Progress and pitfalls in the use of immunotherapy for patients with triple negative breast cancer

Abstract

Introduction:Triple negative breast cancer (TNBC) is an area of high unmet medical need in terms of new effective treatment strategies. Although breast cancer is traditionally considered a 'cold' tumor type, TNBC is the most appropriate subtype for immunotherapeutic strategies; this is due to the high level of tumor infiltrating lymphocytes, PD-L1 expression, and tumor mutational burden compared to other breast cancer subtypes. Areas covered: This review examines the available evidence on the use of immunotherapeutic strategies in early and advanced TNBC, discusses the pitfalls and limitations often encountered in clinical research, and summarizes data on novel promising immunomodulatory approaches that have been explored in early-phase trials. Expert opinion: PD-1-blockade is approved for stage II/III TNBC and for first-line treatment of PD-L1positive TNBC patients with metastatic disease and should be considered standard of care. However, question marks and difficulties remain; these include the identification of predictive biomarkers to select patients who benefit from the addition of PD1-blockade and the balance between efficacy and long-term toxicity for an individual patient. Numerous treatment combinations and new immunotherapeutic strategies beyond PD1 blockade are being evaluated, thus reflecting a promising evolution towards a more personalized approach, and extended clinical benefit in TNBC. Abbreviations:Triple-negative breast cancer (TNBC); breast cancers (BCs); estrogen receptor (ER); progesterone receptor (PgR); human epidermal growth factor-2 (HER-2); basal-like 1 (BL1), basal-like 2 (BL2); mesenchymal (MES); mesenchymal stem-like (MSL); immunomodulatory (IM); luminal androgen receptor (LAR); basal-like immunosuppressed (BLIS); basal-like immune-activated (BLIA); tumorinfiltrating lymphocytes (TILs); tumor mutational burden (TMB); immune cells (ICs); immunohistochemistry (IHC); overall response rate (ORR); overall survival (OS); progression-free survival (PFS); intention-totreat (ITT); hazard ratio (HR); confidence interval (CI); Food and Drug Administration (FDA); European Medicines Agency (EMA); immune checkpoint inhibitors (ICI); Combined Positive Score (CPS); disease control rate (DCR); neoadjuvant chemotherapy (NACT); pathological complete response (pCR); eventfree survival (EFS); disease-free survival (DFS); residual cancer burden (RCB); San Antonio Breast Cancer Symposium (SABCS); antibody-drug conjugates (ADCs); PARP inhibitors (PARPi); clinical benefit rate (CBR); Histone deacetylase inhibitors (HDACi); Dendritic cell (DC); talimogene laherparepvec (TVEC); granulocyte-macrophage colony-stimulating factor (GM-CSF); mismatch repair deficiency (dMMR).

Prognosis Prediction Through an Integrated Analysis of Single-Cell and Bulk RNA-Sequencing Data in Triple-Negative Breast Cancer

“…Moreover, all of the above findings might contribute to the notion of cancer immunoediting. Breast cancer has traditionally been considered less immunogenic except TNBC, which is regarded as the optimum subtype for immunotherapy because of high mutational frequency and increased concentrations of tumorinfiltrating lymphocytes (Agostinetto et al, 2022). Our study also showed that immune cells and related activities were lower in the high-risk group.…”

Targeting myeloid-derived suppressor cells in combination with tumor cell vaccination predicts anti-tumor immunity and breast cancer dormancy: an in silico experiment

“…Subsequently, anti-PD1 in combination with neoadjuvant chemotherapy was approved for high-risk early-stage TNBC for curative intent. In spite of these successes, responses to check point inhibitors remain limited to a subset of TNBC patients [57][58][59] . As TILs frequency and PD1/PDL1 expression are not sufficient to predict response efforts have been concentrated on identifying additional predictive markers.…”

Tertiary Lymphoid Structures (TLSs) and Stromal Blood Vessels Have Significant and Heterogeneous Impact on Recurrence, Lymphovascular and Perineural Invasion amongst Breast Cancer Molecular Subtypes

“…TLSs were studied predominantly in TNBC and HER2-BC molecular subtypes [ 40 , 41 , 42 , 43 ]. Most of the papers studied intratumor TLSs while stromal TLSs are not very well characterized regarding their topography and interrelation to peritumor adipose tissue.…”