Marta Nerone

BackgroundA polygenic risk score derived from 313 polymorphisms (PRS313) can modify breast cancer lifetime risk estimates when integrated into CanRisk (BOADICEA v5), yet its real-world reclassification impact remains poorly defined.MethodsPRoScreen is a prospective multicenter cohort study across ten Swiss breast centers (May 2023 – December 2025) enrolling 252 women aged 25 - 60 years, unaffected with cancer, with a family history of breast cancer and negative testing for pathogenic variants in BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, PALB2, ATM, and CHEK2. Lifetime risk (LTR) was calculated using CanRisk alone (CR) and with PRS313 integrated (CR+PRS), stratified as near-population (<17%), moderate (17–29%), and high (≥30%) risk per international guidelines. In a subgroup of 89 participants, analyses were repeated with and without family history.ResultsPRS313 reclassified 94/252 participants (37%): 49 (19.4%) moved to a higher risk category and 45 (17.9%) to a lower one. The high-risk group doubled (18 to 36; 7% to 14%) while the moderate-risk group shrank (127 to 96; 50% to 38%). Mean LTR was unchanged (19.6% vs 19.7%), but standard deviation widened from 6.9% to 9.7%, reflecting greater dispersion. Removing family history in a subgroup reduced median CR from 19.8% to 13.0% and median CR+PRS from 18.3% to 14.1%, downgrading 50.6% by at least one category.ConclusionsIn women with a familial breast cancer history without pathogenic variant, PRS313 integration into CanRisk reclassified over one-third of participants, doubling those meeting high-risk surveillance criteria. These findings support further investigation of PRS313 in clinical risk assessment.

Objectives: The objective of this single-site retrospective study was to assess the association between Computed Tomography (CT)-based whole-body composition values with dose reduction in patients with a diagnosis of epithelial ovarian cancer (EOC) treated with poly ADP-ribose polymerase (PARP) inhibitors (PARPi). Methods: Forty-eight patients (median age 61 years; interquartile range 53–68.5) with EOC who had a thorax and abdomen CT scan (performed before starting PARPi) were enrolled. Recorded clinical data included age, weight, height, stage, start and end date of PARPi, dose reduction, premature discontinuation of therapy, date of last contact, progression, and death. Body composition values were automatically extracted by dedicated software. Given the exploratory nature of the study, the statistical analysis combined univariate assessments (univariate logistic regression) used to evaluate the individual effect of each variable on the probability of dose reduction, with a classification tree approach—a data-driven machine learning method considering all variables simultaneously as covariates. This integrated strategy was designed to identify empirical cut-offs defining body composition profiles associated with increased risk of toxicity. Results: Univariate logistic regression showed no statistically significant effect of body composition variables on the probability of dose reduction. Due to the complexity of variable relations, a machine-learning approach with a classification tree showed that SKM (skeletal muscle) was the sole body composition variable significantly associated with dose reduction. Specifically, there was a higher risk of dose reduction with SKM values ≥ 7506 cm³ and < 8650 cm³ (p = 0.0118). Conclusions: In this exploratory study, a significant association of whole-body composition parameters (SKM) with dose reduction was observed in patients with a 7506 cm³ ≤ SKM < 8650 cm³. If confirmed in larger cohorts, these findings could help clinicians identify patients who might benefit from an upfront reduced PARPi dose.

We explored the outcomes of germline BRCA1/2 pathogenic/likely pathogenic variants (PVs/LPVs) in the endocrine-sensitive disease treated with first-line standard of care cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Three studies retrospectively showed a reduction in the overall survival (OS) and progression-free survival (PFS) in gBRCA1/2m patients compared to both the germinal BRCA1/2 wild type (gBRCA1/2wt) and the untested population. Regarding the efficacy of PI3Kα inhibitors, there are no subgroups or biomarker analyses in which germinal BRCA status was explored. However, the biological interactions between the PIK3CA/AKT/mTOR pathway and BRCA1/2 at a molecular level could help us to understand the activity of these drugs when used to treat BC in BRCA1/2 PVs/LPVs carriers. The efficacy of trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate (ADC) targeting HER2 for HER2-low and HER2-positive (HER2+) BC, has been increasingly described. Unfortunately, data on T-DXd in HER2+ or HER2-low metastatic BC harboring germinal BRCA1/2 PVs/LPVs is lacking. Including germinal BRCA1/2 status in the subgroup analysis of the registration trials of this ADC would be of great interest, especially in the phase III trial DESTINY-breast04. This trial enrolled patients with HER2-negative (HER2−) and both HR+ and HR− metastatic disease, which can now be categorized as HER2-low. The HER2-low subgroup includes tumors that were previously classified as triple negative, so it is highly likely that some women were germline BRCA1/2 PVs/LPVs carriers and this data was not reported. Germline BRCA1/2 status will be available for a higher number of individuals with BC in the near future, and data on the prognostic and predictive role of these PVs/LPVs is needed in order to choose the best treatment options.

Background: The primary objective of this study was to assess the associations of computed tomography (CT)-based whole-body composition values with overall survival (OS) and progression-free survival (PFS) in epithelial ovarian cancer (EOC) patients. The secondary objective was the association of body composition with chemotherapy-related toxicity. Methods: Thirty-four patients (median age 64.9 years; interquartile range 55.4–75.4) with EOC and thorax and abdomen CT scans were included. Clinical data recorded: age; weight; height; stage; chemotherapy-related toxicity; and date of last contact, progression and death. Automatic extraction of body composition values was performed by dedicated software. Sarcopenia was defined according to predefined cutoffs. Statistical analysis included univariate tests to investigate associations of sarcopenia and body composition with chemotoxicity. Association of body composition parameters and OS/PFS was evaluated by log-rank test and Cox proportional hazard model. Multivariate models were adjusted for FIGO stage and/or age at diagnosis. Results: We found significant associations of skeletal muscle volume with OS (p = 0.04) and PFS (p = 0.04); intramuscular fat volume with PFS (p = 0.03); and visceral adipose tissue, epicardial and paracardial fat with PFS (p = 0.04, 0.01 and 0.02, respectively). We found no significant associations between body composition parameters and chemotherapy-related toxicity. Conclusions: In this exploratory study, we found significant associations of whole-body composition parameters with OS and PFS. These results open a window to the possibility to perform body composition profiling without approximate estimations.

We explored the outcomes of germline BRCA1/2 pathogenic/likely pathogenic variants (PVs/LPVs) in the endocrine-sensitive disease treated with first line standard of care cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Three studies retrospectively showed a reduction in overall survival (OS) and progression free survival (PFS) in gBRCA1/2m patients compared to both germinal BRCA1/2 wild type (gBRCA1/2wt) and to the untested population. Regarding the efficacy of PI3K inhibitors, there are no subgroup or biomarker analyses in which germinal BRCA status was explored. However, the biological interactions between the PIK3CA/AKT/mTOR pathway and BRCA1/2 at a molecular level could help us to understand the activity of these drugs when used to treat BC in BRCA1/2 PVs/LPVs carriers. The efficacy of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) targeting HER2 for HER2-low and HER2-positive (HER2+) BC, has been increasingly described. Unfortunately, data on T-DXd in HER2+ or HER2-low metastatic BC harboring germinal BRCA1/2 PVs/LPVs is lacking. Including germinal BRCA1/2 status in the subgroup analysis of the registration trials of this ADC would be of great interest, especially in the phase III trial DESTINY-breast04. This trial enrolled patients with HER2-negative (HER2-) and both HR+ and HR- metastatic disease, which can now be categorized as HER2-low. The HER2-low subgroup includes tumors that were previously classified as triple negative, so it is highly likely that some women were germline BRCA1/2 PVs/LPVs carriers and this data was not reported. Germline BRCA1/2 status will be available for a higher number of individuals with BC in the near future and data on the prognostic and predictive role of these PVs/LPVs is needed in order to choose the best treatment options.

Antibody-drug conjugates (ADCs) represent a new class of therapeutic agents designed to target specific antigens on tumor cells, combining the specificity of monoclonal antibodies to the cytotoxicity of classic chemotherapy agents. These drugs have been extensively studied both in solid and hematologic malignancies, leading to substantial improvement in the therapeutic landscape for several tumors. Despite no ADC have been yet approved for the treatment of gynecological malignancies, some agents have shown promising results and might have the potential to become part of the standard of care. Among them, mirvetuximab soravtansine has shown activity in platinum-resistant ovarian cancer with high folate-α receptor expression, as a single agent and in combination. Tisotumab vedotin is active in patients with pre-treated cervical cancer, and further investigation is ongoing. The purpose of this review is to summarize the structural and functional characteristics of ADCs and analyze the most recent and promising data regarding the clinical development of ADCs in gynecological malignancies. The available data on the efficacy of the more studied ADCs in ovarian, endometrial, and cervical cancers will be discussed along with toxicities of special interest, the mechanisms of resistance, and future possible drugs combination.