Adjuvant treatment with metformin does not improve the outcomes of patients with HR-positive or negative early breast cancer, suggest trial data presented at the 2021 San Antonio Breast Cancer Symposium.

Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab significantly improves event-free survival rates versus neoadjuvant chemotherapy alone in people with a new diagnosis of early-stage triple-negative breast cancer, KEYNOTE-522 study data show.

A major histocompatibility complex-II tumor cell expression rate of 5% or more could identify HER2-negative breast cancer patients likely to benefit from the addition of PD-1 or PD-L1 inhibitors to standard neoadjuvant chemotherapy, research findings suggest.

Adding the PD-L1 inhibitor durvalumab to neoadjuvant chemotherapy may improve survival outcomes in people with triple-negative breast cancer, show GeparNUEVO data presented at the 2021 ASCO Annual Meeting.

The addition of indoximod to taxane chemotherapy does not improve the outcomes of patients with HER2-negative metastatic breast cancer, research suggests.

The addition of durvalumab and olaparib to neoadjuvant chemotherapy is associated with improved pathologic complete response in women with stage II or III HER2-negative breast cancer, show data from the I-SPY 2 trial.

Results for the IMpassion130 trial support the combination of atezolizumab and nab-paclitaxel for the treatment of metastatic triple-negative breast cancer, especially among patients with programmed cell death ligand 1-positive disease.

Results for the IMpassion130 trial support the combination of atezolizumab and nab-paclitaxel for the treatment of metastatic triple-negative breast cancer, especially among patients with programmed cell death ligand 1-positive disease.

The AVAST-M and E5103 trial results rule out the use of bevacizumab in the adjuvant setting in high-risk patients with cutaneous melanoma and HER2-negative breast cancer, respectively.

This book chapter explores newly-discovered molecular subtypes of triple-negative breast cancer and how genetic profiling can be used to target therapy. Summary points Triple-negative breast cancers (TNBC) are those that lack expression of the breast cancer prognostic markers estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2), and account for about 15% of all breast cancers. Recent increased understanding of the molecular mechanisms responsible for the initiation and propagation of this breast cancer subtype has been gained through gene expression profiling, the study of cancer genetics and the study of host antitumor immunity. The majority of TNBCs cluster within a basal-like subgroup, characterized by a low expression of hormone receptor and HER2-related genes and high expression of proliferation genes characteristic of the basal epithelial cell layer. The therapeutic significance of basal-like versus non-basal-like TNBC is yet to be determined. Despite this association, substantial molecular heterogeneity in TNBC defined by immunophenotyping exists. Six subtypes of TNBC have been identified, including two basal-like (BL-1 and BL-2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. Breast cancer in women with a germline BRCA1 mutation are overwhelmingly triple negative. Given the known role of BRCA1 and BRCA2 in homologous recombination DNA repair, treatment with platinum chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors has been associated with high levels of anticancer activity. In addition to germline BRCA1 and BRCA2 mutation status, biomarkers of genomic instability have been developed that detect genomic ‘scarring’ caused by accumulated DNA damage. Therapeutic strategies are currently being investigated to assess whether these germline and genetic biomarkers can identify groups of patients with TNBC with underlying DNA repair deficiency more likely to benefit from DNA repair defect targeted therapies. Telli ML. In: Molecular Pathology of Breast Cancer . Edited by Badve S and Gökmen-Polar Y. Springer, Cham, 2016. doi:10.1007/978-3-319-41761-5_6

This study aimed to characterize the metabolite profiles of triple-negative breast cancer in comparison with ‘triple-positive’ breast cancer, and how this may help targeted treatment strategies. Summary points This study aimed to characterize the metabolite profiles of triple-negative breast cancer (TNBC) in comparison with triple-positive breast cancer (TPBC; estrogen receptor [ER], progesterone receptor [PR] and human epidermal growth factor receptor 2 [HER2] positive). The influences of ER, PR and HER2 status individually on breast cancer metabolism were also examined. 75 patients aged 34 to 90 and diagnosed with breast cancer without known distant metastases were included in this study. Tumor metabolite content was identified and quantified using high resolution magic angle spinning magnetic resonance spectroscopy. Choline levels were found to be higher in TNBC compared to TPBC, which is possibly related to cell proliferation and oncogenic signaling. TNBC tumors also had a lower level of glutamine and a higher level of glutamate compared to TPBC tumors, which indicates an increase in glutaminolysis metabolism and suggests the development of glutamine dependent cell growth, or ‘glutamine addiction’. Significantly higher levels of glycine were found in HER2-positive breast cancer, which supports the potential of glycine as a marker for tumor aggressiveness. Metabolic alterations caused by the individual and combined receptors involved in breast cancer progression can provide a better understanding of the biochemical changes underlying the different breast cancer subtypes. Further research is needed to validate the potential of metabolic markers as targets for personalized treatment of breast cancer subtypes. Cao MD, Lamichhane S, Lundgren S et al. BMC Cancer 2014;14:941. doi:10.1186/1471-2407-14-941

This review article describes the different subtypes of triple-negative breast cancer and potential therapeutic strategies and novel approaches to targeted therapy. Summary points Approximately 15% of invasive breast cancers lack expression of endocrine receptors for estrogen and progesterone (ER and PR, respectively) and human epidermal growth factor receptor 2 (HER2); these are known as ‘triple-negative breast cancers’ (TNBCs). Most TNBCs are classified as the ‘basal-like subtype’, which is characterized by lack of ER/PR/HER2 expression and increased expression of cytokeratins 5 or 6, 14, and 17, P-cadherin, p53, and epidermal growth factor receptor; however, a significant number of basal-like breast cancers do express ER/PR or HER2, and 20–30% of clinical TNBCs are not basal-like by microarray analysis. Clinically, TNBCs are a group of aggressive breast cancers with a greater incidence of relapse, stage-for-stage, than ER/PR-positive and HER2-positive breast cancers, despite optimum loco-regional and systemic therapy. Recently, gene expression analysis identified six distinct TNBC subtypes, each with unique biology and pathologic complete response. To date, no single targeted therapy has been approved for treatment of TNBC, and cytotoxic chemotherapy remains the standard systemic treatment. Potential targeted therapeutic approaches for basal-like TNBCs include poly(ADP-ribose) polymerase (PARP) inhibition, PI3K inhibition, and luminal androgen receptor targeting. Combining two or more targeted agents with or without chemotherapy may be required to develop a more rational and optimum approach to TNBC treatment, because combination of ‘complementary’ pathway inhibitors would potentially maximize efficacy, and would minimize therapeutic resistance. Abramson VG and Mayer IA. Curr Breast Cancer Rep 2014;6:154. doi:10.1007/s12609-014-0152-1

The final analysis of the CALOR trial confirms the disease-free survival benefit of adjuvant chemotherapy for breast cancer patients with resected isolated locoregional recurrences that are estrogen receptor-negative and rules out its use in the ER-positive scenario.

Adding the oral AKT inhibitor ipatasertib to paclitaxel significantly prolongs progression-free survival, compared with placebo plus paclitaxel, when used as first-line therapy for triple-negative breast cancer, phase II study data show.

This review of the literature explores the role of the androgen receptor in triple-negative breast cancer, and how it may be used as a prognostic and therapeutic target. Summary points There are currently no targeted therapies approved for triple-negative breast cancer (TNBC) due to the fact that TNBC tumors lack estrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2); as such TNBC has a poor prognosis. However, some TNBC tumors express androgen receptor (AR) (nuclear AR expression [as detected by IHC] ranges from 12–55% depending on the study) and therefore may benefit from AR-targeted therapies. Emerging data suggest that AR significantly influences breast cancer gene expression profiles and affects tumorigenic properties of TNBC. Studies comparing AR expression in primary versus metastatic disease found that AR is frequently retained in metastatic samples from patients with AR+ primary tumors. The prognostic significance of AR in TNBC is controversial as AR expression has been associated with both a good and bad prognosis in multiple studies. The existence of the luminal AR (LAR) TNBC subtype, with strong AR expression driving a luminal-like expression pattern in the absence of ER, is evidence that AR signaling can play a strong role in the biology of TNBC tumors. AR expression is associated with decreased proliferation in TNBC, but LAR tumors have a particularly poor prognosis, possibly because of their poor response to chemotherapy. Anti-androgens have shown particular efficacy in preclinical studies of LAR models and may be useful in improving the treatment of LAR tumors. Recently reported and ongoing clinical trials using bicalutamide or enzalutamide (a new generation anti-androgen) in TNBC have shown an increase in progression-free survival, suggesting that AR-targeted therapies may improve patient prognosis and supporting a reclassification of TNBC into AR-positive and ‘quadruple negative’ disease. Barton VN, D’Amato NC, Gordon MA et al. Horm Canc 2015;6:206–213. doi:10.1007/s12672-015-0232-3

Messina C et al. Breast Cancer Res Treat 2018; 172: 9. doi:10.1007/s10549-018-4901-0