Working together for the family: determination of HER oncogene co-amplifications in breast cancer

EMANUEL CAMPOY; URRUTIA GUILLERMO; GLATSTEIN TELMA; SAVOLA SUVI ; LAURITO SERGIO; REAL SEBASTIAN; GAGO FRANCISCO; DE LA IGLESIA PAOLA; MARIA ROQUE ; BRANHAM MARÍA TERESITA; CUETO JUAN; TELLO OLGA; ATANESYAN LILIT

Oncotarget

Impact Journals LLC

Lugar: New York; Año: 2020 vol. 11 p. 2774 - 2792

1949-2553

HER2 is a well-studied tyrosine kinase (TK) membrane receptor which functions as a therapeutic target in invasive ductal breast carcinomas (IDC). The standard of care for the treatment of HER2-positive breast is the antibody trastuzumab. Despite specific treatment unfortunately, 20% of primary and 70% of metastatic HER2 tumors develop resistance. HER2 belongs to a gene family, with four members (HER1-4) and these members could be involved in resistance to anti-HER2 therapies. In this study we designed a probemix to detect the amplification of the four HER oncogenes in a single reaction. In addition, we developed a protocol based on the combination of MLPA with ddPCR to detect the tumor proportion of co-amplified HERs. On 111 IDC, the HER2 MLPA results were validated by FISH (Adjusted r2 = 0,91, p < 0,0001), CISH (Adjusted r2 = 0,938, p < 0,0001) and IHC (Adjusted r2 = 0,31, p < 0,0001). HER1-4 MLPA results were validated by RT-qPCR assays (Spearman Rank test p < 0,05). Of the 111 samples, 26% presented at least one HER amplified, of which 23% showed co-amplifications with other HERs. The percentage of cells with HER2 co-amplified varied among the tumors (from 2-72,6%). Independent in-silico findings show that the outcome of HER2+ patients is conditioned by the status of HER3 and HER4. Our results encourage further studies to investigate the relationship with patient´s response to single or combined treatment. The approach could serve as proof of principle for other tumors in which the HER oncogenes are involved.