F-C Bidard1, C K Y Ng2, P Cottu3, S Piscuoglio2, L Escalup4, R A Sakr5, F Reyal6, P Mariani6, R Lim2, L Wang2, L Norton7, V Servois8, B Sigal9, A Vincent-Salomon9, B Weigelt2, J-Y Pierga10, J S Reis-Filho11. 1. Department of Medical Oncology, Institut Curie, Paris, France Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA fcbidard@curie.fr. 2. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA. 3. Department of Medical Oncology, Institut Curie, Paris, France. 4. Department of Pharmacy, Institut Curie, Paris, France. 5. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA. 6. Department of Surgery, Institut Curie, Paris, France. 7. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. 8. Department of Radiology, Institut Curie, Paris. 9. Department of Pathology, Institut Curie, Paris. 10. Department of Medical Oncology, Institut Curie, Paris, France Paris Descartes University, Paris, France. 11. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, USA.
Abstract
BACKGROUND: HER3 activating mutations have been shown in preclinical models to be oncogenic and ligand-independent, but to depend on kinase-active HER2. PATIENTS AND METHODS: Whole-exome sequencing of the primary HER2-negative breast cancer and its HER2-negative synchronous liver metastasis from a 46-year-old female revealed the presence of an activating and clonal HER3 G284R mutation. RESULTS: HER2 dual blockade with trastuzumab and lapatinib as third-line therapy led to complete metabolic response in 2 weeks and confirmed radiological partial response after 8 weeks. Following the resection of the liver metastasis, the patient remains disease-free 40 weeks after initiation of the HER2 dual blockade therapy. Immunohistochemical analysis demonstrated a substantial reduction of phospho-rpS6 and phospho-AKT in the post-therapy biopsy of the liver metastasis. DISCUSSION: This is the first-in-man evidence that anti-HER2 therapies are likely effective in breast cancers harboring HER3 activating mutations.
BACKGROUND:HER3 activating mutations have been shown in preclinical models to be oncogenic and ligand-independent, but to depend on kinase-active HER2. PATIENTS AND METHODS: Whole-exome sequencing of the primary HER2-negative breast cancer and its HER2-negative synchronous liver metastasis from a 46-year-old female revealed the presence of an activating and clonal HER3G284R mutation. RESULTS:HER2 dual blockade with trastuzumab and lapatinib as third-line therapy led to complete metabolic response in 2 weeks and confirmed radiological partial response after 8 weeks. Following the resection of the liver metastasis, the patient remains disease-free 40 weeks after initiation of the HER2 dual blockade therapy. Immunohistochemical analysis demonstrated a substantial reduction of phospho-rpS6 and phospho-AKT in the post-therapy biopsy of the liver metastasis. DISCUSSION: This is the first-in-man evidence that anti-HER2 therapies are likely effective in breast cancers harboring HER3 activating mutations.
Authors: Charlotte K Y Ng; Francois-Clement Bidard; Salvatore Piscuoglio; Felipe C Geyer; Raymond S Lim; Ino de Bruijn; Ronglai Shen; Fresia Pareja; Samuel H Berman; Lu Wang; Jean-Yves Pierga; Anne Vincent-Salomon; Agnes Viale; Larry Norton; Brigitte Sigal; Britta Weigelt; Paul Cottu; Jorge S Reis-Filho Journal: Clin Cancer Res Date: 2017-03-28 Impact factor: 12.531
Authors: Nicola Fusco; Felipe C Geyer; Maria R De Filippo; Luciano G Martelotto; Charlotte K Y Ng; Salvatore Piscuoglio; Elena Guerini-Rocco; Anne M Schultheis; Laetitia Fuhrmann; Lu Wang; Achim A Jungbluth; Kathleen A Burke; Raymond S Lim; Anne Vincent-Salomon; Masamichi Bamba; Suzuko Moritani; Sunil S Badve; Shu Ichihara; Ian O Ellis; Jorge S Reis-Filho; Britta Weigelt Journal: Mod Pathol Date: 2016-08-05 Impact factor: 7.842
Authors: Gabrielle Deniziaut; Jean Christophe Tille; François-Clément Bidard; Sophie Vacher; Anne Schnitzler; Walid Chemlali; Laurence Trémoulet; Laetitia Fuhrmann; Paul Cottu; Roman Rouzier; Ivan Bièche; Anne Vincent-Salomon Journal: Oncotarget Date: 2016-11-08
Authors: Jeffrey S Ross; Marwan Fakih; Siraj M Ali; Julia A Elvin; Alexa B Schrock; James Suh; Jo-Anne Vergilio; Shakti Ramkissoon; Eric Severson; Sugganth Daniel; David Fabrizio; Garrett Frampton; James Sun; Vincent A Miller; Philip J Stephens; Laurie M Gay Journal: Cancer Date: 2018-01-16 Impact factor: 6.860