Research advances and new challenges in overcoming triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is a pathological term used to identify invasive breast cancers that lack expression of estrogen and progesterone receptors and do not have pathologic overexpression of the HER2 receptor or harbor ERBB2 gene amplification. TNBC includes a collection of multiple distinct disease entities based upon genomic, transcriptomic and phenotypic characterization. Despite improved clinical outcomes with the development of novel therapeutics, TNBC still yields the worst prognosis among all clinical subtypes of breast cancer. We will systematically review evidence of the genomic evolution of TNBC, as well as potential mechanisms of disease progression and treatment resistance, defined in part by advances in next-generation DNA sequencing technology (including single cell sequencing), providing a new perspective on treatment strategies, and promise to reveal new potential therapeutic targets. Moreover, we review novel therapies aimed at homologous recombination deficiency, PI3 kinase/AKT/PTEN pathway activation, androgen receptor blockade, immune checkpoint inhibition, as well as antibody-drug conjugates engaging novel cell surface targets, including recent progress in pre-clinical and clinical studies which further validate the role of targeted therapies in TNBC. Despite major advances in treatment for TNBC, including FDA approval of 2 PARP inhibitors for metastatic TNBC, the crossing of the superiority boundary in a phase 3, placebo-controlled study of adjuvant olaparib in early-stage patients with germline BRCA-mutated high-risk HER2-negative early breast cancer, the FDA approval of 2 PD-(L)1 checkpoint antibodies for metastatic TNBC, and the FDA approval of the first antibody drug conjugate for TNBC, significant challenges remain. For example, despite the dawn of immunotherapy in metastatic TNBC, durable responses are limited to a small subset of patients, definitive biomarkers for patient selection are lacking, and the Oncology Drug Advisory Committee to the FDA has recently voted against approval of an anti-PD-1 checkpoint antibody high risk early-stage TNBC in the neoadjuvant setting. Also, despite early positive randomized phase 2 studies of AKT inhibition in metastatic TNBC, a recent phase 3 registration trial failed to validate earlier phase 2 data. Finally, we note that level one evidence for clinical efficacy of androgen receptor blockade in TNBC is still lacking. To meet these and other challenges, we will catalogue the ongoing exponential increase in interest in basic, translational, and clinical research to develop new treatment paradigms for TNBC.

Keywords: Triple negative breast cancer; antibody-drug conjugates; genomic evolution; homologous recombination deficiency; immunotherapy; subtypes; therapeutic targets; tumor immune microenvironment.

Figure 1

Automated image analysis pipeline delineates ordered immune composition in TNBC, using MIBI-TOF. A: Top: Pseudo-coloring of tumor-infiltrating immune cells in a patient with TNBC. Bottom: Expression of 7 markers demonstrating the repertoire of infiltrating immune cells as well as their spatial location, including cell-cell contacts; B: Top: Cartoon depicting 3 archetypes of tumor-immune composition and organization in TNBC. Cold tumors have few immune cells, mainly macrophages. Mixed tumors have an admixture of tumor and immune cells. IDO and PD-L1, if expressed, are expressed primarily on tumor cells and PD-1 on CD8+ T cells. In compartmentalized tumors, the immune and tumor cells are spatially segregated. Neutrophils are enriched near the border, whereas B cells form secondary lymphoid structures further away. IDO and PD-L1 are expressed primarily on immune cells and PD-1 on CD4+ T cells. Bottom: Kaplan-Meier analysis showing survival as a function of time for patients with compartmentalized or mixed tumor-immune organizations. This figure is adapted with permission from Keren et al.^[135]. Copyright 2018 by Elsevier.