée 'Ligue contre le cancer' , Marseille , France.
authors.forename: E
authors.initials: E
authors.lastname: Charafe-Jauffret
authors.affiliation: Aix Marseille Université, CNRS, INSERM , Institut Paoli-Calmettes, CRCM, Equipe Oncologie Moléculaire labellisée 'Ligue contre le cancer' , Marseille , France.
authors.forename: D
authors.initials: D
authors.lastname: Birnbaum
authors.affiliation: Centre de Cancérologie de Marseille, INSERM U1068, Equipe Immunité et Cancer, Institut Paoli-Calmettes, Aix-Marseille Université, CNRS, UMR7258, Marseille, France.
authors.forename: D
authors.initials: D
authors.lastname: Olive
authors.affiliation: Aix Marseille Université, CNRS, INSERM , Institut Paoli-Calmettes, CRCM, Equipe Oncologie Moléculaire labellisée 'Ligue contre le cancer' , Marseille , France.|Département d'Oncologie Médicale, Institut Paoli Calmettes, Aix-Marseille Université, UM 105, Marseille, France.
authors.forename: F
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Aix Marseille Université, CNRS, INSERM , Institut Paoli-Calmettes, CRCM, Equipe Oncologie Moléculaire labellisée 'Ligue contre le cancer' , Marseille , France.
authors.forename: M
authors.initials: M
authors.lastname: Lopez
mesh_terms: D000328:Adult; D062365:Aminobenzoates / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000494:pharmacology; D011379:Prognosis; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000075983:Nectins
chemical_list: D062365:Aminobenzoates; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D009842:Oligopeptides; C543533:auristatin; C442228:NECTIN4 protein, human; D000075983:Nectins
keywords: ADC targeting; TNBC; biomarker; breast cancer; nectin-4; survival