Current Status of Clinical Genomics in Patients with Metastatic Breast Cancer

Abstract

Breast cancer is the leading cause of cancer-related death among women worldwide. The exact number of new cases of metastatic breast cancer (MBC) encountered each year includes those initially diagnosed as stage IV disease and metastatic recurrence in patients who had early-stage disease. Approximately 6% to 10% of newly diagnosed patients with breast cancer belong to the de novo metastatic group, with stage IV disease, and 20% to 30% to the latter group. Due to advances in early detection and adjuvant treatment, mortality rates from breast cancer have been decreasing steadily in most Western countries since the 1990s. However, despite significant advances in breast cancer management, MBC is largely incurable, with 5-year survival rates of only 22% in patients who have metastatic disease at diagnosis. The main goal in the treatment of most patients with MBC is palliation, with the aim of maintaining quality of life and possibly improving survival. There are few proven standards of care in MBC management; therefore, enrollment in well-designed prospective randomized clinical trials is a priority. In recent years, our understanding of the genomic landscape of breast cancer has advanced significantly. The genetic alterations of breast cancer have been outlined through initiatives by The Cancer Genome Atlas and the International Cancer Genome Consortium. The most common genetic alterations across all genomic subtypes of breast cancer include TP53 and PIK3CA mutations, which account for 28% of all cases for both genes. Amplifications of ERBB2, FGFR1, and CCND1 occur in 10% to 20% of all breast cancer subtypes. Less frequent alterations include PTEN mutations and deletions and AKT1, RB1, BRCA1, or BRCA2 mutations. Mutations in other genes that occur much less frequently and that may have a role in the biology of breast cancer include KRAS, APC, NF1, SKT11, MAP2K4, MAP3K1, and AKT2. A proteomic analysis of The Cancer Genome Atlas dataset has demonstrated that PI3K/AKT/ mTOR, p53, and CCND1/CDK4/Rb are the 3 pathways that are activated across all subtypes in early-stage breast cancer. The identification of molecular alterations accelerated the development of drugs for targeting oncogenic drivers and components of the signaling pathways, which led to the initiation of several clinical trials. Figure 1 depicts several of