Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer Journal Article


Authors: Elster, N.; Toomey, S.; Fan, Y.; Cremona, M.; Morgan, C.; Gorzel, K. W.; Bhreathnach, U.; Milewska, M.; Murphy, M.; Madden, S.; Naidoo, J.; Fay, J.; Kay, E.; Carr, A.; Kennedy, S.; Furney, S.; Mezynski, J.; Breathhnach, O.; Morris, P.; Grogan, L.; Hill, A.; Kennedy, S.; Crown, J.; Gallagher, W.; Hennessy, B.; Eustace, A.
Article Title: Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer
Abstract: Background: Somatic mutations in the ERBB genes (epidermal growth factor receptor: EGFR, ERBB2, ERBB3, ERBB4) promote oncogenesis and lapatinib resistance in metastatic HER2+ (human epidermal growth factor-like receptor 2) breast cancer in vitro. Our study aimed to determine the frequency of mutations in four genes: EGFR, ERBB2, ERBB3 and ERBB4 and to investigate whether these mutations affect cellular behaviour and therapy response in vitro and outcomes after adjuvant trastuzumab-based therapy in clinical samples. Methods: We performed Agena MassArray analysis of 227 HER2+ breast cancer samples to identify the type and frequency of ERBB family mutations. Of these, two mutations, the somatic mutations ERBB4-V721I and ERBB4-S303F, were stably transfected into HCC1954 (PIK3CA mutant), HCC1569 (PIK3CA wildtype) and BT474 (PIK3CA mutant, ER positive) HER2+ breast cancer cell lines for functional in vitro experiments. Results: A total of 12 somatic, likely deleterious mutations in the kinase and furin-like domains of the ERBB genes (3 EGFR, 1 ERBB2, 3 ERBB3, 5 ERBB4) were identified in 7% of HER2+ breast cancers, with ERBB4 the most frequently mutated gene. The ERBB4-V721I kinase domain mutation significantly increased 3D-colony formation in 3/3 cell lines, whereas ERBB4-S303F did not increase growth rate or 3D colony formation in vitro. ERBB4-V721I sensitized HCC1569 cells (PIK3CA wildtype) to the pan class I PI3K inhibitor copanlisib but increased resistance to the pan-HER family inhibitor afatinib. The combinations of copanlisib with trastuzumab, lapatinib, or afatinib remained synergistic regardless of ERBB4-V721I or ERBB4-S303F mutation status. Conclusions: ERBB gene family mutations, which are present in 7% of our HER2+ breast cancer cohort, may have the potential to alter cellular behaviour and the efficacy of HER- and PI3K-inhibition. © The Author(s), 2018.
Keywords: breast cancer; pi3k; somatic mutations; trastuzumab resistance; pi3k inhibition; her2+ bc
Journal Title: Therapeutic Advances in Medical Oncology
Volume: 10
ISSN: 1758-8340
Publisher: Sage Publications Ltd.  
Date Published: 2018-07-13
Language: English
DOI: 10.1177/1758835918778297
PROVIDER: scopus
PMCID: PMC6047239
PUBMED: 30023006
DOI/URL:
Notes: Article -- Export Date: 1 November 2018 -- Source: Scopus
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  1. Jarushka Naidoo
    31 Naidoo