Molecular diagnostics for precision medicine in breast cancer treatment: what does the future hold?

Abstract

Personalized medicine or precision medicine is one of the most interesting topics in current clinical cancer research. When compared to other types of solid cancer, breast cancer has been utilized sub-personalized (subtyping) treatment strategy for a very long time. In the 1980s, the presence of estrogen receptor (ER) was evaluated by a dextran-coated charcoal assay (ligand binding assay) and endocrine therapy was administered to specific patients with ER-positive breast cancer [1]. LHRH analog for premenopausal patients is another subtyping approach. However, recent technological advances in multi-gene assay and whole genome sequencing have made it possible to divide breast cancer subtyping into more detailed categories. In addition, classical RT-PCR technique for mRNA expression analysis was developed to digital PCR assay with high sensitivity. Based on these technological advances, we are trying to administer the right drug at the right time to the right patient. The development of molecular diagnostic tools is a key element for realizing precision and personalized medicine in clinical practice. These tools should be industrialized and approved by a regulatory agency. This special feature issue of Breast Cancer includes five review articles related to molecular diagnostics. Figure 1 shows the application of each molecular diagnostic in clinical breast cancer time course. For instance, multi-gene classifiers are used for prediction of risk of recurrence, and companion diagnostics are applied for choosing a specific drug for each patient. Sato et al. cover the basic knowledge of ‘‘genomic tumor evolution’’. Recent progress of comprehensive genome-wide analysis has revealed information regarding genomic mutations and rearrangements in each individual tumor [2]; however, during the process of tumor invasion, metastasis and treatment exposure, cancer genomes are dynamically changing and evolving. At this moment, no established technique exists for tracking this genomic tumor evolution in the living tumor of a patient, although liquid biopsy to detect circulating tumor cells and circulating cell-free DNA could be a promising approach. Naoi et al. reported multi-gene classifiers for predicting recurrence risk for early breast cancer patients [3]. In contrast to conventional biomarkers such as ER, PgR and HER2, multi-gene assay evaluates multiple target mRNA expressions at one time, providing a significant amount of information for treatment decision. Although many multigene assays have been developed to date, most success case is the Oncotype DX assay which calculates the recurrence score (RS) based on the expression of 21 genes using RNA extracted from FFPE tumor tissues. Very recently, the first survival data of the TAILORx study with Oncotype DX has been reported [4]. Early breast cancer patients with ERpositive HER2-negative node-negative tumors and those whose tumors were classified as low RS (equal or less than 10) showed remarkable good prognosis without adjuvant chemotherapy. This is the first prospective evidence for treatment decision to have been made using multi-gene assay. Tazawa reported on the development of companion diagnostics for indication of molecular targeting drugs [5]. Though many molecular targeting drugs for breast cancer have been developed to date, the most scene-changing drug has been trastuzumab for HER2-positive tumor. Trastuzumab was developed through clinical trials that & Shigehira Saji ssaji@fmu.ac.jp