Antibody-drug conjugates (ADCs) represent a novel class of molecules composed of a recombinant monoclonal antibody targeted to a specific cell surface antigen, conjugated to a cytotoxic agent through a cleavable or non-cleavable synthetic linker. The rationale behind the development of ADCs is to overcome the limitations of conventional chemotherapy, such as the narrow therapeutic window and the emergence of resistance mechanisms. ADCs had already revolutionized the treatment algorithm of HER2-positive breast cancer. Currently, emergent non-HER2 targeted ADCs are gaining momentum, with special focus on triple-negative disease therapeutic landscape. Sacituzumab govitecan (SG) is an ADC consisting of a humanized monoclonal antibody hRS7 targeting trophoblast cell surface antigen 2 (Trop2), linked to the topoisomerase I inhibitor SN-38 by a hydrolysable linker. It currently stands as the only non-HER2 targeted ADC that already received approval for the treatment of unresectable locally advanced or metastatic triple negative breast cancer (TNBC) in patients who had received two or more prior systemic therapies, with at least one for advanced disease. The purpose of these review is to analyze the available evidence regarding ADCs in TNBC, alongside with providing an overview on the ongoing and future research horizons in this field.

Background: Non-melanoma skin cancer (NMSC) stands as an umbrella term for common cutaneous malignancies, including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), together with rarer cutaneous cancers, such as Merkel cell carcinoma (MCC) and other forms of adnexal cancers. The majority of NMSCs can be successfully treated with surgery or radiotherapy, but advanced and metastatic stages may require systemic approaches such as immunotherapy with immune checkpoint inhibitors (ICIs). Summary: Since immunotherapy is not effective in all patients and can potentially lead to severe adverse effects, an important clinical question is how to properly identify those who could be suitable candidates for this therapeutic choice. In this paper, we review the potential features and biomarkers used to predict the outcome of ICIs therapy for NMSCs. Moreover, we analyze the role of immunotherapy in special populations, such as the elderly, immunocompromised patients, organ transplant recipients, and subjects suffering from autoimmune conditions. Key messages: Many clinical, serum, histopathological, and genetic features have been investigated as potential predictors of response in NMSCs treated with ICIs. Although this field of research is very promising, definitive, cost-effective, and reproducible biomarkers are still lacking and further efforts are needed to validate the suggested predictors in larger cohorts.

Estimating patient attrition across lines of treatment (i.e. the probability that upon treatment failure the patient will not be able to receive a subsequent treatment) may be a valuable tool for optimizing treatment sequencing. We sought to describe the first-to-second-line attrition rate and factors associated with attrition in a real-world cohort of patients with metastatic breast cancer. The Gruppo Italiano Mammella (GIM)14/BIO-META (NCT02284581) is an ongoing, ambispective observational multicenter study enrolling patients with metastatic breast cancer receiving first-line therapy. In patients experiencing disease progression, attrition was defined as no further anticancer treatment and death within 6 months from the end of first-line therapy. The attrition rate from the first-to-second line was studied by descriptive analyses and univariate and multivariable logistic models were used to explore potentially predictive factors. From January 2000 to December 2021, 3109 patients with metastatic breast cancer were enrolled in the GIM14/BIO-META study. Among them, 2498 patients experienced first-line treatment failure. Overall, first-to-second line attrition was 9.0% (95% confidence interval 7.9% to 10.1%), with similar attrition for patients with hormone receptor-positive/HER2-negative (8.5%) and HER2-positive (7.1%) breast cancer. Patients with triple-negative disease experienced the highest attrition (13.0%). Age, menopausal status, disease-free interval from primary tumor diagnosis, type of metastatic spread, and tumor subtype independently predicted first-to-second-line attrition. These findings could inform treatment decisions and guide clinical research on treatment sequencing. For instance, patients with the lowest risk of attrition may be the ideal candidates for trials exploring de-escalated first-line regimens, followed by more aggressive treatments upon progression.

The advent of immune checkpoint inhibitors in combination with multitarget tyrosine kinase inhibitors has become a standard first-line treatment for metastatic renal cell cancer. Along with survival improvement, new toxicities have emerged. Such adverse events are still complex to be managed and some of them are rare and could be insidious or even fatal. Medical oncologists dispose of guidelines about the management of toxicities from immune checkpoint inhibitors but not for combinations. Therefore, it is still difficult to properly attribute and manage additive or overlapping adverse events. We report two clinical cases regarding rare treatment-related endocrine toxicities—hypophysitis and thyroiditis—with particular focus on their management. To this purpose, immune checkpoint-related toxicities guidelines represent the starting point. However, their implementation with additional measures is needed, considering the increasing complexity of current clinical scenarios. The goal is to correctly recognize adverse events and address side effects, so as not to discontinue effective treatments. We, therefore, aim at discussing the points of proper management of toxicities and individuating potential areas of improvement.

Neoplastic alopecia (NA) is defined as an organized hair loss in single or multiple areas of the scalp caused by a primary tumor that has metastasized to the skin of the scalp. Due to its localization and clinical appearance, NA should be placed in differential diagnosis with alopecia areata or other entities. To date, pathognomonic dermoscopic criteria of NA have not yet been described: the absence of classical criteria of other scalp diseases in addition to a major neovascularization with on-focus arborizing vessels and erosions or ulcerations may help the clinician to suspect a diagnosis of secondary alopecia. Dermatologists should pay more attention to these rare forms of secondarism because in exceptional cases, a simple alopecia of the scalp can hide a new, relapsing or metastatic neoplasia.

Background: Hormone-receptor-positive (HR+)/HER2-negative (HER2−) breast cancer (BC) is characterized by low immunogenicity and an immunosuppressive microenvironment. These features likely contribute to the inconsistent clinical activity of immune checkpoint inhibitors (ICIs) in this BC subtype. We conducted a systematic review of clinical trials evaluating ICIs in HR+/HER2− BC patients, focusing on potential biomarkers of response and resistance to these drugs. Methods: We systematically searched in Medline via PubMed, EMBASE, and CENTRAL for phase II/III clinical trials published between 2013 and 2023, testing ICIs alone or in combination with other agents in HR+/HER2− BC patients at any stage. All the searches were performed up to 27 January 2024. Data on study characteristics, clinical outcomes, and biomarker profiles were extracted, and due to study heterogeneity, a narrative synthesis was performed, without risk-of-bias assessment or meta-analysis. Results: Twenty-five studies were included, with 3298 patients enrolled overall. Eighteen of these trials enrolled patients with advanced disease. All trials investigated ICI combination regimens, more frequently with chemotherapy, CDK4/6 inhibitors, or other immunotherapeutic agents. Most of the studies enrolling patients with advanced disease failed to show a significant clinical activity of ICIs. In the early setting, neoadjuvant chemo-immunotherapy with nivolumab or pembrolizumab increased the rate of complete responses compared to chemotherapy alone. Moreover, high programmed death-ligand 1 (PD-L1) expression, low ER (estrogen receptor), and high tumor-infiltrating lymphocyte (TIL) levels correlated with improved outcomes. Consistently, markers indicating enhanced immune activation, such as the MammaPrint High 2 (MP2) genomic signature, were associated with increased ICI sensitivity. Discussion: Despite the limited overall efficacy, ICIs may represent a viable therapeutic option for a selected subset of HR+/HER2− BC patients. However, this systematic review is limited by study heterogeneity and the inclusion of ongoing or immature trials, which prevents quantitative analysis and may affect future conclusions on ICIs in HR+/HER2− breast cancer. Finally, optimized combination strategies could enhance tumor immunogenicity, while predictive biomarkers such as PD-L1, TILs, or specific genomic signatures could identify responsive patients.