Jane has decades of experience in breast, gynaecological and reproductive pathology. She has been at the forefront of using genomic technologies in research and in solving a wide range of difficult diagnostic cases. She has also been an advisor to pharmaceutical and biotech companies.
Title: “Genome sequencing as a diagnostic aid.”
There is wide acceptance of the concept of genotype-phenotype correlation in cancers. This concept has been extensively explored in breast carcinogenesis. Early work identified a strong phenotypic signature of breast cancer which arose in patients with germline BRCA1 mutation. Subsequent data identified four broad intrinsic subtypes of breast cancer, with one being a group of “basal-like” breast cancers, referring to their over-expression of basal cytokeratin markers. Over time, and with transition of intrinsic subtyping to the clinic, the concept of triple-negative breast cancers (i.e., not expressing ER, PR or HER2 by IHC or ISH) evolved as a phenotypic surrogate for “”basal-like” breast cancers. This surrogate was acceptable, given that therapeutic targets available in breast cancer were limited to those directed at the ER/PR pathway and HER2, neither of which were expressed in basal-like breast cancers.
The genomes of several cohorts of triple negative breast cancer have since been analysed. It is clear that they are a heterogeneous group of cancers at the molecular level, with general agreement that some remain true to the basal-like genotype, whilst others have a predominant “immune-activated” or a “mesenchymal” genomic footprint. Still others are nominated “luminal androgen receptor” and are non-basal-like in their molecular profile.
Concomitantly, there has been evolving interest in targeted therapies for TNBC, including targets for basal-like and luminal androgen receptor breast cancers. However, there has been little application of this refined molecular stratification of TNBC in the clinic, possibly due to inaccessibility of genomic analysis for the majority of breast cancers and the fact that the morphological correlates of these TNBC remain under-explored. New technologies, including digital imaging of histology phenotypes, can potentially be recruited to help determine phenotypic subgroups of TNBC relevant to their genotype and therefore their potential targeted therapies. It is possible that these digitally-discovered phenotypes can be applied to stratify TNBC in the routine clinical setting.