Treating triple-negative breast cancer (TNBC) in the era of precision oncology

Avishek Roy

Scientific Liaison Manager
4baseCare

Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast carcinomas and is associated with earlier age of onset, an aggressive clinical course, and a poor prognosis compared to other breast carcinomas. TNBC refers to breast cancers that have low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).  TNBC had a 5-year survival rate of 77% in a study of nearly 50,000 women with breast cancer, compared to 93 % for other breast cancer subtypes. Furthermore, TNBC patients had lower breast cancer-specific survival and overall survival in a 2012 study of almost 12,000 women. Early recurrence rates of 10–15 % per year for the first several years following first surgery, compared to 3–5 % per year in ER-positive and PR-positive breast cancer, which can recur decades after diagnosis, explain the worse prognosis in TNBC.

TNBC remains the most aggressive molecular subtype secondary to a lack of therapeutic targets. Despite significant advances with many novel agents targeting HER2 or ER, TNBC treatment options have been restricted to cytotoxic chemotherapy as the cornerstone of systemic therapy for the past 20 years, with few alternatives available. Due to the scarcity of effective therapies for this subtype of breast cancer, several efforts have been made in recent years to enhance TNBC patients’ therapeutic options. Fortunately, immunotherapy for breast cancer has progressed dramatically in recent years. The first breast cancer immunotherapy treatment was approved by the USFDA in March 2019 (though atezolizumab has been withdrawn voluntarily by the agency) on 27th August, 2021, and the second in November 2020, both for patients with advanced or metastatic TNBC. Genomic and transcriptome analyses have offered further insight into the inter-tumoral heterogeneity of TNBC, due to developments in next-generation sequencing technologies. TNBCs have been classified into several molecular subgroups based on genetic abnormalities and expression profiles, and new therapeutic targets have been discovered.

Carcinogenesis is driven by genetic changes that disrupt signaling networks that control cellular differentiation, proliferation, and apoptosis. The PI3K signaling pathway is involved in the control of cell growth and survival. Its activation is linked to tumor progression and resistance to chemotherapy, and it’s a common genomic aberration seen in TNBCs. In around 25% of primary TNBCs, the PI3K pathway is disrupted, and the percentage is significantly greater in metastatic TNBCs. Several clinical studies have been carried out to evaluate the effectiveness of various PI3K pathway inhibitors. Buparlisib, PI3K inhibitor, has been shown to be effective in HR+HER2- breast cancer with PIK3CA mutations. In patients with advanced TNBC, however, an interim analysis of the BELLE-4 study found that adding buparlisib to paclitaxel resulted in a lower progression free survival (PFS). AKT inhibitors showed promise effectiveness in the first line treatment of metastatic TNBCs in two phase II clinical studies. In the LOTUS study, median PFS was 6.2 months with ipatasertib plus paclitaxel against 49% with placebo plus paclitaxel in the intention-to-treat group. The effectiveness of PI3K pathway inhibitors was investigated in different TNBC subtypes since the frequency of PI3K pathway alterations varied. For example, in advanced metaplastic TNBC, which was used as a surrogate for MES TNBC, a phase I study evaluated the combination of mTOR inhibitors temsirolimus or everolimus with liposomal doxorubicin and bevacizumab. A 21% objective response rate was recorded, and activation of the PI3K pathway was found to be linked to a higher response rate.

TNBCs have changes in the EGFR, VEGF JAK/STAT, and NOTCH signaling pathways, in addition to the PI3K signalling pathway. A significant majority of TNBCs have EGFR overexpression and a high EGFR gene copy number. In patients with metastatic TNBC, a monoclonal antibody against EGFR (cetuximab or panitumumab) was added to chemotherapy in several phase II studies. Anti-EGFR monoclonal antibodies in conjunction with chemotherapy as neoadjuvant treatment for operable, stage II–III TNBC were studied in two phase II trials by Nabholtz et al. The addition of panitumumab to anthracycline/taxane-based chemotherapy appeared to be efficacious, although cetuximab with docetaxel showed relatively limited efficacy.

TNBC progression and chemo-resistance are facilitated by the mitogen-activated protein kinase (MAPK) pathway. MEK is a major component of this system, and MEK inhibitors have shown antitumor activity in preclinical experiments against TNBC cells. Despite this, clinical studies have shown that MEK1/2 inhibitors have minimal effectiveness in TNBC. The activation of the JAK/STAT signaling system in TNBC has been reported in preclinical research, as well as the anticancer effectiveness of inhibiting the JAK/STAT pathway. Despite the fact that researchers have tried hard to identify genetically altered signaling pathways and develop targeted therapeutics for TNBC, numerous clinical studies have failed to show that targeting these pathways improves patient outcomes in a statistically significant way.
In the last several decades, immune checkpoint blockade (ICB) immunotherapy has gained a lot of attention as a cancer therapeutic option. The most researched immune checkpoint inhibitors (ICI) targets are programmed cell death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1). Atezolizumab is a PD-L1-targeting monoclonal antibody. The IMpassion130 phase 3 trial compared atezolizumab plus nab-paclitaxel to placebo plus nab-paclitaxel as the first-line therapy for unresectable locally advanced or metastatic TNBC. The combination of atezolizumab plus nab-paclitaxel prolonged PFS in both the intention-to-treat population and the subset of patients with PD-L1 immune cell-positive tumors, according to the study.

Pembrolizumab is a monoclonal antibody against PD-1 that is highly selective. Pembrolizumab was investigated as a monotherapy in patients with metastatic TNBC in the phase II KEYNOTE-086 trial. Pembrolizumab monotherapy showed long-term anticancer efficacy in patients with previously untreated, PD-L1-positive mTNBC or previously treated metastatic TNBC, independent of PD-L1 expression. The phase II TOPACIO trial found that a combination of niraparib and pembrolizumab had potential anticancer efficacy in individuals with advanced or metastatic TNBC, particularly those with tumor BRCA mutations.

TNBC is gradually being recognized as a heterogeneous disease. Although advances in precision oncology have made it easier to identify potentially actionable targets, and few of the findings have been translated into clinical practices due to the limited benefit of targeted therapy in clinical trials for unselected TNBC patients. TNBC molecular sub-typing allows for the identification of molecularly homogenous groups with a high prevalence of certain genetic abnormalities. Clinical trials targeting certain subtypes might be a useful tool for drug development. With the growing body of data from clinical trials, a precision medicine paradigm based on transcriptome sub-typing for TNBC patients may be built and fine-tuned. The potential of precision oncology medicine in treating TNBC and other solid cancers is apparent, and a combination of multi-omics approach and phenotypic screening might considerably speed up the development of novel treatments.