Abstract
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 OncoScantm 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.
Highlights
Breast cancer (BC) is the most prevalent non-skin cancer in women, accounting for ~40,000 deaths per year in the USA (Siegel et al 2012)
22 samples were submitted to DNA microarray panel (Affymetrix OncoscanTM), a genomic screening tool based on molecular inversion probe (MIP) technology for identifying copy number alterations, loss of heterozygosity (LOH), and somatic mutations (Wang et al 2005, 2007, 2009)
21 of those are represented in the group of 201 mutations described in The Cancer Genome Atlas (TCGA) in BC (Ciriello et al 2015)
Summary
Breast cancer (BC) is the most prevalent non-skin cancer in women, accounting for ~40,000 deaths per year in the USA (Siegel et al 2012). The majority of patients with Her2-positive disease receive trastuzumab as part of their treatment. This monoclonal antibody targets the extracellular domain of the HER2 receptor and has significantly increased OS for this subset of patients (Slamon et al 2001). Not all patients respond to trastuzumab-based therapies and some develop secondary resistance after disease remission. The precise mechanisms behind trastuzumab resistance are not fully understood, but some have implicated activation of the phosphoinositol 3-kinase (PI3K) pathway (Berns et al 2007). Activation of PI3K pathway through PIK3CA mutations or PTEN loss would lead to cell growth through mTOR-mediated signaling, effectively rendering proliferating signals from epidermal growth factor receptors, such as HER2, redundant
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