Research aim

The goals of the molecular pathology programme are to advance breast cancer diagnosis and treatment by applying high throughput pathology and molecular methods to define:

  • Breast cancer taxonomy based on a combination of classic morphological and immunohistochemical characteristics and genome-wide molecular features of specific subgroups of breast cancer
  • Potential therapeutic targets
  • Prevention of progression

  

Overview

Breast cancer is a heterogeneous disease encompassing a multitude of pathological entities that have distinct morphological features and clinical behaviour. The complexity of breast cancer has been long acknowledged by histopathologists, who have endeavoured to devise classification systems to account for this diversity. Although an accurate histological diagnosis is of paramount importance for patient management, it is clear that, in the era of tailored therapy, additional markers with higher predictive and prognostic impact are needed. 

Current classification systems are largely descriptive and based on morphological entities, which do not necessarily reflect the underlying molecular genetic differences. For the success of targeted therapies and individualised medicine, a predictive, rather than purely prognostic, classification system that better reflects the biological and clinical characteristics of breast cancers is required.

Our group has hypothesised that by combining traditional pathology with high throughput molecular analysis, a refined breast cancer classification system that would be more biologically and clinically meaningful could be devised. In fact, the combination of traditional pathology methods, immunohistochemistry and in situ hybridisation, with high throughput methods, including microarray comparative genomic hybridisation, mRNA and miRNA profiling and global methylation analysis, has been instrumental in solving contentious issues of breast cancer taxonomy and clarifying the role of putative breast cancer precursor lesions. With the advent of next generation sequencing, we are now in a position to catalogue all genetic, transcriptomic and epigenetic aberrations in specific types of breast cancer. Integrating these new data with pathological characteristics of breast cancers will offer a unique opportunity to define the biological drivers and the therapeutic targets of specific subgroups of breast cancer.

Figure 1 Jorge Reis-Filho Pathology

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Our research

In collaboration with other laboratories at the Breakthrough Research Centre, the Royal Marsden Hospital and institutions in Europe and USA, we have been analysing special types of breast cancer in great depth and have already identified molecular traits that are currently being used to refine breast cancer classification. Furthermore, this approach has led to identification of FGFR1 and PPM1D as potential therapeutic targets for a specific subgroup of oestrogen receptor positive and HER2-positive breast cancers harbouring amplification of these genes, respectively. 

Our projects address the molecular pathology of i) special histological types of breast cancer, with a special emphasis on lobular carcinomas, ii) basal-like carcinomas, and iii) HER2-positive breast cancers. In these projects, a combination of thorough histological analysis, immunohistochemistry for prognostic and predictive markers and molecular genetics have allowed us to tease out interesting biological aspects and most importantly, refine the definition of these entities. With the identification of therapeutic targets and more accurate molecular definitions, clinical trials using tailored therapies may prove more successful. Furthermore, we are investigating whether the morphological diversity of breast cancers is underpinned by distinct genetic changes.

Major achievements since 2006

  1. Identification of FGFR1 as a potential therapeutic target for a subgroup of patients with lobular and ER-positive breast cancers.
  2. Identification of PPM1D as a therapeutic target for a subgroup of patients with ER positive and HER2-positive breast cancers and ovarian clear cell cancers.
  3. Characterisation of the molecular pathology of basal-like breast cancers and development of a mouse model for these cancers based on their BRCA1 pathway dysfunction.
  4. Characterisation of the molecular pathology features of invasive micropapillary carcinomas and pleomorphic lobular carcinomas.
  5. Contributed to the identification of BRCA2 intragenic deletions as a mechanism of resistance to platinum salts and PARP inhibitors, in collaboration with Alan Ashworth’s group.