Triple negative breast cancer: Key role of Tumor-Associated Macrophages in regulating the activity of anti-PD-1/PD-L1 agents.

Triple-negative breast cancer (TNBC) is associated with a poor prognosis, due to its aggressive behaviour and lack of effective targeted therapies. Immunocheckpoint inhibitors, such as anti-programmed cell death 1 (PD-1) and anti-PD-ligand(L)1 agents, are in course of investigation in TNBC, used alone or in combination with other systemic or local approaches. However, the high cost of these drugs and the lack of validated predictive biomarkers support the development of strategies aimed to overcome resistance and optimize the efficacy of these approaches. Tumor-Associated Macrophages (TAMs) derive from peripheral blood monocytes recruited into the TNBC microenvironment and, in response to several stimuli, undergo M1 (classical) or M2 (alternative) activation. In TNBC, TAMs promote tumor growth and progression by several mechanisms that include the secretion of inhibitory cytokines, the reduction of effector functions of Tumor Infiltrating Lymphocytes (TILs) and the promotion of Regulatory T cell (Treg). Interestingly, TAMs have been shown to directly and indirectly modulate PD-1/PD-L1 expression in tumor environment. On this scenario, several TAM-centered strategies have been proposed, such as the suppression of TAM recruitment, the depletion of their number, the switch of M2 TAMs into antitumor M1 phenotype and the inhibition of TAM-associated molecules. In this review, we will illustrate the activity of TAMs and associated molecules in TNBC, focusing on their role in modulating the expression of PD-1/PD-L1 and on the emerging TAM-tailored strategies for TNBC patients.

A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First-Line Exemestane: Results From a Prospective Study.

INTRODUCTION: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival. PATIENTS AND METHODS: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility. RESULTS: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively. CONCLUSION: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management.

Risk of fatigue in cancer patients treated with anti programmed cell death-1/anti programmed cell death ligand-1 agents: a systematic review and meta-analysis.

AIM: We aimed to assess the incidence and relative risk (RR) of fatigue in cancer patients treated with anti programmed cell death-1 (PD-1) and anti programmed cell death ligand-1 (PD-L1) agents. PATIENTS & METHODS: Eligible studies were selected according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Incidence, RR and 95% CIs were calculated using random or fixed-effects models. RESULTS: Thirty-eight studies were included in this analysis, with a total of 11,719 patients. The incidences were 23.4 and 2.1% for all- and high-grade fatigue, respectively. The highest incidence of high-grade fatigue was reported by the combination of nivolumab and ipilimumab. Overall RR of high-grade fatigue with anti-PD-1/PD-L1 compared with chemotherapy or targeted therapy was 0.48. CONCLUSION: Treatment with anti-PD-1/PD-L1 agents correlates with lower incidence and RR of fatigue compared with standard therapies.

Hypoallergenic properties of donkey's milk: a preliminary study.

Cow's milk protein allergy (CMPA) is an abnormal immunological response to cow milk proteins, which results in IgE-mediated reactions. The therapeutic strategy to respond to CMPA envisages the total elimination of milk or the administration of cow's milk substitutes. For this reason the use of milk from other mammalian species was tested. Among them, donkey's milk proved to be the best alternative in feeding infants affected by CMPA, since its chemical composition is comparable to human milk. In this work an in vitrostudy was performed in order to analyze the IgE reactivity to milk protein allergens from cow, donkey and goat. In particular, immunoblotting experiments using sera from milk-allergic and non-allergic adult volunteers were conducted with the aim of verifying the hypoallergenic property of donkey's milk. This study provided a preliminary evidence of the hypoallergenicity of donkey's milk when compared to bovine and goat milk. Considering the obtained results, it would be possible to develop a sensitive diagnostic method for CMPA detection, based on chromatographic and immunoblotting analysis.