Jacopo Canzian

Background: The surrogacy of progression-free survival (PFS) for overall survival (OS) at the trial-level in randomized clinical trials (RCTs) testing immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancers (NSCLC) is influenced by several clinical-pathological factors. However, potential heterogeneity of PFS surrogacy according to patients’ sex has never been investigated. Methods: RCTs testing ICIs as monotherapy or combined with chemotherapy in patients with advanced NSCLC reporting hazard ratios (HRs) for PFS and OS according to patients’ sex were included. The main objective was to assess sex-based heterogeneity in the trial-level association between PFS (surrogate endpoint) and OS (reference endpoint), overall and in subgroups defined by treatment type (ICIs as monotherapy vs ICIs plus chemotherapy). We used the coefficient of determination (R2) to quantify surrogacy. Results: Twenty RCTs, for a total of 7528 male and 3008 female patients, were included. Overall, the association between OS-HR and PFS-HR was moderate: the R2 from a model adjusted by the type of treatment administered in the experimental arm was 0.69 (95% confidence interval [CI] = 0.34 to 0.88). Sex-disaggregated analysis showed heterogeneity in PFS surrogacy: the association was strong in male patients (adjusted R2 = 0.77; 95% CI = 0.56 to 0.89), but poor in female (adjusted R2 = 0.31, 95% CI = 0.03 to 0.63). Consistent results were obtained in subgroups analyses by treatment type, and in cross-validation analysis. Conclusions: In RCTs testing ICIs alone or combined with chemotherapy in patients with advanced NSCLC, PFS is a robust surrogate endpoint for OS in male patients but not in female.

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.

Background: Neoadjuvant therapy (NAT) plays a crucial role in breast cancer (BC) management by enabling tumor and nodal downstaging. While axillary lymph node dissection (ALND) remains the standard for patients with residual nodal disease after NAT, its prognostic benefit is debated. Identifying predictors of high-burden residual axillary disease may guide treatment intensification and surgical de-escalation strategies. Methods: We retrospectively analyzed 262 BC patients treated with NAT followed by ALND between 2006 and 2023. Patients were stratified into low- (ypN0-mi-1) and high-burden (ypN2-3) residual axillary disease groups. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of high-burden residual disease. Results: High-burden residual axillary disease was observed in 35.9% of patients. Baseline cN+ status (OR = 7.697, p = 0.013), HR+/HER2− subtype (OR = 3.945, p = 0.003), and larger post-NAT tumor size (OR = 1.043, p < 0.001) were independent predictors. Conclusions: Identifying patients at risk of high-burden residual axillary disease is essential to optimize neoadjuvant strategies. Increasing axillary pathological complete response may reduce the need for ALND, minimizing surgical morbidity without compromising oncological outcomes.

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.

Backgrounds: Neoadjuvant therapy (NAT) is a cornerstone in the management of breast cancer (BC), enabling tumor downstaging and improved surgical options. Methods: This study retrospectively analyzed 607 BC patients treated with NAT and surgery at IRCCS Humanitas Research Hospital, Milan, Italy, to compare long-term oncologic outcomes of breast-conserving surgery (BCS) versus mastectomy. Patient demographics, tumor characteristics, and treatment details were analyzed using descriptive statistics, logistic regression, and Cox proportional hazards models. Results: Of the 607 patients, 54.7% underwent BCS, and 45.3% had mastectomy. BCS was associated with significantly superior 10-year outcomes compared to mastectomy, including disease-free survival (DFS, 75.2% vs. 71.1%, p = 0.001), distant DFS (75.2% vs. 71.1%, p = 0.001), overall survival (OS, 82.9% vs. 78.1%, p = 0.002), and BC-specific survival (BCSS, 87.7% vs. 83.1%, p = 0.001). Pathologic complete response (pCR) emerged as a protective factor across all endpoints, while mastectomy was independently associated with worse BCSS (HR: 2.068, 95% CI: 1.016–4.210, p = 0.045). Conclusions: Our findings demonstrate the oncologic safety and potential superiority of BCS over mastectomy in NAT-treated BC patients, highlighting the importance of individualized surgical decision-making to optimize survival outcomes.