Breast cancer targeted therapy: successes and challenges

Abstract

This Lancet issue features a three-part Series on targeted treatment for the three most common breast cancer subtypes: oestrogen-receptor-positive (ER+), HER2-positive (HER2+), and the more heterogenous triple-negative disease. “Sometimes we have the feeling that not much has happened in everyday clinical practice” Series author Sibylle Loibl, chair of the German Breast Group says in an accompanying podcast, “but if you take a closer look then quite a bit has changed”. Indeed when the first Lancet breast cancer Series was published in 2011, the focus was on gene expression profiling to inform prognosis and predict response to conventional therapy, whereas this Series describes the clinical use of novel targeted agents in newly defined genetic subtypes of breast cancer. The first paper in the Series examines ER+ advanced breast cancer and new agents targeting the molecular mechanism of endocrine resistance. The most notable advance is the addition of CDK4 and CDK6 inhibitors to metastatic ER+ breast cancer treatment. The second paper discusses HER2+ breast cancer, a subtype which, although several established targeted treatments have been shown to improve both progression-free and overall survival, is still responsible for considerable mortality. The final paper is on triple-negative breast cancer in which targeted agents have had much less effect. PARP inhibitors are currently the most promising agents in this group, based on the similarity of this subtype to ovarian cancers. The high survival rate in early breast cancer is a success story, achieved by incremental gains over the years in all types of interventions. In the next 5 years, more targeted agents will be developed, genetic tests will become more affordable, and selection of treatment by mutation will offer opportunities for treatment innovation. Questions remain on why many types of breast cancer do not respond well to targeted treatment, particularly immunotherapy. Targeted therapy in breast cancer also faces the challenges of diminishing returns, increasing cancer care costs, and the risk of overtreatment. Despite the excitement surrounding targeted agents, gaps remain. Acknowledging this is a necessary step towards real progress against breast cancer in the near future. Advances in the treatment of advanced oestrogen-receptor-positive breast cancerOestrogen-receptor-positive breast cancer is the most common subtype of breast cancer. Endocrine therapies that target the dependence of this subtype on the oestrogen receptor have substantial activity, yet the development of resistance to therapy is inevitable in advanced cancer. Major progress has been made in identifying the drivers of oestrogen-receptor-positive breast cancer and the mechanisms of resistance to endocrine therapy. This progress has translated into major advances in the treatment of advanced breast cancer, with several targeted therapies that enhance the efficacy of endocrine therapy; inhibitors of mTOR and inhibitors of the cyclin-dependent kinases CDK4 and CDK6 substantially improve progression-free survival. Full-Text PDF HER2-positive breast cancerAnti-HER2 treatment for HER2-positive breast cancer has changed the natural biology of this disease. This Series article reviews the main achievements so far in the treatment of both metastatic and early HER2-positive breast cancer. The success of neoadjuvant therapy in HER2-positive early breast cancer is especially acknowledged, as pertuzumab has been approved on the basis of a higher proportion of patients achieving a pathological complete response with pertuzumab and trastuzumab than with trastuzumab alone in a neoadjuvant study. Full-Text PDF Molecular alterations in triple-negative breast cancer—the road to new treatment strategiesTriple-negative breast cancer is a heterogeneous disease and specific therapies have not been available for a long time. Therefore, conventional chemotherapy is still considered the clinical state of the art. Different subgroups of triple-negative breast cancer have been identified on the basis of protein expression, mRNA signatures, and genomic alterations. Important elements of triple-negative breast cancer biology include high proliferative activity, an increased immunological infiltrate, a basal-like and a mesenchymal phenotype, and deficiency in homologous recombination, which is in part associated with loss of BRCA1 or BRCA2 function. Full-Text PDF