Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer

M. M-Rabet (1) , O. Cabaud (1) , E. Josselin (1) , P. Finetti (1) , R. Castellano (2) , A. Farina (1) , E. Agavnian-Couquiaud (1) , G. Saviane (1) , Y. Collette (1, 2) , P. Viens (1) , A. Goncalves (1) , C. Ginestier (1) , E. Charafe-Jauffret (1) , D. Birnbaum (3, 1) , D. Olive (1) , F. Bertucci (1) , M. Lopez (1)

1 CRCM - Centre de Recherche en Cancérologie de Marseille
2 TrGET Platform
3 Inserm U599/IPC - Cancérologie

Background: Triple-negative breast cancers (TNBCs) are associated with a poor prognosis. In contrast to other molecular sub-types, 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 prognos-tic 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. Materials and methods: 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. Results: High nectin-4/PVRL4 mRNA expression was associated with poor-prognosis features including the TN and basal sub-types. 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. Conclusion: Nectin-4 is both a new promising prognostic biomarker and specific therapeutic target for ADC in the very limited armamentarium against TNBC.

Mots clés: ADC targeting; biomarker; breast cancer; nectin-4; survival; TNBC

Domaines: Sciences du Vivant [q-bio]; Cancer

M. M-Rabet, O. Cabaud, E. Josselin, P. Finetti, R. Castellano, et al.. Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer. Annals of Oncology, 2017, ⟨10.1093/annonc/mdw678⟩. ⟨hal-01787533⟩