TIP in Patients Affected by Metastatic TNBC

Overview

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) expression on cancer cells. TNBCs accounts for 15-20% of all breast cancers (BC).1 It is characterized by a worse prognosis, increased risk of metastasis to vital organs and a relative lack of therapeutic target if compared to other BC subtypes.2 Therefore, the identification of new molecular targets and therapeutic strategies is a critical need in both early and metastatic setting. TNBC appears to be more immunogenic compared to other BC6. Immunotherapy has recently changed the landscape of therapeutic options in TNBC. Recent clinical trials have shown a significant clinical benefit in patients with metastatic TNBC treated with a combination of chemotherapy and anti PD-1 agents.11-12-13-14-15 In particular, results from IMPASSION 130 trial showed a significant benefit in both progression free survival (PFS) and overall survival (OS) in PD-L1 positive (PD-L1+) patients treated with a combination of atezolizumab and nab-paclitaxel.20 However, about 70% of PD-L1+ patients has experienced a disease progression after one year and about 50% was alive at 2 year. Moreover, no difference in survival endpoint has been seen in PD-L1 negative (PD-L1-) population, with an increase of toxicity and costs related to the addition of a checkpoint-inhibitor. Therefore, the identification of novel biomarkers in addition to PD-L1 and the combination of several biomarkers in a profile with higher predictive capacity is considered an area of urgent clinical need. Some immune-related features that can be identified in tumor microenvironment have been demonstrated to be independent prognostic and predictive factors: TILs, PD-L1, CD73. 1. Tumour-infiltrating lymphocytes (TILs) control the clinical progression of various types of cancer7. Breast cancer with higher levels of infiltrating CD8+ cytotoxic T cells have been associated with better patient survival8. Moreover, high levels of stromal CD8+ TILs (sTILs) correlate with higher probability of pCR9. Not only quantitative, but also qualitative analysis of TILs is a promising research area. Some studies suggest that different subtypes of TILs may have an opposite role in tumor microenvironment allowing the induction of both immune activating (es. CD8+) or immune suppressive (es FOXP3+) environment8-9-10. 2. The interaction between programmed cell death protein 1 (PD-1) and its ligand (PD-L1) represents one of the principal mechanisms of immune escape and a therapeutic target for several malignancies13-14. PD-1/PD-L1 interaction attenuates lymphocyte activation and promotes T-regulatory cell development and function, allowing to terminate the immune response15. In breast cancer the prognostic role of PD-1/PD-L1 axis is still uncertain with limited and contrasting data. PD-L1 positivity (≥1%) on immune cells (IC) is the clinical most used threshold, according to the results of IMPASSION 130 trial.18-24 3. Recently, CD73 has been identified as a possible further molecular immunosuppressive target in triple negative breast cancer28. CD73 is expressed on the surface of tumoral cells, stromal cells and immunological cells. By increasing extracellular levels of adenosine monophosphate , CD73 suppresses immune responses. CD73 has been found to be overexpressed in several types of human cancers, and it has been associated with a poor prognosis29-30-31. Particularly Loi et al demonstrated that high CD73 expression is associated with poor prognosis in TNBC and to a low rate of pathological complete response32. We defined a tissue immune profile positive (TIP+) as the simultaneous presence of TILs≥50%, CD73≤40% and PD-L1≥1%. Any other combination was defined as TIP negative (TIP-) In conclusion, we will evaluate the association between TIP and clinical outcomes (ORR, PFS, OS).