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Towards personalized medicine for metastatic breast cancer

Authors: Angelo Di Leo Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Italy

Metastatic breast cancer is the most frequent cause of cancer death for women worldwide and, for the most common subtype, endocrine receptor-positive breast cancer, endocrine treatment constitutes the therapeutic cornerstone.1 However, endocrine resistance frequently develops2 and newer treatments are urgently required. This need could in part be met in the future by precision medicine whereby breast cancer molecular subtypes are determined and matched with appropriate targeted therapeutic agents. This requires highly sensitive and specific biomarkers, which necessitate refinement beyond established markers such as endocrine-receptor, progesterone receptor and human epidermal growth factor receptor-2. The availability of such biomarkers may also improve the cost-effectiveness of treatment, allowing the adoption of new treatments that would otherwise be considered too expensive.

Genomic tools have been used to identify prognostic and predictive biomarkers in tumour tissue though these are subject to selection bias and other limitations such as difficulty in obtaining the biopsy from the metastatic site.3 Recently, circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) has been detected in the blood of patients diagnosed with breast cancer, providing an alternative, non-invasive approach to try to detect and follow progression of disease.4

Many targeted therapies are under clinical development though to realise their potential, target and biomarker validation is needed in innovatively designed studies. In one recent trial, AURORA, which was launched by the Breast International Group (BIG), blood and plasma specimens from 1300 patients with metastatic breast cancer will be analysed by next generation sequencing for a panel of cancer-related genes ( Identifier: NCT02102165). Depending on the molecular profiles found, patients can be directed to clinical trials assessing molecularly targeted agents. To interpret the clinical results, more needs to be known about the dynamic biology of CTC and ctDNA release. ctDNA represents mainly the genome of dying tumour cells, but cancer progression and therapy resistance is driven by viable tumour cells.5 The selection of the appropriate time points for ctDNA screening will be vital to detect those ctDNA species that are derived from the resistant tumour clones.

Logistical issues to be overcome include the low incidence of most candidate genomic alterations and possible solutions to this are scaling-up the number of patients screened for identifying a genomic alteration, and the clustering of genomic alterations into pathways.6 Alongside this, highly sensitive and standardized techniques to assay circulating biomarkers will be critical. In addition, improvements in functional imaging studies will help to evaluate both the effect of and response to treatment, allowing for more precise decision making than is currently possible.

Precision medicine is yet to come of age however, with scepticism among many medical oncologists: a recent investigation of attitudes towards the integration of breast sequencing in breast cancer management, showed that lack of evidence is a major concern against the wider use of a genotype -driven approach to breast cancer.7

While novel agents, strategies, and improved regimens are changing the future of breast cancer therapy, the patient–doctor relationship will become even more important. Patient individuality must be respected, for example, side effects that some patients find most problematic often differ from those that most concern doctors. To maximise the potential of innovation in breast cancer management, collaboration will be required between all major stakeholders, in particular, the patients.

Support: This Insight article was supported by AstraZeneca. Acknowledgements: Medical writing assistance was provided by Catherine Amey at Touch Medical Media.

1. Jemal A, Bray F, Center MM, et al., Global cancer statistics, CA Cancer J Clin, 2011;61:69-90.

2. Osborne CK, Schiff R, Mechanisms of endocrine resistance in breast cancer, Annu Rev Med, 2011;62:233-47.

3. Curtis C, Genomic profiling of breast cancers, Curr Opin Obstet Gynecol, 2015;27:34-9.

4. De Mattos-Arruda L, Cortes J, Santarpia L, et al., Circulating tumour cells and cell-free DNA as tools for managing breast cancer, Nat Rev Clin Oncol, 2013;10:377-89.

5. Alix-Panabieres C, Pantel K, Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy, Cancer Discov, 2016;6:479-91.

6. Arnedos M, Vicier C, Loi S, et al., Precision medicine for metastatic breast cancer–limitations and solutions, Nat Rev Clin Oncol, 2015;12:693-704.

7. Gingras I, Sonnenblick A, de Azambuja E, et al., The current use and attitudes towards tumor genome sequencing in breast cancer, Sci Rep, 2016;6:22517.

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