Genomic characteristics of trastuzumab-resistant Her2-positive metastatic breast cancerReportar como inadecuado

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Journal of Cancer Research and Clinical Oncology

, Volume 143, Issue 7, pp 1255–1262

First Online: 28 February 2017Received: 23 January 2017Accepted: 27 January 2017DOI: 10.1007-s00432-017-2358-x

Cite this article as: de Oliveira Taveira, M., Nabavi, S., Wang, Y. et al. J Cancer Res Clin Oncol 2017 143: 1255. doi:10.1007-s00432-017-2358-x


PurposeResistance to trastuzumab therapy is linked to phosphoinositol 3-kinase PI3K pathway activation. One key downstream effector and regulator of this pathway is the mechanistic target of rapamycin mTOR. In 2011, a phase I-II study evaluated the combination of trastuzumab and everolimus a mTOR inhibitor for treatment of Her2-positive metastatic breast cancer MBC for patients who had progressed on trastuzumab-based therapy.

MethodsWe retrospectively analyzed GeneChip microarray data from 22 of 47 patients included in the study.

ResultsUsing an unbiased approach, we found that mutations in BRAF, EGFR and KIT are significantly more common in this heavily treated population when compared with the cohort of invasive breast carcinoma patients in The Cancer Genome Atlas TCGA. Furthermore, 10 out of 22 patients had PIK3CA mutations 45.4% but PI3KCA status was not predictive of PFS in our cohort. Finally, the use of OncoScan has allowed us to detected mutations in five genes that have not been shown to be mutated in TCGA subset of Her-2 overexpressing breast cancer: CTNNB1, HRAS, KRAS, NF2 and SMARCB1.

ConclusionMutational burden in heavily treated trastuzumab-resistant Her2-positive metastatic breast cancer is highly variable and not directly correlated with outcome. Activation of the MAPK-ERK pathway through mutations in EGFR, BRAF or KIT may mediate resistance to trastuzumab.

KeywordsHer2 Trastuzumab Everolimus Metastatic breast cancer Phosphoinositol 3-kinase mTOR 

Autor: Mateus de Oliveira Taveira - Sheida Nabavi - Yuker Wang - Peter Tonellato - Francisco J. Esteva - Lewis C. Cantley - Gerbu


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