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

• Published in: Therapeutic advances in medical oncology 2018-01, Vol.10, p.1758835918778297-1758835918778297
• Main Authors: Elster, Naomi, Toomey, Sinead, Fan, Yue, Cremona, Mattia, Morgan, Clare, Weiner Gorzel, Karolina, Bhreathnach, Una, Milewska, Malgorzata, Murphy, Madeline, Madden, Stephen, Naidoo, Jarushka, Fay, Joanna, Kay, Elaine, Carr, Aoife, Kennedy, Sean, Furney, Simon, Mezynski, Janusz, Breathhnach, Oscar, Morris, Patrick, Grogan, Liam, Hill, Arnold, Kennedy, Susan, Crown, John, Gallagher, William, Hennessy, Bryan, Eustace, Alex
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Breast cancer; Colonies; Epidermal growth factor; Epidermal growth factor receptors; ErbB protein; ErbB-2 protein; ErbB-3 protein; Genes; Growth rate; Immunotherapy; Kinases; Metastases; Monoclonal antibodies; Mutation; Original Research; Targeted cancer therapy; Trastuzumab; Tumor cell lines; Tumorigenesis
• ISSN: 1758-8340; 1758-8359; 1758-8359
• DOI: 10.1177/1758835918778297

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.