The Challenges of Treating Triple-negative Breast Cancer

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A panel at the 2016 San Antonio Breast Cancer Symposium discussed the state of research and treatment of triple negative breast cancer.
A panel at the 2016 San Antonio Breast Cancer Symposium discussed the state of research and treatment of triple negative breast cancer.

A panel at the 2016 San Antonio Breast Cancer Symposium discussed the state of research and treatment of triple negative breast cancer (TNBC).1 The panel was moderated by Hope Rugo, MD, director of the breast oncology clinical trials program at the Helen Diller Family Comprehensive Cancer Center in San Francisco, California. Dr Rugo's research focuses on combining novel targeted therapeutics with standard treatment for both early- and late-stage breast cancer. Panelists will discuss the biology and heterogeneity of TNBC, new targets and treatment strategies of the disease, and adjuvant systemic therapy for TNBC. 

Charles Perou, PhD, of the University of North Carolina, Chapel Hill, discussed the biology and heterogeneity of TNBC. Dr Perou researches the genetic alterations that give rise to breast cancer, with the goal of identifying new therapeutic strategies to target those cancer-causing events.

Dr Perou was the primary author of a recent study in Disease Models & Mechanisms that identified potential targets for personalized therapy for TNBC.2 In this study, genetic profiling of 2 subsets of murine mammary cancers that resemble human TNBC found 5 potential personalized drug target genes that are amplified in both murine and human TNBC tumors. Inhibition of Met, 1 of the target genes, using crizotinib, a small-molecule tyrosine kinase inhibitor (TKI), resulted in initial complete regression of murine tumors. The results, the authors wrote, not only identified Met as a promising genetic target, but “also highlight the importance of comparative genomic studies” to find personalized drug targets.

In a 2015 commentary in Cancer Cell, Dr Perou discussed the intratumoral heterogeneity (ITH) of breast tumors, which he said could have important ramifications for the development of resistant disease, metastasis, and efforts at clinical sequencing.3

Dr Perou's commentary related to a study in Nature Medicine in which researchers applied whole-genome and targeted sequencing to more than 300 tumor samples from 4 patients with multi-focal breast cancer.4 Evidence from the sequencing suggested that individual foci arose from a common genetic ancestor, and that each underwent a “clonal sweep,” in which sequential mutations arise and exploit a favorable environment to outcompete previously dominant clones.5 Additionally, the sequencing showed that genetic variants were present at higher proportions of mutated alleles, or variant allele fractions (VAF), in the metastases, and at lower VAF in the primary tumor.

“The clinical utility of ITH as a biomarker has yet to be demonstrated, and it is on this front where the unanswered questions are the most clinically challenging,” wrote Dr Perou. These questions, he wrote, include ITH's prognostic potential, as well as what should be done with a clinically actionable sub-clonal variant.

Stacy L Moulder, MD, MSci, of the University of Texas MD Anderson Cancer Center in Houston, discussed new targets and treatment strategies for TNBC. Dr Moulder's research focuses on early drug development, clinical trial design, and determining pathways for drug resistance in breast cancer. She is the principal investigator of an ongoing study on new therapies for TNBC (ClinicalTrials.gov identifier: NCT02456857).6[JG1] 

In the study, researchers first take tumor biopsies from patients with localized TNBC that are larger than 1 cm, and who have been advised to undergo chemotherapy before surgery. Patients then begin the first round of 2 chemotherapy treatments. During the first round of treatment, biopsied tumor samples are subjected to a predictive chemotherapy-sensitivity test. The testing determines whether tumors are likely to respond to chemotherapy and identifies the patient's TNBC subtype.

Patients whose tumors are identified as “chemo-sensitive” are given the second round of chemotherapy prior to surgery. Those who have “chemo-insensitive” tumors are enrolled in clinical trials that combine chemotherapy with targeted therapies that are personalized to their tumor subtype and molecular makeup. The goal is to determine whether adding targeted therapy based on molecular results will result in improved outcomes for patients with TNBC.

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