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Sci Signal. 2018 Oct 9;11(551). pii: eaat9773. doi: 10.1126/scisignal.aat9773.

Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2).

Author information

1
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
2
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
3
Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
4
Unit of Investigative Clinical Oncology (INCO), Candiolo Cancer Institute, FPO-IRCCS, Str. Provinciale 142, 10060 Candiolo, Italy.
5
Unit of Surgical Pathology, Fondazione del Piemonte per l'Oncologia, Candiolo Cancer Institute, FPO-IRCCS, Str. Provinciale 142, 10060 Candiolo, Italy.
6
Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC 3000, Australia.
7
START, 4383 Medical Dr, San Antonio, TX 78229, USA.
8
Puma Biotechnology Inc., 10880 Wilshire Blvd, Los Angeles, CA 90024, USA.
9
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
10
START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Sanchinarro, Calle de Oña 10, 28050 Madrid, Spain.
11
Unit of Investigative Clinical Oncology (INCO), Candiolo Cancer Institute, FPO-IRCCS, Str. Provinciale 142, 10060 Candiolo, Italy. filippo.montemurro@ircc.it scaltrim@mskcc.org.
12
Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. filippo.montemurro@ircc.it scaltrim@mskcc.org.

Abstract

Mutations in ERBB2, the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common in and drive the growth of "HER2-negative" (not ERBB2 amplified) tumors but are rare in "HER2-positive" (ERBB2 amplified) breast cancer. We analyzed DNA-sequencing data from HER2-positive patients and used cell lines and a patient-derived xenograft model to test the consequence of HER2 mutations on the efficacy of anti-HER2 agents such as trastuzumab, lapatinib, and neratinib, an irreversible pan-EGFR inhibitor. HER2 mutations were present in ~7% of HER2-positive tumors, all of which were metastatic but not all were previously treated. Compared to HER2 amplification alone, in both patients and cultured cell lines, the co-occurrence of HER2 mutation and amplification was associated with poor response to trastuzumab and lapatinib, the standard-of-care anti-HER2 agents. In mice, xenografts established from a patient whose HER2-positive tumor acquired a D769Y mutation in HER2 after progression on trastuzumab-based therapy were resistant to trastuzumab or lapatinib but were sensitive to neratinib. Clinical data revealed that six heavily pretreated patients with tumors bearing coincident HER2 amplification and mutation subsequently exhibited a statistically significant response to neratinib monotherapy. Thus, these findings indicate that coincident HER2 mutation reduces the efficacy of therapies commonly used to treat HER2-positive breast cancer, particularly in metastatic and previously HER2 inhibitor-treated patients, as well as potentially in patients scheduled for first-line treatment. Therefore, we propose that clinical studies testing the efficacy of neratinib are warranted selectively in breast cancer patients whose tumors carry both amplification and mutation of ERBB2/HER2.

PMID:
30301790
DOI:
10.1126/scisignal.aat9773

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