Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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The Long-HER Study

ABSTRACT: Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. Some of these patients may become long-term survivors. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression to trastuzumab. 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Sixty-five per cent of tumours were poorly differentiated ductal carcinomas and hormonal receptors were present in 47%. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median progression-free survival was 10.6 years after the diagnosis of metastatic disease. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival . Gene ontology analysis demonstrated that genes involved in HIF activation, EGF receptor signalling pathway, PI3 kinase pathway, apoptosis signalling pathway and p53 pathway significantly correlated with response. The PI3K pathway was the most strongly associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most. These findings support that trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression to trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy. 53 FFPE samples, which passed the RNA quality control criteria, were analyzed (45 primary tumours and 8 metastases). Among these 53 samples, 35 samples corresponded to long-term responders and 18 to the control group.

ORGANISM(S): Homo sapiens

SUBMITTER: Juan Ãngel Fresno Vara

PROVIDER: E-GEOD-44272 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:HER2 targeting with trastuzumab has changed the prognosis of breast cancer patients carrying amplification and/or overexpression of this oncogene. Despite this progress, however, resistance to trastuzumab occurs in the vast majority of patients. Newer anti-HER2 therapies, like the dual tyrosine-kinase inhibitor (TKI) lapatinib, show antitumor activity in a limited proportion of patients, indicating that HER2 can be still exploited as a target after trastuzumab failure. However, due to the high proportion of patients that fail to respond to these alternative strategies, it is reasonable to assume that cells escaping HER2 targeting may rely on alternative pathways not involving HER2 to sustain their growth. Their knowledge is relevant for exploiting new therapies. To investigate this hypothesis we generated a human HER2 overexpressing breast cancer cell line resistant to trastuzumab and lapatinib (T100) and we have characterized it genetically and molecularly. In T100 cells, the previously proposed mechanisms of resistance to HER2 inhibitors did not explain cell escape. Notably, silencing HER2 by shRNA did not affect the growth of T100 cells, suggesting loss of reliance upon HER2. Among the alternative pathways that we explored, altered levels of the antiapoptoptic proteins Mcl-1 and Survivin were observed. This suggested the possibility of targeting resistant cells with the multitarget inhibitor sorafenib. Moreover, sorafenib, nearly inactive in parental cells, strongly inhibited the in vitro growth of T100 cells. In conclusion, we provide a new model where the activation of HER2 independent mechanisms sustains the growth of tumor cells, significantly increasing the sensitivity to sorafenib. Keywords: HER2, breast cancer, resistance, trastuzumab, lapatinib, sorafenib Total RNA was isolated using TRIZOL reagent (Life Technologies, Gathersburg, MD) and quantified by Bioanalyzer 2100 (Agilent Technologies); following the isolation procedure, mRNA was amplified starting from 1μg using MessageAmp II aRNA Amplification kit (Ambion Inc. Austin TX, USA). Ammino-allyl modified nucleotides were incorporated in in vitro transcription step according to the manufacturer’s protocol. Labeling was performed using NHS (N-hydroxysuccinimidyl) ester Cy3 or Cy5 dies (GE Healthcare Europe GMBH, Upsala - Sweden) able to react with the modified RNA. At least 5 μg of mRNA, for each sample, were labeled and purified with columns respectively. The Dye-Swap replication procedure was applied, in order to increase the accuracy of results. Samples were hybridized on 44K glass arrays (Agilent Technologies). Arrays were scanned and the images obtained were analyzed by the Feature Extraction software Agilent (version 9.5) and the text files were then processed using the Bioconductor package Limma (Linear models for microarray analysis).

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The Long-HER Study

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