Molecular Re-classification of Breast Cancer – Part 1

Q. How will breast cancer be classified in 5 to 10 years?

Metastatic breast cancer is the leading global cause of cancer death for women.¹ Established classifications of breast cancer that are currently used to make treatment decisions centre upon tumour immunohistochemistry (IHC; oestrogen, progesterone and human-epidermal growth factor-2 [HER2] receptors). However, since these IHC classifications were established the ability to assess tumours and their changes over time has improved significantly. Molecular analyses have revealed that tumours with the same IHC classification not only have different characteristics between patients, but also that (i) they may have different characteristics within an individual patient dependent on their location, and (ii) that these characteristics can evolve over time.² Tumour evolution (e.g. emerging resistance to endocrine therapy) means that breast cancer classification is very complex, especially as there are no established driver mutations that can be specifically targeted.

New treatments are therefore required, and the drive is towards personalised or precision medicine, where a tumour could be biopsied at any given time to determine its susceptibilities and treated accordingly. One area of investigation is genomic profiling, and a recent addition to the established IHC classifications is BRCA gene status. Both BRCA1 and BRCA2 are tumour suppressor genes associated with DNA repair. Germline mutations in BRCA1 or BRCA2 confer an average breast cancer risk of 65% and 45% by the age of 70, respectively,³ and it is estimated that up to 8% of all breast cancers are associated with these mutations.⁴

Because of the roles of BRCA genes, tumours with BRCA1 or BRCA2 mutations have homologous recombination deficiencies, making them susceptible to synthetic lethality via the inhibition of polyadenosine 5’diphosphoribose polymerisation (PARP) enzymes.^5,6 These PARP enzymes are essential for repairing single strand DNA breaks, so inhibiting them leads to the persistence of these breaks and their conversion to double-strand DNA breaks during replication. Unlike cells with functional DNA repair mechanisms, tumour cells with homologous recombination deficiencies are then unable to repair the double-strand DNA damage, resulting in increased cell death.^5,6

Proof-of-concept for this approach has recently been demonstrated in the OlympiAD study (NCT02000622). This was a Phase III study of the oral PARP inhibitor olaparib versus standard single-agent chemotherapy in over 300 patients with HER2-negative metastatic breast cancer and a germline BRCA mutation.⁷ Olaparib significantly increased progression-free survival (7.0 versus 4.2 months) and health-related quality of life compared with chemotherapy, with efficacy extending beyond the first progression.⁷ Objective response rates with olaparib and chemotherapy were 59.9% and 28.8%, respectively, and adverse events of grade 3 or higher were 36.6% and 50.5%.⁷ While these findings are promising, the heterogeneity of breast cancer may mean that a combination of treatments (PARP inhibitors/endocrine therapy/chemotherapy) may provide greater efficacy than PARP inhibition alone, though future studies will be required to confirm this.

Looking to the future, it is hoped the development of new therapies will enable personalised treatment to provide the optimal therapeutic ratio. As understanding of the heterogeneity of breast cancer tumours increases and molecular and genetic classifications emerge, the field is moving towards a multi-level approach to treatment involving genomics, proteomics, metabolomics and the interplay between the three. Currently, new therapies are in development targeting signalling pathways that may confer resistance to endocrine therapies, such as cyclin-dependent kinase 4/6 inhibitors, phosphoinositide 3 kinase inhibitors and the mammalian target of rapamycin inhibitors.⁸ Initial Phase III study results are promising, showing that endocrine sensitivity can be restored in cancer cells, and potentially open up a new avenue of combination treatments that may be beneficial in patients with endocrine resistant cancers.⁸

In addition, the ability to detect circulating tumour cells and circulating tumour DNA from blood samples may reveal additional genetic targets in metastatic breast cancer.⁹ The ongoing AURORA study (NCT02102165) by the Breast International Group is assessing blood and plasma samples from 1300 patients with metastatic breast cancer for a panel of cancer-related genes, with the goal of constructing molecular profiles for patients and assigning them to appropriate clinical trials of targeted therapies.¹⁰ Overall, it is hoped that in the future we will be able to look at not just IHC classifications and one gene such as BRCA, but be able to screen for a complex signature of genes and proteins associated with individual tumours that would identify the best treatment for a patient.

Support: This Insight article was supported by AstraZeneca.

Acknowledgements: Medical writing assistance was provided by Stuart Wakelin at Touch Medical Media.

References

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