KEYNOTE-522, IMpassion031 and GeparNUEVO: changing the paradigm of neoadjuvant immune checkpoint inhibitors in early triple-negative breast cancer

Abstract

Stage I–III triple-negative breast cancer accounts for approximately 15–20% of new diagnoses of early breast cancer. Novel systemic treatment options have recently been assessed as part of the neoadjuvant approach, such as the addition of immune checkpoint inhibitors to cytotoxic chemotherapy. However, several questions remain unanswered, including the identification of predictors of response to immunotherapy in this setting, and further efforts aimed at identifying reliable predictors and clarifying the effective role of PD-L1 status, tumor mutational burden, tumor-infiltrating lymphocytes and other biomarkers are warranted. Herein we will provide an overview of recent clinical studies of neoadjuvant immune checkpoint inhibitors in patients with triple-negative breast cancer, especially focusing on the recently presented and published KEYNOTE-522, IMpassion031 and GeparNUEVO trials.

Lactylproteome analysis indicates histone H4K12 lactylation as a novel biomarker in triple-negative breast cancer

“…However, recent evidence suggests lactate production and the resultant acidification of the tumor microenvironment play crucial roles in angiogenesis, invasion, metastasis, and immune evasion in certain cancer (19,30,32). Intriguingly, further studies have validated that lactylation occurs in both histone and nonhistone proteins and that protein lysine lactylation is vital for lactate function (4,14,22). Although histone lactylation has been primarily associated with non-neoplastic diseases (33,34), its presence in cancer has been infrequently reported.…”

“…According to data from the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO), breast cancer (BC) has now become the most common malignant tumor globally, surpassing lung cancer ( 1 , 2 ). Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, represents approximately 15%–20% of all BC cases ( 3 , 4 ). TNBC poses a greater clinical challenge compared to other BC types due to its higher rates of recurrence and metastasis, shorter median survival, and poorer prognosis ( 3 , 5 , 6 ).…”

Defining the Emergence of New Immunotherapy Approaches in Breast Cancer: Role of Myeloid-Derived Suppressor Cells

“…Another FDA-approved regimen is atezolizumab with CT based on the results of the IMPASSION 130 trial (NCT02425891) for PD-L1-expressing metastatic TNBC, which demonstrated that atezolizumab with nanoparticle albumin-bound (nab)-paclitaxel prolonged PFS in patients with PD-L1-expressing metastatic TNBC compared to patients receiving placebo plus nab-paclitaxel. A variety of clinical trials are still ongoing to study alternative combinations of IBCs with other drugs in luminal tumors, HER2+ and TNBC [ 12 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 ].…”

Immunotherapy Targeting PD-1/PD-L1 in Early-Stage Triple-Negative Breast Cancer

“…Favorably, there was a statistically significant tendency for improved three-year survival, including invasive disease-free survival (iDFS), distant disease-free survival (DDFS), overall survival (OS), and no new safety signals occurring. In the durvalumab group and placebo group, iDFS was 85.6% vs. 77.2% ( p = 0.036), DDFS was 91.7% vs. 78.4% ( p = 0.005), and OS was 95.2% vs. 83.5% ( p = 0.006), respectively [ 34 , 35 , 36 ].…”

“…The study suggested that the addition of immunotherapy reduced RCB scores and improved EFS. Based on a series of promising results and the relatively mild side effects of pembrolizumab from KEYNOTE-522 and other studies, both the European Medicines Agency (EMA) and the FDA approved joining pembrolizumab and chemotherapy for neoadjuvant therapy and subsequent adjuvant therapy, establishing the first immunotherapy regimen approved in high-risk, early-stage TNBC [ 36 , 43 ].…”