Hormone receptor-positive/HER2-negative breast cancer (BC) is the most common subtype of BC and typically occurs as an early, operable disease. In patients receiving neoadjuvant chemotherapy (NACT), pathological complete response (pCR) is rare and multiple efforts have been made to predict disease recurrence. We developed a framework to predict pCR using clinicopathological characteristics widely available at diagnosis. The machine learning (ML) models were trained to predict pCR (n = 463), evaluated in an internal validation cohort (n = 109) and validated in an external validation cohort (n = 151). The best model was an Elastic Net, which achieved an area under the curve (AUC) of respectively 0.86 and 0.81. Our results highlight how simpler models using few input variables can be as valuable as more complex ML architectures. Our model is freely available and can be used to enhance the stratification of BC patients receiving NACT, providing a framework for the development of risk-adapted clinical trials.

PURPOSE: The clinical and research FPG500 program (ClinicalTrials.gov identifier: NCT06020625 ) is currently ongoing at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS to tailor matched targeted therapies (MTTs) according to biomarkers predictive of response identified by comprehensive genome profiling (CGP). MATERIALS AND METHODS: The non–small cell lung cancer (NSCLC) cohort results from the FPG500 program are outlined. CGP was performed by TruSight Oncology 500 High Throughput (TSO500HT) assay or Oncomine Focus Assay plus Archer's FusionPlex Lung Panel according to tumor cell content and DNA/RNA quantity. Relevant issues for Molecular Tumor Board (MTB) evaluation included uncommon genomic findings, evaluation for off-label therapies, uncertain result confirmation, and variants of suspect germline origin requiring genetic counseling. Progression-free survival (PFS) and overall survival (OS) for the enrolled patients were assessed using Kaplan-Meier analysis. RESULTS: In 2022, 283 patients with NSCLC were considered for sequencing, with 93% meeting eligibility criteria. TSO500HT sequencing was conducted in 76% of patients. Follow-up data were obtained for 187 patients, among whom 81% received treatment. Potential driver alterations were identified in 59% of patients, with 41% receiving MTT: 25% were prescribed approved MTTs, whereas 16% gained access to experimental drugs post-MTB evaluation; of note, 18% did not receive any MTT because the regimen was not yet reimbursed in our country. Median PFS and OS varied among treatment groups, with standard chemotherapy/immunotherapy at 7.7 and 10.7 months, approved tyrosine kinase inhibitors at 18.8 and 23.9 months, and MTT post-MTB discussion at 14 and 23.4 months, respectively. CONCLUSION: The early data of the FPG program (NSCLC cohort) support the implementation of CGP and MTB in clinical practice to grant access to patients harboring actionable molecular alterations to the most effective and individualized available treatment options, thus improving their survival outcomes.

Background/Objectives: Malnutrition, sarcopenia, cachexia, and frailty often coexist in older cancer patients and are associated with worse treatment tolerance, reduced quality of life, and increased mortality. These syndromes can be underrecognized, and the therapeutic approach is often fragmented. In light of this, the aim of this review was to synthesize current evidence on the screening and clinical management of nutritional aspects and the related tools, favoring multidimensional and personalized nutritional care. Methods: This narrative review was conducted according to the SANRA guidelines. A comprehensive literature search was performed on PubMed for studies published between January 2000 and June 2025, with no language restrictions. Eligible studies included adults aged ≥65 with cancer, addressing malnutrition, sarcopenia, cachexia, frailty, or nutrition-related interventions. Results: Malnutrition affects 30–80% of older cancer patients and is strongly associated with reduced survival, impaired treatment tolerance, and poorer quality of life. Tools such as PG-SGA, G8, GNRI, and CONUT offer practical options for early risk identification. Nutritional interventions, including oral supplements, dietary counseling, symptom management, and multimodal strategies (nutrition plus exercise), are associated with improved clinical outcomes. Evidence also supports the prognostic value of early screening and individualized nutrition care pathways. Conclusions: Malnutrition represents a modifiable risk factor in geriatric oncology and should be assessed considering other related conditions such as sarcopenia, cachexia, and frailty. Systematic screening and targeted interventions should be integrated into standard cancer care to improve outcomes in older adults. Future research should prioritize personalized nutrition strategies and multicenter trials focused on survival, function, and quality of life.

Background: In early breast cancer (BC) the impact of denosumab on survival outcomes is still unclear. We undertook a systematic review and meta-analysis to assess efficacy and safety of adjuvant denosumab in addition to standard anticancer therapy. Methods: PubMed, CENTRAL, Scopus, Embase, and oncological meetings websites were screened to identify potentially eligible randomized controlled trials (RCTs). Survival outcomes were disease-free survival (DFS), bone-metastasis-free survival (BMFS), and overall survival (OS). Fracture incidence and time to first fracture were bone-health outcomes. Osteonecrosis of the jaw (ONJ), atypical femur fractures (AFF), and other adverse events were also evaluated. Pooled hazard ratios (HRs) and risk ratios (RR) with respective 95% confidence interval (95% CI) were computed using a random-effects model. Exploratory subgroup analyses were performed. Results: Two phase III RCTs were included, the Austrian Breast & Colorectal Cancer Study Group-18 (ABCSG-18) and the D-CARE trials, for a total of 7929 patients. In the ABCSG-18 trial, denosumab was administered every 6 months during endocrine therapy (for a median of seven cycles) while the D-CARE trial used an intensive schedule for a total treatment duration of 5 years. Adjuvant denosumab showed no difference in DFS (HR: 0.932; 95% CI: 0.748–1.162), BMFS (HR: 0.9896; 95% CI: 0.751–1.070), and OS (HR: 0.917; 95% CI: 0.718–1.171) compared to placebo in the overall population. In hormone receptor positive/human epidermal growth factor receptor 2 (HER2) negative BC patients, a DFS (HR: 0.883; 95% CI: 0.782–0.996) and BMFS (HR: 0.832; 95% CI: 0.714–0.970) benefit was observed and BMFS was prolonged in all hormone receptor positive patients (HR: 0.850; 95% CI: 0.735–0.983). Fracture incidence (RR: 0.787; 95% CI: 0.696–0.890) and time to first fracture (HR: 0.760; 95% CI: 0.665–0.869) were also improved. No increase in overall toxicity was seen with denosumab and no differences were observed for ONJ and AFF between the 60-mg every 6-month schedule and placebo. Conclusion: Denosumab addition to anticancer treatment does not improve DFS, BMFS, or OS in the overall population, although a DFS improvement was observed in hormone receptor positive/HER2 negative BC patients and a BMFS improvement in all hormone receptor positive patients. Bone-health outcomes were improved with no added toxicity with the 60-mg schedule. Registration: PROSPERO identifier: CRD42022332787.

In RAS wild type (wt) metastatic colorectal cancer (mCRC) maintenance therapy after induction with fluoropyrimidine (FP)-based cytotoxic therapy (CT) plus anti-EGFR agents is controversial. Phase II-III randomized trials were included. Maintenance strategies considered were: observation, anti-EGFR or FP monotherapy, FP + anti-EGFR, doublet CT + anti-EGFR. Maintenance with FP + anti-EGFR (HR 0.56, 95% CrI 0.36-0.89) showed the greatest PFS benefit compared to observation, ranking first on SUCRA analysis (96.4%). Considering OS, doublet CT+ anti-EGFR, FP + anti-EGFR and anti-EGFR monotherapy yielded similar results. For PFS, FP + anti-EGFR confirmed to be valuable in BRAF wt patients and left sided tumors. In left sided tumors, the OS benefit of adding CT was limited. FP plus anti-EGFR showed a favourable safety profile compared to doublet CT + anti-EGFR. FP + anti-EGFR can be considered a valuable maintenance option in RAS wt mCRC. EGFR monotherapy can be considered, especially in left-sided tumors.

Background: Muscle strength is one of the key components in the diagnosis of sarcopenia. The aim of this study was to train a machine learning model to predict reference values and percentiles for handgrip strength and chair‐stand test (CST), in a large cohort of community dwellers recruited in the Longevity check‐up (Lookup) 8+ project.Methods: The longevity checkup project is an ongoing initiative conducted in unconventional settings in Italy from 1 June 2015. Eligible participants were 18+ years and provided written informed consent. After a 70/20/10 split in training, validation and test set, a quantile regression forest (QRF) was trained. Performance metrics were R‐squared (R²), mean squared error (MSE), root mean squared error (RMSE) and mean Winkler interval score (MWIS) with 90% prediction coverage (PC). Metrics 95% confidence intervals (CI) were calculated using a bootstrap approach. Variable contribution was analysed using SHapley Additive exPlanations (SHAP) values. Probable sarcopenia (PS) was defined according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria.Results: Between 1 June 2015 and 23 November 2024, a total of 21 171 individuals were enrolled, of which 19 995 were included in our analyses. In the overall population, 11 019 (55.1%) were females. Median age was 56 years (IQR 47.0–67.0). Five variables were included: age, sex, height, weight and BMI. After the train/validation/test split, 13 996 subjects were included in the train set, 4199 in validation set and 1800 in the test set. For handgrip strength, the R² was 0.65 (95% CI 0.63–0.67) in the validation set and 0.64 (95% CI 0.62–0.67) in the test set. PCs were 91.5% and 91.2%, respectively. For CST test, the R² was 0.23 (95% CI 0.20–0.25) in the validation set and 0.24 (95% CI 0.20–0.28) in the test set. The PCs were 89.5% and 89.3%. Gender was the most influential variable for handgrip and age for CST. In the validation set, 23% of subjects in the first quartile for handgrip and 13% of subjects in the fourth quartile for CST test met criteria of PS.Conclusions: We developed and validated a QRF model to predict subject‐specific quantiles for handgrip and CST. These models hold promise for integration into clinical practice, facilitating cost‐effective and time‐efficient early identification of individuals at elevated risk of sarcopenia. The predictive outputs of these models may serve as surrogate biomarkers of the aging process, capturing functional decline.