PURPOSE: In recent years, unprecedented benefits have been observed with the development of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for the treatment of hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer. However, there is scarce evidence of their value in specific populations, such as patients carrying germline pathogenic variants in DNA repair–related genes. PATIENTS AND METHODS: We retrospectively studied the efficacy of CDK 4/6 inhibitors plus endocrine therapy in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer. Three cohorts were compared, including patients harboring germline pathogenic variants in DNA repair–related genes (g BRCA1/2- ATM- CHEK2 mutated), those tested without these mutations (wild type [WT]), and the nontested subgroup. Relevant prognostic factors including age, metastatic site (visceral v nonvisceral), Eastern Cooperative Oncology Group, and prior treatment with CDK 4/6 inhibitors were stratified by univariate and multivariate Cox regression models. RESULTS: Among the total population (n = 217), 15 (6.9%) patients carried g BRCA1/2 (n = 10)- ATM (n = 4)- CHEK2 (n = 1) pathogenic variants, 45 (20.7%) were WT, and 157 (72.4%) were nontested. Gene pathogenic variant carriers were younger ( P < .001). Most patients (164, 75.6%) had not received prior endocrine therapy in the advanced setting. Median progression-free survival was shorter in patients with evaluated germline pathogenic variants (10.2 months [95% CI, 5.7 to 14.7]), compared with WT and nontested patients (15.6 months [95% CI, 7.8 to 23.4], and (17.6 months [95% CI, 12.9 to 22.2]; P = .002). Consistently, a worse median overall survival was observed in the subgroup with germline pathogenic variants than in the WT group ( P = .006). Multivariable analysis showed that mutation status was an independent prognostic factor of progression-free survival ( P = .020) and overall survival ( P = .012). CONCLUSION: In this retrospective real-world study, g BRCA1/ 2- ATM-CHEK2 pathogenic variants were independently associated with poor outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors.

Malignant melanoma represents the most aggressive type of skin cancer. Modern therapies, including targeted agents and immune checkpoint inhibitors, have changed the dismal prognosis that characterized this disease. However, most evidence was obtained by studying patients with frequent subtypes of cutaneous melanoma (CM). Consequently, there is an emerging need to understand the molecular basis and treatment approaches for unusual melanoma subtypes. Even a standardized definition of infrequent or rare melanoma is not clearly established. For that reason, we reviewed this challenging topic considering clinical and molecular perspectives, including uncommon CMs—not associated with classical V600E/K BRAF mutations—malignant mucosal and uveal melanomas, and some unusual independent entities, such as amelanotic, desmoplastic, or spitzoid melanomas. Finally, we collected information regarding melanomas from non-traditional primary sites, which emerge from locations as unique as meninges, dermis, lymph nodes, the esophagus, and breasts. The aim of this review is to summarize and highlight the main scientific evidence regarding rare melanomas, with a particular focus on treatment perspectives.

This narrative review aims to clarify the role of tertiary lymphoid structures in breast cancer. We examine their development, composition, and prognostic value, and current ways of recognizing them. A comprehensive literature review was performed using the PubMed/Medline, Scopus, and EMBASE databases. A significant area of interest in breast cancer research involves targeting immune checkpoint molecules, particularly in the triple-negative subtype, where treatment options remain limited. However, existing biomarkers have limitations in accurately predicting treatment response. In this context, tertiary lymphoid structures (TLSs) emerge as a prognostic biomarker and also as a promising predictive marker for response. TLSs are ectopic lymphoid formations or neo-organogenesis that can develop after prolonged exposure to inflammatory signals mediated by chemokines and cytokines. Their presence is inversely correlated with estrogen receptor (ER) and/or progesterone receptor (PR) expression, but positively associated with a higher pathologic complete response rate and improved overall survival. In certain scenarios, TLS-positive tumors were associated with improved outcomes regardless of the presence of PDL-1 (programmed cell death ligand 1) expression or TILs (tumor-infiltrating lymphocytes).