Navigating the Nexus: HIV and Breast Cancer-A Critical Review.

Despite significant advances in the management of antiretroviral therapy (ART), leading to improved life expectancy for people living with HIV (PLWH), the incidence of non-AIDS-defining cancers, including breast cancer, has emerged as a critical concern. This review synthesizes current evidence on the epidemiology of breast cancer among HIV-infected individuals, highlighting the potential for an altered risk profile, earlier onset, and more advanced disease at diagnosis. It delves into the molecular considerations underpinning the relationship between HIV and breast cancer, including the role of immunosuppression, chronic inflammation, and gene expression alterations. Additionally, it examines the complexities of managing breast cancer in the context of HIV, particularly the challenges posed by ART and anticancer agents' cross-toxicities and drug-drug interactions. The review also addresses survival disparities, underscoring the need for improved cancer care in this population. By identifying gaps in knowledge and areas requiring further research, this review aims to illuminate the complexities of HIV-associated breast cancer, fostering a deeper understanding of its epidemiology, molecular basis, and clinical management challenges, thereby contributing to better outcomes for individuals at the intersection of these two conditions. This narrative review systematically explores the intersection of HIV infection and breast cancer, focusing on the impact of HIV on breast cancer risk, outcomes, and treatment challenges.

A New Kid on the Block: Sacituzumab Govitecan for the Treatment of Breast Cancer and Other Solid Tumors.

Human trophoblast cell-surface antigen-2 (Trop-2) is a membrane glycoprotein involved in cell proliferation and motility, frequently overexpressed in epithelial tumors. Thus, it represents an attractive target for anticancer therapies. Sacituzumab govitecan (SG) is a third-generation antibody-drug conjugate, consisting of an anti-Trop-2 monoclonal antibody (hRS7), a hydrolyzable linker, and a cytotoxin (SN38), which inhibits topoisomerase 1. Specific pharmacological features, such as the high antibody to payload ratio, the ultra-toxic nature of SN38, and the capacity to kill surrounding tumor cells (the bystander effect), make SG a very promising drug for cancer treatment. Indeed, unprecedented results have been observed with SG in patients with heavily pretreated advanced triple-negative breast cancer and urothelial carcinomas, and the drug has already received approval for these indications. These results are coupled with a manageable toxicity profile, with neutropenia and diarrhea as the most frequent adverse events, mainly of grades 1-2. While several trials are exploring SG activity in different tumor types and settings, potential biomarkers of response are under investigation. Among these, Trop-2 overexpression and the presence of BRCA1/2 mutations seem to be the most promising. We review the available literature concerning SG, with a focus on its toxicity spectrum and possible biomarkers of its response.

Antibody-drug conjugates combinations in cancer treatment.

Antibody-drug conjugates (ADCs) have emerged as a promising class of anticancer agents. Currently, the Food and Drug Administration has granted approval to 12 compounds, with 2 later undergoing withdrawal. Moreover, several other compounds are currently under clinical development at different stages. Despite substantial antitumoral activity observed among different tumor types, adverse events and the development of resistance represent significant challenges in their use. Over the last years, an increasing number of clinical trials have been testing these drugs in different combinations with other anticancer agents, such as traditional chemotherapy, immune checkpoint inhibitors, monoclonal antibodies, and small targeted agents, reporting promising results based on possible synergistic effects and a potential for improved treatment outcomes among different tumor types. Here we will review combinations of ADCs with other antitumor agents aiming at describing the current state of the art and future directions.

Giant Paratesticular Liposarcoma: Molecular Characterization and Management Principles with a Review of the Literature.

Paratesticular liposarcomas are extremely rare malignant tumors originating from fat tissues, with an often-challenging diagnosis. We present here the case of a 76-year-old man with a giant paratesticular liposarcoma, initially misdiagnosed as a scrotal hernia. After two years, the progressively enlarging mass underwent surgical resection, and a diagnosis of well-differentiated liposarcoma (lipoma-like subtype) was made. Post-operative treatments were not indicated, and the patient remains relapse free. Next generation sequencing performed on the neoplastic tissue showed co-amplification of MDM2 and CDK4. These alterations are molecular hallmarks of well-differentiated liposarcomas and corroborate the histological diagnosis. Clinical and molecular features of the presented case are in line with the majority of previously published experiences. In conclusion, the presence of a liposarcoma should be taken into account during the diagnostic workup of scrotal masses, in order to minimize the rate of misdiagnosis and improper management. Molecular analysis may support histological characterization of these rare entities and potentially disclose novel therapeutic targets.

Mechanistic Translation of Melanoma Genetic Landscape in Enriched Pathways and Oncogenic Protein-Protein Interactions.

BACKGROUND/AIM: Malignant melanoma is a skin cancer originating from the oncogenic transformation of melanocytes located in the epidermal layers. Usually, the patient's prognosis depends on timing of disease detection and molecular and genetic profiling, which may all significantly influence mortality rates. Genetic analyses often detect somatic BRAF, NRAS and cKIT mutations, germline substitutions in CDKN2A, and alterations of the PI3K-AKT-PTEN pathway. A peculiar molecular future of melanoma is its high immunogenicity, making this tumor targetable by programmed cell death protein 1-specific antibodies. MATERIALS AND METHODS: Ten formalin-fixed paraffin embedded samples derived from melanoma patients were subjected to next-generation sequencing (NGS) analysis using the FDA-approved FoundationOne CDx™ test. The molecular features of each case were then analyzed employing several in silico prediction tools. RESULTS: We analyzed the mutational landscape of patients with metastatic or relapsed cutaneous melanoma to define enriched pathways and protein-protein interactions. The analysis showed that both known genetic alterations and variants of unknown significance rely on redundant signaling converging on similar gene ontology biological processes. Complex informatics analyses of NGS-based genetic results identified pivotal signaling pathways that could provide additional targets for cancer treatment. CONCLUSION: Our data suggest an additional role for NGS in melanoma, as analysis of comprehensive genetic findings using innovative informatic tools may lengthen the list of druggable molecular targets that impact patient outcome.

AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?

The serine/threonine kinase AKT is a key component of the PI3K/AKT/mTOR signaling pathway as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Deregulation of this pathway is a common event in breast cancer including hormone receptor-positive (HR+) disease, HER2-amplified, and triple negative tumors. Hence, targeting AKT represents an attractive treatment option for many breast cancer subtypes, especially those resistant to conventional treatments. Several AKT inhibitors have been recently developed and two ATP-competitive compounds, capivasertib and ipatasertib, have been extensively tested in phase I and II clinical trials either alone, with chemotherapy, or with hormonal agents. Additionally, phase III trials of capivasertib and ipatasertib are already under way in HR+ and triple-negative breast cancer. While the identification of predictive biomarkers of response and resistance to AKT inhibition represents an unmet need, new combination strategies are under investigation aiming to boost the therapeutic efficacy of these drugs. As such, trials combining capivasertib and ipatasertib with CDK4/6 inhibitors, immune checkpoint inhibitors, and PARP inhibitors are currently ongoing. This review summarizes the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies.

Early Gastrointestinal Progression to Immunotherapy in Lung Cancer: A Report of Two Cases.

Intestinal and pancreatic metastases are rare and often challenging to recognize and manage. Lung cancer patients with enteric involvement usually display poor outcomes. Hyperprogression to immunotherapy represents a concern, even though there is currently no agreement on its exact definition. Gastrointestinal hyperprogression to immune checkpoint inhibitors has not been described so far. In these cases, distinguishing disease-related symptoms from immune-related adverse events may represent a diagnostic conundrum. Here, we report two cases of non-small-cell lung cancer experiencing a rapid pancreatic and colic progression to immunotherapy, respectively. While further investigations to identify biomarkers associated with hyperprogression are warranted, clinicians should be aware of the potential unusual clinical presentations of this phenomenon.

p2PSA for predicting biochemical recurrence of prostate cancer earlier than total prostate-specific antigen after radical prostatectomy: an observational prospective cohort study.

BACKGROUND: There is an unmet clinical need for more biochemical specific tests that may detect clinically significant recurrent PCa at an early stage after radical prostatectomy (RP). Our purpose is to test the hypothesis that p2PSA (Index test) detects prostate cancer relapse (BCR) earlier than the current Reference Standard Test (total prostate-specific antigen [tPSA]) in patients who underwent RP for localized PCa. METHODS: This is an observational, prospective, cohort, follow-up study in patients subjected to RALP (robotic assisted laparoscopic radical prostatectomy) for clinically localized PCa from January 2013 to July 2013 at a high-volume Institution (450 average RP/year). A blood sample, for tPSA and p2PSA, was prospectively drawn after 3, 6, and 12 months and then every 6 months during the following two years. The primary outcome is to determine whether or not kinetics in rising of p2PSA significantly anticipates the tPSA kinetics. Exploratory data analysis was used to identify relationship between different variables. RESULTS: Over 134 patients 20 BCRs were detected according to tPSA cut-off. Five patients showed a contemporary increase of tPSA and p2PSA, 11 presented a p2PSA increase earlier than tPSA increase (13.9 months ±9.7). In four patients, the increase of PSA was not associated with a p2PSA>0.8 pg/mL. The correlation between tPSA and p2PSA according to Sperman's rho coefficient was statistically significant at 3, 6, 18 and 30 months: 0.416 (P<0.01), 0.255 (P<0.01), 0.359 (P<0.01) and 0.413 (P<0.01) respectively. When subjects were stratified according to stage/grade and margins (positive vs. negative), patients with higher stage and positive surgical margins could be considered the target categories. The low rate of observed BCR and high rate of p2PSA false positive are the main limitations. CONCLUSIONS: The current findings showed that p2PSA might be more sensitive than tPSA in detecting earlier BCR within 3-year follow-up. Further studies with a longer follow-up and larger population remain mandatory before considering p2PSA for clinical decision-making.

The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults.

Lipid peroxidation has been implicated in a variety of pathophysiological processes, including inflammation, atherogenesis, neurodegeneration, and the ageing process. Phospholipid hydroperoxide glutathione peroxidase (GPX4) is the only major antioxidant enzyme known to directly reduce phospholipid hydroperoxides within membranes and lipoproteins, acting in conjunction with alpha tocopherol (vitamin E) to inhibit lipid peroxidation. Here we describe the generation and characterization of GPX4-deficient mice by targeted disruption of the murine Gpx4 locus through homologous recombination in embryonic stem cells. Gpx4(-/-) embryos die in utero by midgestation (E7.5) and are associated with a lack of normal structural compartmentalization. Gpx4(+/-) mice display reduced levels of Gpx4 mRNA and protein in various tissues. Interestingly, cell lines derived from Gpx4(+/-) mice are markedly sensitive to inducers of oxidative stress, including gamma-irradiation, paraquat, tert-butylhydroperoxide, and hydrogen peroxide, as compared to cell lines derived from wild-type control littermates. Gpx4(+/-) mice also display reduced survival in response to gamma-irradiation. Our observations establish GPX4 as an essential antioxidant enzyme in mice and suggest that it performs broad functions as a component of the mammalian antioxidant network.