Jose Rodríguez-Morató

Despite a decade in, immunotherapy (IO) treatment selection in non-small cell lung cancer (NSCLC) remains largely guided by subgroup analyses and imperfect programmed death ligand 1 (PD-L1) and clinical scores. To our knowledge, I ³ LUNG ( NCT05537922 ) is currently the largest international, real-world, multimodal, artificial intelligence (AI)-based study, enrolling 2,396 patients. We integrated real-world clinical and blood (CB) data, computed tomography (CT) images, digital pathology (DP), and genomics into machine learning early fusion (MLEF) and deep learning intermediate fusion (DLIF) models. Machine learning (ML) and deep learning (DL) CB-only models achieved consistent performance across outcomes with area under the curve (AUC) up to 0.77 in the test (TEST) set. Performance drop in external validation (EXVAL) likely reflects population differences (AUC range: 0.55–0.72). AI models significantly surpassed PD-L1, Eastern Cooperative Oncology Group performance status (ECOG PS), neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH) and Lung Immune Prognostic Index (LIPI) score in the independent TEST set. The clinical usability study showed that lung expert and nonexpert physicians improved their prediction with the explainable AI (XAI) ML CB-only based tool. Although multimodal integration with MLEF (CB+CT+DP) was associated with higher performance, its incremental benefit remains uncertain, not translated in TEST and EXVAL. The I ³ LUNG project is a pioneering framework showing the clinical usefulness of AI tools. A prospective validation of the decision support system (both CB and multimodal) is currently undergoing in more than 2,000 patients.

PHERGain is a randomized, non-comparative phase 2 trial evaluating an 18F-FDG-PET–guided, pathological complete response (pCR)-adapted strategy to omit chemotherapy in HER2-positive early breast cancer (EBC). Patients were randomized to receive chemotherapy plus trastuzumab and pertuzumab (HP; group A) or HP ± endocrine therapy (ET; group B). In group B, treatment was adapted according to PET response after two cycles and pCR, with chemotherapy administered to non-responders or patients without pCR. After a median follow-up of 5.6 years, 5-year invasive disease-free survival (iDFS) was 89.5% (95% CI, 85.7–93.4) in group B and 92.4% (95% CI, 86.7–98.5) among PET responders achieving pCR without chemotherapy, with one distant recurrence. Detectable ctDNA at baseline or during treatment was associated with inferior iDFS, whereas ctDNA clearance correlated with higher pCR rates and improved long-term outcomes. These findings continue to support the clinical validity of a PET-guided, pCR-adapted approach and suggest a potential role for ctDNA in refining treatment individualization.

Leptomeningeal metastatic disease (LMD) is a severe complication of solid cancers with poor outcomes and limited treatment options. The antibody–drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated efficacy in breast and lung cancers, and HER3 is involved in central nervous system metastases, particularly in parenchymal colonization. In this study, we investigated HER3-DXd efficacy and safety in patients with LMD in cohort 3 of the TUXEDO-3 phase 2 trial. Key eligibility criteria included age ≥18 years, treatment-naive LMD or LMD progressing after radiotherapy from any solid tumor and Eastern Cooperative Oncology Group performance status of 0–2. Between January and July 2024, 20 evaluable patients (nine with type I and 11 with type II LMD) were accrued and received HER3-DXd 5.6 mg kg⁻¹ intravenously every 3 weeks. Main primary tumor types included breast (60%) and lung (30%) cancers. Median follow-up time was 5.4 months. The primary endpoint was met with 65.0% patients alive after 3 months. The Kaplan–Meier-estimated 3-month and 6-month overall survival rates were 69.6% and 58.9%, respectively. Overall response rate was 11.1% for intracranial, 30.8% for extracranial and 26.3% for overall lesions. Clinical benefit rate was 50.0% for intracranial, 38.5% for extracranial and 47.4% for overall lesions. Neurological symptoms and quality of life remained stable or improved during study treatment. No new neurological adverse events were observed. The most common adverse events of any grade were anemia (nine (40.9%) patients, one (4.5%) grade ≥3), nausea (seven (31.8%) patients, no grade ≥3), neutropenia (six (27.3%) patients, three (13.6%) grade ≥3), diarrhea (six (27.3%) patients, one (4.5%) grade ≥3), asthenia (six (27.3%) patients, no grade ≥3) and thrombocytopenia and headache (five (22.7%) patients, one (4.5%) grade ≥3 each). TUXEDO-3 showed clinically relevant HER3-DXd activity in patients with LMD. ClinicalTrials.gov identifier: NCT05865990.

Extra virgin olive oil (EVOO) represents a significant source of monounsaturated fatty acids (MUFA) and vitamin E, but it is also considered a functional food, due to the content of peculiar bioactive molecules, such as phenolic compounds, being able to modulate various processes related to aging and the most common metabolic and degenerative diseases. A lot of experimental research has focused on some of these components, but in most cases, the studies were performed in vitro testing compounds at non-physiological concentrations and achieving results that cannot easily be translated in vivo. Recent clinical studies demonstrated that in vivo these compounds are able to regulate physiological functions and prevent several pathological events including metabolic and cardiovascular diseases (CVDs), which represent the main causes of death worldwide. This review aims to sum up the major evidence on the beneficial effects of EVOO phenolic compounds in vivo on these pathologies, describing and evaluating the efficacy in relation to the mechanisms of diseases of the whole phenolic fraction and some of its specific components.

Purpose The prognostic and predictive role of trophoblast cell-surface antigen-2 (Trop-2) overexpression in human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer is currently unknown. We retrospectively analyzed Trop-2 expression and its correlation with clinicopathologic features and pathological complete response (pCR) in HER2-positive early breast cancer (EBC) patients treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab in the PHERGain study. Methods Trop-2 expression at baseline was determined in formalin-fixed, paraffin-embedded primary tumor biopsies by immunohistochemistry and was first classified into expressing (Trop-2-positive) or not-expressing (Trop-2-negative) tumors. Then, it was classified by histochemical score (H-score) according to its intensity into low (0–9), intermediate (10–49), and high (≥ 50). The association between clinicopathologic features, pCR, and Trop-2 expression was performed with Fisher’s exact test. Results Forty-one patients with tissue evaluable for Trop-2 expression were included, with 28 (68.3%) Trop-2-positive tumors. Overall, 17 (41.46%), 14 (34.15%), and 10 (24.40%) tumors were classified as low, intermediate, and high, respectively. Trop-2 expression was significantly associated with decreased pCR rates (50.0% vs. 92.3%; odds ratio [OR] 0.05; 95% CI, 0.002–0.360]; p adjusted = 0.01) but was not correlated with any clinicopathologic features (p ≥ 0.05). Tumors with the highest Trop-2 H-score were less likely to obtain a pCR (OR 0.03; 95% CI, 0.001–0.290, p adjusted < 0.01). This association was confirmed in univariate and multivariate regression analyses. Conclusion These findings suggest a potential role of Trop-2 expression as a biomarker of resistance to neoadjuvant chemotherapy plus dual HER2 blockade and may become a strategic target for future combinations in HER2-positive EBC patients.

Changes occurring in host-associated microbial communities (i.e., the microbiota) may modulate responses to checkpoint blockade immunotherapy. We previously showed that anti-programmed cell death protein 1, pembrolizumab, plus microtubule-targeting chemotherapy, eribulin, has encouraging antitumor activity in previously pre-treated hormone receptor (HR)-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer patients in the KELLY phase II study (NCT03222856). Faecal (58) and saliva (67) samples were prospectively collected at baseline, after three treatment cycles, and end of treatment from a subset of 28 patients included in this trial. Shotgun metagenomic and 16S ribosomal ribonucleic acid gene amplicon sequencing, and bioinformatics and statistical approaches were used to characterize faecal and oral microbiota profiles. Overall, treatment did not cause significant gut or oral microbiota perturbations, indicating limited drug-related microbial toxicity. Dominant gut microbiota genera included Bacteroidesand Faecalibacterium, with a common oral microbe, Prevotella, also present. Several typical oral microbes i.e., Prevotella and Streptococcus, were observed in both saliva and faecal samples, suggesting potential translocation along the oral-gut axis. Further analysis appeared to show that clinical benefit was driven, in part, by gut-associated Bacteroides fragilis and baseline oral-associated Streptococcus with an abundance ≥40%. We also observed that cell-free supernatant from Bacteroides fragilis NCTC 9343 stimulated lactate dehydrogenase release, in a dose-dependent manner from the MCF-7 (HR-positive/HER2-negative) breast cancer cell line. These data suggest that certain gut and oral microbiota members influence efficacy of new combinatory anti-breast cancer therapies, which may in part be mediated via microbial metabolites.