Identifying novel predictive markers and therapeutic targets for HER2-positive breast cancers.

HER2-positive breast cancer accounts for up to 25% of all breast cancers and constitute a heterogeneous group at the histopathological and genomic levels. Patients with HER2-positive cancers are managed with a combination of chemotherapy and anti-HER2 humanised monoclonal antibodies or HER2 tyrosine kinase inhibitors. Although anti-HER2 tailored therapy has changed the management of patients with this breast cancer subtype, the majority of patients are either de novo resistant or acquire resistance to these therapies over time. Previous studies have demonstrated that genes whose inhibition overcomes either de novo or acquired resistance to specific therapeutic agents can be identified though a combination of high throughput molecular profiling of breast cancers coupled with RNA interference (RNAi) screens.

Our preliminary analysis of 26 HER2 amplified breast cancers has revealed that >90% of these cancers harbour a ‘firestorm’ genomic pattern, being characterised by multiple clustered amplifications mapping to single chromosomes or chromosomal arms. These amplifications involve not only 17q12, the HER2 locus, but also multiple other regions in the genome. 

Given the high prevalence of recurrent amplifications in HER2-positive cancers, we have hypothesised that:

1 – HER2 amplified breast cancer cells may be dependent on the function and/ or signalling of genes mapping to recurrently amplified regions other than 17q12.
2 – Amplification of specific oncogenes may be associated with de novo or acquired resistance to anti-HER2 agents.
3 – Inhibition of specific oncogenes may sensitise cells that are resistant to anti-HER2 agents, such as Trastuzumab, Pertuzumab and Lapatinib.
4 – Specific oncogenes that are recurrently amplified in HER2 amplified breast cancers may be associated with poor outcome in patients treated with Trastuzumab.

To test these hypotheses, we have profiled a large series of primary HER2-positive breast cancers and HER2 amplified cell lines with microarray-based comparative genomic hybridisation and expression arrays. This has led to the identification of genes recurrently amplified in HER2-positive disease and genes that are consistently overexpressed when amplified in these cancers. 

Our aims are to identify novel genes whose amplification is essential for the survival of subgroups of HER2-positive cancers, with the intention of exploring these findings clinically, as novel therapeutic targets for subgroups of HER2-positive patients.

In collaboration with Prof Alan Ashworth and Dr Chris Lord, we are developing high throughput functional assays to determine whether the survival of HER2-positive cancer cells depends on the expression and function of the genes recurrently amplified. These analyses will determine whether these genes represent novel targets for subgroups of HER2 amplified cancers and whether these genes modify response to therapy (i.e. Trastuzumab, Pertuzumab and Lapatinib).

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The prevalence and impact on outcome of regions harbouring novel genes of interest will be interrogated in large cohorts of patients with HER2-positive breast cancer treated with Trastuzumab ± chemotherapy using a combination of in situ hybridisation, immunohistochemistry and qRT-PCR. This analysis will help determine if specific amplifications are associated with poor outcome or are predictive of response to anti-HER2 agents.