Triple-negative breast cancer (TNBC), the most aggressive and difficult-to-treat form of breast cancer, has lacked markers that can indicate a patient's prognosis or likely response to treatment. In a new study published in Nature Communications, researchers have developed the first classification system that distinguishes patients whose TNBC can be cured from those likely to experience a relapse.
Because TNBC is caused by numerous genetic mutations acting in unique combinations for each patient, investigators have been unable to find dominant mutations that indicate prognosis or drug treatment response. When researchers from the Spanish National Cancer Research Centre (CNIO) created their classification system, instead of analyzing the genes involved in TNBC, they analyzed the proteins whose synthesis is ordered by those genes. They hypothesized that patients' numerous genetic mutations could translate into recognizable patterns of the tumor's proteome, the functional (activation) status of all its proteins.
The researchers identified 6 protein kinases whose functional status predicts the prognosis of a patient's TNBC. The kinases split the validation set in to two patterns. One, without hyperactive kinases, was associated with a relapse-free rate of over 90%; the other, involving one or more hyperactive kinases, was associated with a relapse risk up to 9.5 times higher.
The 6 kinases can be inhibited using drugs, some of which are already in use. Using human TNBC cell lines and patient-derived xenografts—TNBC tumors transplanted from human patients onto mice—the researchers tested the antitumor activity of 15 different combinations of drugs in relation to the activation profile of the 6 kinases. The results were promising, with the combinations increasing median overall survival compared with monotherapy in the vast majority of cases.
"Until now, it has not been possible to establish a link between the presence of certain mutations in triple negative breast cancer and a prognosis or response to drug treatment. We have shown for the first time that proteomics can be used to predict the evolution of triple negative breast cancer, and to select combinations of pairs of drugs as candidates for clinical trials," stated Miguel Ángel Quintela, MD, PhD, senior author of the paper and director of the CNIO Breast Cancer Clinical Research Unit.
What comes next? Quintela says that the researchers are focusing on "validating these markers in other stages of diseases, standardizing kinase determinations by way of a diagnostic test, and organizing clinical trials using the therapeutic combinations described in this paper on patients with advanced disease." Developing a regular clinical test for the 6 kinases will be crucial to offering each patient with TNBC the therapeutic combination most likely to improve survival.
For More Information
Zagorac I, Fernandez-Gaitero S, Penning R, et al (2018). In vivo phosphoproteomics reveals kinase activity profiles that predict treatment outcome in triple-negative breast cancer. Nat Commun, 9:3501. DOI:10.1038/s41467-018-05742-z