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To date, only few marine natural compounds have been proved to be active in breast cancer (BC). The main marine-derived drugs that have been studied for the treatment of BC are tubulin-binding agents (eribulin and plocabulin), DNA-targeting agents (cytarabine and minor groove binders—trabectedin and lurbinectedin) and Antibody-Drug Conjugates (ADCs). Notably, eribulin is the only approved cytotoxic drug for the treatment of advanced BC (ABC), while cytarabine has a limited indication in case of leptomeningeal diffusion of the disease. Also plocabulin showed limited activity in ABC but further research is needed to define its ultimate potential role. The available clinical data for both trabectedin and lurbinectedin are of particular interest in the treatment of BRCA-mutated tumours and HR deficient disease, probably due to a possible immune-mediated mechanism of action. One of the most innovative therapeutic options for the treatment of BC, particularly in TNBC and HER2-positive BC, are ADCs. Some of the ADCs were developed using a specific marine-derived cytotoxic molecule as payload called auristatin. Among these, clinical data are available on ladiratuzumab vedotin and glembatumumab vedotin in TNBC, and on disitamab vedotin and ALT-P7 in HER2-positive patients. A deeper knowledge of the mechanism of action and of the potential predictive factors for response to marine-derived drugs is important for their rational and effective use, alone or in combination. In this narrative review, we discuss the role of marine-derived drugs for the treatment of BC, although most of them are not approved, and the opportunities that could arise from the potential treasure trove of the sea for novel BC therapeutics.

Visceral crisis is a life-threatening clinical condition requiring urgent treatment and accounts for 10–15% of new advanced breast cancer diagnoses, mainly hormone receptor-positive/human epidermal growth factor 2 negative. As its clinical definition is an open topic with nebulous criteria and much room for subjective interpretation, it poses a challenge for daily clinical practice. International guidelines recommend combined chemotherapy as first-line treatment for patients with visceral crisis, but with modest results and a very poor prognosis. Visceral crisis has always been a common exclusion criterion in breast cancer trials, and the available evidence mainly comes from limited retrospective studies which are not sufficient to draw solid conclusions. The outstanding efficacy of innovative drugs, such as CDK4/6 inhibitors, questions the role of chemotherapy in this setting. In the lack of clinical reviews, we aim to critically discuss the management of visceral crisis, advocating future treatment perspectives for this challenging condition.

Based on the unprecedented results observed in recent clinical trials, antibody-drug conjugates (ADCs) have revolutionized the treatment algorithm of metastatic breast cancer (mBC). The strategy of sequencing different ADCs in other lines of therapy is highly attractive, but the proportion of patients who have undergone such a strategy in the context of published clinical trials is still limited, especially for modern ADCs. HER2-positive disease is primarily managed with a sequence of different ADCs. Historically, trastuzumab emtansine (T-DM1) has been the most commonly used ADC for both early and metastatic HER2-positive disease. Considering the recent evidence related to trastuzumab deruxtecan (T-DXd), it is expected to assume the role of the main ADC in our clinical practice. Herein, we report a retrospective analysis of the sequence of different ADCs relying on available published data from clinical trials.

Modern healthcare is experiencing a significant transformation, utilizing technology to improve patient outcomes and make processes more efficient. Breast cancer, being the most commonly diagnosed cancer in women globally, requires innovative approaches for effective management. Digital Therapeutics (DTx) and Clinical Decision Support Systems (CDSSs) have emerged as pivotal technologies, offering personalized, patient-centered care and optimizing clinical decision-making. This review provides a comprehensive analysis of the applications, benefits, and challenges of these digital tools in breast cancer treatment. We examine DTx tools’ ability to offer real-time symptom monitoring, treatment adherence, psychological support, and lifestyle modification guidance. Simultaneously, the role of CDSSs in providing personalized treatment recommendations, early detection, data analysis, and enhancing multidisciplinary collaborations is evaluated. The challenges of implementing these technologies, such as data privacy, interoperability, and accessibility are also discussed, along with potential solutions. By exploring the current research findings, the review underscores the significant impact of DTx and CDSSs on patient outcomes, treatment efficiency, and overall quality of life. This manuscript concludes with a forward-looking perspective, emphasizing the importance of collaborative efforts to overcome obstacles and unlock the full potential of digital innovations in breast cancer oncology. Our analysis suggests that adopting these digital tools can lead to more holistic, efficient, and patient-centric cancer care, marking a significant shift in the paradigm of breast cancer management.

Triple-negative breast cancer (TNBC) holds a poor prognosis compared to other breast cancer subtypes, and the development of new effective treatment strategies is an unmet medical need. TNBC has traditionally been considered not amenable to treatment with targeted agents due to a lack of actionable targets. Therefore, chemotherapy has remained the mainstay of systemic treatment for many decades. The advent of immunotherapy raised very hopeful expectations in TNBC, possibly due to higher levels of tumor-infiltrating lymphocytes, PD-L1 expression and tumor mutational burden compared to other breast cancer subtypes, that predict an effective anti-tumor immune-engagement. The results of clinical trials testing immunotherapy in TNBC led to the approval of the combination of immune checkpoint inhibitors and chemotherapy in both early and advanced settings. However, some open questions about the use of immunotherapy in TNBC still exist. These include a deeper understanding of the heterogeneity of the disease, identification of reliable predictive biomarkers of response, determination of the most appropriate chemotherapy backbone and appropriate management of potential long-term immune-related adverse events. In this review we aim to examine the available evidence on the use of immunotherapy strategies in both early and advanced TNBC, to critically discuss some of the limitations encountered in clinical research and to summarize data on novel promising immunotherapeutic strategies beyond PD-(L)1 blockade that have been investigated in the most recent trials.

Significant sex-based differences exist in the immune system and antitumor immune responses, potentially leading to variations in both the efficacy and toxicity of anticancer immunotherapies. Women generally mount stronger innate and adaptive immune responses than men, which can result in more severe immune-related adverse events (irAEs) during treatments with immune checkpoint inhibitors (ICIs). However, the importance of sex dimorphism in the safety of cancer immunotherapy remains underexplored in clinical oncology, despite its profound implications for treatment outcomes. Our review highlights the critical influence of biological sex on pharmacokinetics, pharmacodynamics, and immune responses, shaping ICI efficacy and the prevalence, type, and severity of irAEs. Integrating sex as a critical variable in cancer treatment and clinical trial design is essential for personalizing therapeutic strategies, bridging existing knowledge gaps, and enhancing survival rates and quality of life for patients across genders.

Abstract Background Abemaciclib-induced diarrhea is a relevant concern in clinical practice. Postbiotics have emerged as a promising option for managing it. Materials and Methods We conducted a retrospective-prospective, 2-group, observational study to assess the impact of the postbiotic PostbiotiX-Restore, derived by Lactobacillus paracasei CNCM I-5220, on abemaciclib-induced diarrhea in patients with hormone receptor-positive HER2-negative breast cancer. The prospective population (Postbio group) received postbiotic during the first cycle of abemaciclib, while the retrospective one received standard care (Standard group). Diarrhea grading was defined according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Results During the first cycle, diarrhea occurred in 78.9% of patients in the Standard cohort and 97.1% in the Postbio one, with most cases being G1-G2. Severe (G3) diarrhea was significantly less frequent in the Postbio group (0%) compared to the Standard one (7.9%; P = .029). Over the entire study period, while the grading difference was not statistically significant, G3 events were less frequent in the Postbio population (5.9%) than the Standard one (15.4%). Moreover, Postbio patients required fewer dose reductions due to diarrhea compared to the Standard group (P = .002). Notably, in the Postbio population, G1 and G2 events had short median durations (3 and 1 days, respectively) and, for the 2 patients experiencing G3 events during the second abemaciclib cycle (off postbiotic), diarrhea lasted only 1 day. Conclusions Our study demonstrates the effect of PostbiotiX-Restore in mitigating abemaciclib-induced diarrhea, resulting in reduced severity, fewer dose reductions, and shorter duration. Further exploration and validation in larger cohorts are needed. Abemaciclib-induced diarrhea is a relevant concern in clinical practice. Postbiotics have emerged as a promising option for managing it.

Abstract The NATALEE trial expanded the use of adjuvant cyclin-dependent kinase 4/6 inhibitors beyond the MonarchE trial’s criteria for early breast cancer (eBC). We conducted a retrospective analysis comparing a large real-world (RW) cohort of 762 consecutive eBC patients with those enrolled in the NATALEE and MonarchE randomized controlled trials (RCTs) to evaluate differences in eligibility. Our analysis revealed that 41.7% of RW patients met NATALEE’s eligibility criteria, significantly more than the 21.8% who met MonarchE’s criteria, reflecting NATALEE’s broader indication. Real-world patients were older, had less advanced tumors, and were less likely to be treated with adjuvant chemotherapy compared to the RCT populations. None of the RW patients was deemed eligible for ribociclib based solely on high genomic risk. These findings underscore significant differences in clinical characteristics and potential treatment eligibility, highlighting the need for critical assessment of RCTs results in clinical practice.

Abstract Patients and methods we retrospectively collected data of patients with HR+/HER2− advanced breast cancer (ABC) treated with endocrine therapy (ET) and a CDK4/6 inhibitor (CDK4/6i) aiming to describe the patterns of post-progression outcomes. Results Among 452 evaluable patients 325 were treated in the first-line setting. Median progression-free survival (mPFS) was 22.8 months overall and 29.7 months in patients treated in first-line setting. Factors associated with outcomes in multivariate analysis were the line of CDK4/6i therapy, de novo vs recurrent disease, visceral vs bone-only metastases, and primary endocrine resistance. A total of 300 patients progressed and 250 overall and 156 in the first-line cohort received a subsequent treatment. Visceral progression and CDK4/6i duration <12 months were associated with a higher likelihood of receiving anthracycline or taxanes (AT) as compared to ET ±everolimus (EET). Post-progression PFS (PPFS) and post-progression OS (PPOS) were statistically significantly better with EET and capecitabine (C) over AT overall and in patients with visceral progression. Multivariate analysis confirmed a significant advantage for EET and C, while visceral progression retained a significant impact only on PPOS. After progression to the first post-CDK4/6i treatment C obtained a significant better PPOS as compared to other treatments. Conclusion We showed in a large real-world series that most patients with HR+/HER2− ABC failing CDK4/6i and ET unselected for the occurrence of molecular mutations retain endocrine sensitivity and may benefit of a subsequent ET ± a targeted therapy delaying the need for chemotherapy regardless of site of progression and prior CDK4/6i therapy duration. Graphical abstract Graphical Abstract

Abstract Background CDK4/6 inhibitors (CDK4/6i) are cornerstone therapies in Hormone Receptor Positive (HR+)/Human Epidermal Growth Factor Receptor 2 Negative (HER2−) Breast Cancer (BC) and emerging evidence suggests that they may influence immune function, potentially enhancing antitumor immunity but also triggering autoimmune reactions. This study aims to investigate the prevalence of autoimmune diseases (AD) in patients with HR+/HER2− BC to identify potential predictive biomarkers and to assess the impact of AD on disease progression. Patients and Methods This retrospective-prospective cohort study included consecutive HR+/HER2- BC patients treated with CDK4/6i at Humanitas Research Hospital. Clinical-pathological features, treatment data, AD occurrence, and blood test values were collected. Descriptive statistics were used to determine AD prevalence, Kaplan-Meier method to estimate progression-free survival (PFS), and log-rank test to compare survival curves. Results 352 patients (median age: 54 years) were enrolled, of which 87.2% had metastatic disease and received palbociclib, abemaciclib, or ribociclib (45.2%, 31.0%, and 23.9%, respectively). 12.8% of patients had early BC and received abemaciclib. ADs were identified in 49 patients: most had pre-existing conditions (38 stable and 4 flaring during treatment) while 7 developed new-onset ADs. The most frequent AD were Hashimoto thyroiditis, vitiligo, and rheumatoid arthritis. In the metastatic setting, the median PFS was significantly longer in patients with AD compared to those without (P = .0013), with patients with flaring or new-onset AD showing a better PFS (P = .0015). No significant predictive biomarkers for AD evolution were found. Conclusion CDK4/6i therapy is feasible in patients with pre-existing AD. Interestingly, the onset or flaring of AD during treatment is associated with improved PFS, suggesting a potential immune activation induced by CDK4/6i. However, further robust and prospective studies are required to validate these findings and explore the underlying mechanisms.