Mathematical models based on partial differential equations (PDEs) can be exploited to integrate heterogeneous clinical and biological data for the interpretation of tumor dynamics during systemic therapy. In this study, a PDE-based model of tumor volume evolution was exercised to investigate the predictive role of clinical and microbiota-derived biomarkers in patients with HER2-positive breast cancer undergoing neoadjuvant chemotherapy. Within a retrospective cohort of 15 patients, a training subset of eight was used to identify and optimize a set of virtual parameters describing tumor proliferation and treatment efficacy. Tumor growth rate ( r ) and drug efficiency for the epirubicin–cyclophosphamide branch (ϵ PD1 ) were modeled as functions of baseline Ki67 expression, while a Spearman correlation analysis identified key microbiota features (Firmicutes/Bacteroidetes ratio and the Simpson Diversity Index) associated with treatment response, or drug efficiency of the taxane–trastuzumab branch (ϵ PD2 ). Model robustness was subsequently assessed in an independent testing subset of seven patients. Simulated tumor volume dynamics did not significantly differ from clinical observations and showed strong predictive capability in discriminating therapeutic response (p = 0.0070), correctly identifying all partial responses and 80% of pathological complete responses. After defining appropriate mathematical assumptions, microbiota-informed drug efficiency parameters were shown to effectively capture inter-patient variability in treatment sensitivity. A simplified model of tumor dynamics integrating microbiota-derived variables was thus demonstrated to provide an upfront prediction of neoadjuvant chemotherapy efficacy. Prospective validation in larger cohorts and correlation with established clinical endpoints are now warranted to confirm the model and support patient-specific optimization of therapeutic strategies in HER2-positive breast cancer.

Several first-line (1L) treatments have been evaluated for patients with metastatic triple-negative breast cancer (mTNBC) ineligible for anti-PD-(L)1 inhibitors, but the optimal approach remains unclear. We conducted a systematic review and trial-level frequentist network meta-analysis of randomized controlled trials evaluating 1L therapies for mTNBC not eligible for anti-PD-(L)1 inhibitors (PROSPERO: CRD420251177761). Progression-free survival (PFS) was the primary endpoint. Ten trials (n = 3,752) were included. Treatments comprised antibody-drug conjugates (ADCs), bevacizumab+chemotherapy (CT), immune-checkpoint inhibitors + CT, and PARP inhibitors (PARPi). Excluding PARPi, datopotamab-deruxtecan (Hazard Ratio [HR] 0.57), sacituzumab-govitecan (HR 0.62), and bevacizumab + CT (HR 0.64) significantly improved PFS versus CT, with no significant differences between ADCs or versus bevacizumab + CT. Dato-DXd also improved overall survival and achieved the highest response rate. In patients with germline (g) BRCA 1/2-mutated disease, PARPi ranked among the most effective treatments. Toxicities varied by regimen. ADCs and bevacizumab + CT appear preferred 1L options, whereas PARPi remain valuable for g BRCA 1/2-mutated disease.

This study investigates the mid-term budget impact of using the Oncotype DX® multigene prognostic test (MPT) in estrogen receptor (ER)+/ human epidermal growth factor receptor 2 (HER2)- early breast cancer (EBC) patients with 0 to 3 positive lymph nodes, following its recent reimbursement approval in Italy. A budget impact analysis was conducted from the perspective of the Italian National Health Service (SSN) over a 5-year time horizon. The analysis compared a strategy using MPT to inform chemotherapy (CT) decisions versus standard clinical practice. A hybrid decision-tree and cohort state-transition model was employed, utilizing data primarily from the Italian BONDx study. Sensitivity analyses, including probabilistic and univariate analyses, were performed to assess the robustness of the results and to determine the test price required to offset the budget impact over a five-year time horizon. In the base-case scenario where all ER+/HER2- EBC patients receive the test, MPT use led to a 40.2

Background Older patients with Hormone Receptor–positive, HER2-negative advanced breast cancer (HR+/HER2− aBC) are often frailer than younger patients. Endocrine therapy (ET) plus CDK4/6 inhibitors (CDK4/6i) is the standard first-line treatment regardless of age; however, CDK4/6i real-world effectiveness in older patients is unknown. Patients and Methods PALMARES-2 (NCT06805812) is a large real-world study investigating first-line ET plus CDK4/6i effectiveness in HR+/HER2− aBC patients. We compared real-world progression-free survival (rwPFS) between older (>75 years) and younger (≤75 years) patients in the whole study cohort, as well as in palbociclib, ribociclib, or abemaciclib sub-cohorts. Cox regression models and inverse probability of treatment weighting (IPTW) were used to adjust for prognostic covariates. Results Older patients accounted for 302 (15.2%) of the PALMARES-2 study cohort (n=1982). Compared with younger patients, older patients were less likely to have ECOG PS 0 or bone-only disease, and more likely to receive palbociclib. At multivariable analysis, older patients had better rwPFS when compared to younger patients (aHR 0.77; 95% CI 0.67–0.90, p=0.001). In younger patients, ribociclib and abemaciclib were more effective than palbociclib, whereas in older patients palbociclib showed similar effectiveness to abemaciclib and superior effectiveness to ribociclib (p for interaction <0.001). Among patients treated with palbociclib, older patients had improved rwPFS compared with younger patients (aHR 0.69; 95% CI 0.57–0.84, p<0.001). Conclusion First-line ET plus CDK4/6i is highly effective in older patients with HR+/HER2− aBC. Based on effectiveness and clinical manageability, palbociclib represents a particularly suitable option in this population.

Background and aims Human Epidermal Growth Factor Receptor 2-positive (HER2+) breast cancer poses significant therapeutic challenges, particularly concerning treatment administration pathways and their associated costs. This study evaluates the managerial and economic impacts of different therapeutic administration scenarios for HER2-positive breast cancer patients, focusing on optimizing hospital workflows, resource utilization, and patient outcomes in Italian oncological centers. Methods A decision tree model was developed to simulate and compare five treatment administration pathways: Standard, Drug-Change, Drug Day, Dedicated Ambulatory, and Optimal Pathway scenarios. The model integrates patient and healthcare professional (HCP) activity and waiting times, infusion chair occupation, and direct and indirect costs. Sensitivity analyses assessed variability in model outcomes. Results Switching from endovenous (EV) to subcutaneous (SC) administration substantially reduced patient throughput times and HCP workloads. The Optimal Pathway scenario yielded the highest resource optimisation, reducing HCP activity time by up to 48 hours, infusional chair occupational time by up to 150 hours, and patients’ total time by up to 753 hours per 100 patients monthly. Cost analyses indicated significant savings in both direct and indirect cost for all the proposed scenarios in comparison to the Standard one. Conclusion The adoption of SC formulations and innovative pathway optimizations enhances treatment organizational efficiency and reduces both direct and indirect costs. These findings underscore the value of tailored approaches to administration based on the structural and organizational characteristics of individual oncology centers, aligning with current Italian healthcare reforms.

PURPOSE:Metronomic chemotherapy with oral capecitabine + vinorelbine (Cape + VNL) provides synergistic cytostatic activity and antiangiogenic and immunomodulatory effects, potentially offering prolonged disease control with limited toxicity in HER2-negative metastatic breast cancer (MBC). However, efficacy in the real-world (RW) setting, especially in late lines, and the impact of dihydropyrimidine dehydrogenase (DPYD) polymorphisms on dose reduction and safety remain limited. METHODS:In this retrospective study, 200 patients with human epidermal growth factor receptor 2 (HER2)-negative MBC were treated at the ASST Cremona Hospital (2015-2023) with metronomic Cape (1000 mg twice daily, in normal metabolizers; 500 mg twice daily, in DPYD variant carriers) + VNL (20 mg/day, once daily, 5-days-on/2-days-off). All patients underwent pretreatment DPYD genotyping and dose adjustment. Treatment was administered in the second-to-fourth setting. The primary end point was time-to-next treatment or death (TNTD); secondary end points included overall survival (OS), disease control rate (DCR) ≥24 weeks, overall response rate (ORR), safety, and genotype-toxicity correlations. RESULTS:The median age was 61 years, and DPYD variants were present in 14.5% of patients; 34%, 41%, and 25% received therapy as second-, third-, and fourth-line treatment. The median TNTD was 22.0 weeks, and the OS was 64.0 weeks. The DCR was 38.5%, and the ORR was 22.0%. Efficacy was comparable between DPYD variant carriers and normal metabolizers (all P values > .05). In later lines, Eastern Cooperative Oncology Group performance status 2 and >2 metastatic sites were independent negative prognostic factors (all values P < .05). Overall, 7.5% grade 3 toxicities occurred, especially in variant carriers without dose reduction and grade 4-5 events. CONCLUSION:These RW data suggest that metronomic Cape + VNL may represent a clinically active and manageable option in heavily pretreated HER2-negative MBC. Our findings support prospective evaluation of DPYD-guided dose individualization as a strategy to optimize the benefit-risk balance of fluoropyrimidine-based metronomic regimens.

Introduction Invasive lobular breast cancer (ILC) is the second most common breast cancer subtype, with distinctive biological and epidemiologic features. Although phase III trials of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive, HER2-negative advanced breast cancer (HR+/HER2- aBC) included patients with ILC, their real-world effectiveness in this population remains poorly characterized. Material and Methods In this sub-analysis of the multicenter, real-world PALMARES-2 study (NCT06805812), we assessed the predictive and prognostic value of lobular histology in HR+/HER2- aBC treated with first-line endocrine therapy (ET) plus CDK4/6i. The primary endpoint was real-world progression-free survival (rwPFS). Associations between histology and outcomes were adjusted for 15 covariates using multivariable Cox-regression and inverse probability of treatment weighting. Results Among 1982 patients, 367 (18.5%) had ILC and 1481 (74.7%) non-special type (NST). Median follow-up was 29.8 and 31.2 months, respectively. ILC was associated with shorter rwPFS versus NST (adjusted hazard ratio [aHR]: 1.24, 95%CI:1.04-1.47, P=0.017). Palbociclib efficacy was not affected by lobular histology (P for interaction=0.553) while abemaciclib was less effective in ILC (P=0.009). All three CDK4/6i achieved similar rwPFS in ILC (ribociclib vs palbociclib: aHR: 1.01, 95%CI: 0.67-1.45, P=0.949; abemaciclib vs palbociclib: aHR: 1.13, 95%CI: 0.75-1.71, P=0.551; abemaciclib vs ribociclib: aHR: 1.15, 95%CI: 0.73-1.80, P=0.549). Conclusions Tumor histology affects the real-world effectiveness of first line ET plus CDK4/6i. In ILC, all three CDK4/6i performed similarly; therefore, treatment selection should prioritize tolerability, manageability, drug-drug interactions, and patient preferences.

Results of the ASCENT-03 trial demonstrated a statistically significant improvement in progression-free survival with sacituzumab govitecan (SG) compared with chemotherapy in patients with previously untreated metastatic triple-negative breast cancer (mTNBC) ineligible for PD-(L)1 inhibitors. This population represents a clear unmet need, as PD-L1 CPS < 10 tumours account for a substantial proportion of mTNBC and many patients do not receive subsequent lines of therapy. However, several methodological considerations temper the strength of the conclusions, underlining the need for mature, crossover-adjusted overall survival analyses before definitively establishing SG as a first-line standard of care.

Hormone receptor-positive/HER2-negative breast cancer evolves in response to therapy, demanding smarter, adaptive biomarker-based treatment strategies. We review emerging dynamic biomarkers to guide therapeutic decision-making, spanning tissue and liquid biopsies, metabolic imaging, and microbiome profiling, that capture tumor or host-related changes over time. By contrasting Academic and Industry approaches, we advocate for a cultural shift in clinical trial design and implementation, aiming to move from reactive to proactive Oncology.

BACKGROUND:Adjuvant abemaciclib + endocrine therapy (ET) improves long-term outcomes in high-risk, hormone receptor-positive (HR+)/HER2-negative early breast cancer (eBC). However, treatment is frequently complicated by diarrhea, affecting adherence and quality-of-life (QoL). Increasing evidence suggests that abemaciclib-induced gastrointestinal toxicity may involve gut microbiota alterations. We conducted a prospective case-control pilot study evaluating the efficacy of MBR-01, a standardized prebiotic/probiotic formulation, in mitigating abemaciclib-induced diarrhea. METHODS:We enrolled 20 postmenopausal patients with high-risk HR+/HER2-negative eBC considered unfit for adjuvant chemotherapy. Patients received abemaciclib + letrozole (control, n = 10) or abemaciclib + letrozole + MBR-01 (experimental, n = 10). The primary endpoint was the incidence and severity of diarrhea; secondary endpoints included treatment adherence, QoL assessments and exploratory baseline/week-12 microbiota characterization according to treatment arm. TRIAL REGISTRATION NUMBER:ISRCTN11948182. RESULTS:Diarrhea occurred in all patients. In the control group, diarrhea was predominantly grade 1 (50%) or grade 2 (40%), with one grade 3 event (10%). In the MBR-01 group, diarrhea frequency and severity were reduced by ∼70% at the end of week-12; 90% of patients experienced only grade 1 diarrhea or none by week-12, and no grade ≥3 events. Dose modification was only required in one control. Decrease in alpha-diversity and F.prausnitzii were associated with earlier diarrhea onset and longer duration; increase in E.coli correlated with higher grade events. MBR-01 supplementation seemed to preserve microbial diversity and limited E.coli expansion. QoL was significantly improved with MBR-01. CONCLUSION:MBR-01 may effectively mitigate abemaciclib-induced diarrhea, likely through the achievement of stabilization of gut microbiota composition. Larger prospective studies are warranted to validate these preliminary findings.

In recent years, head and neck cancer therapy has been revolutionized by immunotherapy, which aims to restore the immune system’s anticancer activity suppressed by cancer cells. The major concern is that only a subset of patients responds to this therapy. Having specific biomarkers that could help identify the patients who are most likely to benefit from immunotherapies would be extremely useful. This review first explains the current immunotherapies tested in head and neck cancer, to then delve into the current prognostic and predictive biomarkers that have been investigated in this field to predict their responses. In our opinion, a broader selection of biomarkers could further improve who will respond best to immunotherapy.

Non-small cell lung cancer (NSCLC) represents a heterogeneous group of malignancies characterised by diverse histological and molecular features. Some NSCLCs, particularly adenocarcinomas, harbour genomic alterations in receptor tyrosine kinases or downstream RAS/RAF signalling pathways, which are targets of effective therapies. NSCLCs lacking actionable genomic alterations often benefit from immune checkpoint inhibitors, though only a minority of patients achieve long-term survival. These tumours often carry alterations in tumour suppressor genes like TP53, KEAP1, STK11, or NF1, for which pharmacological strategies are still under investigation. This review explores emerging therapeutic opportunities unveiled by multi-omics studies in NSCLCs without actionable genomic alterations. Proteogenomic approaches—integrating genomic, transcriptomic and proteomic data—enable a comprehensive understanding of NSCLC molecular landscapes and signalling network dysregulation, helping to identify distinct tumour subtypes and potential therapeutic targets. These tumours exhibit alterations in cell cycle regulation, DNA repair, immune signalling, epigenetic modulation and metabolic and redox pathways. Although therapies targeting tumour suppressor genes like p53 remain highly anticipated, extending our understanding of the broader molecular landscape in these tumours may reveal novel vulnerabilities and inform the development of novel drugs or combination strategies. This could further advance precision oncology for NSCLC.

BACKGROUND:Glioblastoma is a highly aggressive primary central nervous system tumor characterized by poor outcomes. In case of relapse or progression to adjuvant chemotherapy, there is no univocal preferred regimen for relapsing glioblastoma. METHODS:We conducted a systematic review and Bayesian trial-level network meta-analyses (NMA) to identify the regimens associated with the best outcomes. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS) and overall response rates (ORR). We estimated separate treatment rankings based on the surface under the cumulative ranking curve values. Only phase II/III prospective comparative trials were included. RESULTS:Twenty-four studies (3733 patients and 27 different therapies) were ultimately included. Twenty-three different regimens were compared for OS, 21 for PFS, and 26 for ORR. When taking lomustine as a common comparator, only regorafenib was likely to be significantly superior in terms of OS (hazard ratio: 0.50, 95% credible interval: 0.33-0.75). Regorafenib was significantly superior to other 16 (69.6%) regimens, including NovoTTF-100A, bevacizumab monotherapy, and several bevacizumab-based combinations. Regarding PFS and ORR, no treatment was clearly superior to the others. CONCLUSIONS:This NMA supports regorafenib as one of the best available options for relapsing/refractory glioblastoma. Lomustine, NovoTTF-100A, and bevacizumab emerge as other viable alternative regimens. However, evidence on regorafenib is controversial at best. Moreover, most studies were underpowered, with varying inclusion criteria and primary endpoints, and no longer adapted to the most recent glioblastoma classification. A paradigmatic change in clinical trials' design for relapsing/refractory glioblastoma and more effective treatments are urgently required.

Recent advancements in cancer multi-omics have transformed our understanding of cancer biology by integrating genomics, transcriptomics, proteomics, and metabolomics. These integrative approaches have led to the identification of novel biomarkers and therapeutic targets, offering deeper insights into the molecular intricacies of various cancers, including breast, lung, gastric, pancreatic, and glioblastoma. Despite these advances, challenges remain, such as the integration of disparate data types and the interpretation of complex biological interactions. However, developments in proteogenomics and mass spectrometry have enhanced the correlation between molecular profiles and clinical features, refining the prediction of therapeutic responses. Future research in cancer drug discovery is poised to benefit from multi-omics approaches, improving the precision and efficacy of personalized therapies. By developing integrative network-based models, researchers aim to address challenges related to heterogeneity, reproducibility, and data interpretation. A standardized framework for multi-omics data integration could revolutionize cancer research, optimizing the identification of novel drug targets and enhancing our understanding of cancer biology. This complete approach holds the promise of advancing personalized therapies by fully characterizing the molecular landscape of cancer, ultimately improving patient outcomes through more effective and targeted treatment strategies. This narrative review underscores the potential of multi-omics approaches to transform cancer research and improve patient outcomes through more precise and effective treatments.

Breast cancer (BC) and prostate cancer (PCa) are major health problems for women and men worldwide. Although therapeutic approaches have increased, the complexity associated with their heterogeneity and progression requires better ways to monitor them over time. Cell-free DNA integrity (cfDI) represents a viable alternative to needle biopsy and has the potential to be representative of cancer at all stages. In addition to the advantages of liquid biopsy in terms of cost and reduced invasiveness, cfDI can be used to detect repetitive DNA elements (e.g., ALU and LINE1), which could circumvent the problem of mutational heterogeneity in BC and PCa. In this review, we summarise the latest findings on cfDI studies in BC and PCa. The results show that cfDI has the potential to improve early detection, metastasis, and recurrence of BC, while limited studies prevent its clinical value in PCa from being fully defined. However, it is expected that further studies in the near future will help to introduce the use of cfDI as another biomarker for the clinical monitoring of BC and PCa patients.