Journal Article

Precision medicine for metastatic breast cancer—limitations and solutions

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

2015

Overview

Key Points Recent research data defining the genomic landscape of breast cancer have reinforced the notion that this disease is driven by genomic alterations So far very few gene drivers validated in breast cancer have been identified, including ESR1 , ERBB 2 , PIK3CA and ATK1 Identification of drivers, characterization of resistant clones, identification of DNA repair defects and mechanisms of immune suppression are potential uses of genomics to personalize medicine The development of precision medicine for the treatment of breast cancer has several major challenges that include low frequency of targetable molecular alterations, feasibility of high-throughput technologies and availability of targeted therapy 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 authors discuss the limitations, including the identification of driver events, and the possible solutions to the application of precision medicine in the management of patients with metastatic disease, 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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/61/212/2166 / 692/699/67/1059/602 / 692/699/67/1347 / 692/699/67/69 / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Cancer research / Care and treatment / Development and progression / Drug therapy / Female / Gene mutation / Genetic aspects / Genomics - trends / Health aspects / Humans / Medicine & Public Health / Neoplasm Metastasis / Oncology / Precision Medicine / review-article