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25-07-2015 | Breast cancer | Article

Precision medicine for metastatic breast cancer—limitations and solutions

Authors: Monica Arnedos, Cecile Vicier, Sherene Loi, Celine Lefebvre, Stefan Michiels, Herve Bonnefoi, Fabrice Andre

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Abstract

The development of precision medicine for the management of metastatic breast cancer is an appealing concept; however, major scientific and logistical challenges hinder its implementation in the clinic. The identification of driver mutational events remains the biggest challenge, because, with the few exceptions of ER, HER2, PIK3CA and AKT1, no validated oncogenic drivers of breast cancer exist. The development of bioinformatic tools to help identify driver mutations, together with assessment of pathway activation and dependency should help resolve this issue in the future. The occurrence of secondary resistance, such as ESR1 mutations, following endocrine therapy poses a further challenge. Ultra-deep sequencing and monitoring of circulating tumour DNA (ctDNA) could permit early detection of the genetic events underlying resistance and inform on combination therapy approaches. Beside these scientific challenges, logistical and operational issues are a major limitation to the development of precision medicine. For example, the low incidence of most candidate genomic alterations hinders randomized trials, as the number of patients to be screened would be too high. We discuss these limitations and the solutions, which include scaling-up the number of patients screened for identifying a genomic alteration, the clustering of genomic alterations into pathways, and the development of personalized medicine trials.

Nat Rev Clin Oncol 2015; 12: 693–704. doi:10.1038/nrclinonc.2015.123

Subject terms: Breast cancer • Cancer genomics • Personalized medicine • Targeted therapies

The discovery of the oestrogen receptor (ER)1 and human epidermal growth factor receptor-2 (HER2)2 as therapeutic targets in patients with breast cancer has enabled treatment success in terms of patient outcomes with ER or HER2-blocking therapies,3, 4 and set the stage for the development of stratified medicine. Furthermore, progress in cancer genomics research over the past few decades has reinforced the notion that cancer is driven by various genomics alterations.5 As a result of different international initiatives such as The Cancer Genome Atlas (TCGA) or the International Cancer Genome Consortium (ICGC), the use of next-generation sequencing (NGS) has helped define the genomic landscape of early stage breast cancer.6 These studies have revealed the high level of tumour heterogeneity for each breast tumour that consists of several molecular subsets, which are driven by distinct molecular alterations, indicating that tumours could be treated according to their individual molecular landscape. Despite the exciting potential for personalized medicine, ER and HER2 are currently the only targetable molecular alterations with confirmed predictive and prognostic value.3, 4 Other targeted therapies, such as mTOR and CDK4/6 inhibitors, have been approved on the basis of their efficacy in subgroup populations, but no predictive biomarkers have been found.7, 8 In this Review, we discuss the potential applications of genomics to improve the management of metastatic breast cancer (MBC), and consider the challenges that precision medicine must overcome before it can be widely implemented in the clinic—most notably, those challenges that relate to the remarkable cellular complexity of this type of cancer.

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