Abstract Background: RET fusions occur in ∼1-2% of advanced NSCLC (aNSCLC). Selective RET inhibitors (SRIs) significantly improve outcomes, yet ∼10% of patients progress by 6 months and ∼30% by 12 months. Predictors of response or early progression remain poorly defined. Methods: A multicenter retrospective analysis (RET-MAP) of RET+ aNSCLC from 47 international centers evaluated clinical/genomic correlates of SRI outcomes. Multivariable Cox models estimated progression-free (PFS) and overall survival (OS) and tested interactions with first-line (1L) SRI versus chemotherapy ± immune checkpoint inhibitor (CH±ICI). In parallel, genomic/transcriptomic features were characterized in an external Caris Life Sciences (CLS) RET+ aNSCLC cohort. Results: Among 510 RET-MAP patients (median age 63; 59% female; 36% ever-smokers; 92% adenocarcinoma), 401 received an SRI (1L n=151; later lines n=250). Median PFS on SRI (any line) was 17.1 months (95% CI, 14.5-21.1), median OS 30.4 months (95% CI, 27.0-41.1). TP53 co-mutation was present in 27% (78/292 tested) and was associated with shorter PFS (8.9 vs 19.2 months; p<0.001) and OS (22.7 vs 30.9 months; p=0.002), without a significant treatment-by-TP53 interaction for 1L SRI versus CH±ICI (p=0.22). Fusion partner contributed with additional signal: KIF5B (73%, 274/373) had inferior PFS (13.4 vs 60.2 months; p<0.001) and OS (26.6 vs 73.0 months; p=0.002) compared with CCDC6 (17%, 65/373), and a significant treatment-by-fusion interaction favored SRI over CH±ICI in CCDC6 versus KIF5B (p=0.007). On multivariate analysis, shorter PFS and OS were independently associated with TP53 mutation (HR 1.74, p<0.001; HR 1.77, p=0.001), KIF5B fusion (HR 1.98, p=0.002; HR 1.64, p=0.040), ECOG ≥2 (HR 2.20, p<0.001; HR 3.06, p<0.001), and brain metastases (HR 1.59, p=0.003; HR 1.88, p<0.001); worse OS was associated with non-adenocarcinoma histology (HR 1.74, p=0.049) and smoking (HR 1.42, p=0.034). Notably, KIF5B fusions were enriched for TP53 mutations versus CCDC6 (40% vs 19.6%, p=0.011), suggesting partially overlapping biology. In the CLS cohort (N=211), TP53-mutant tumors (74/211) were enriched for RB1 mutations, had higher PD-L1 expression and tumor mutational burden, and demonstrated increased M1 macrophage/B-cell infiltration with reduced neutrophils; by fusion partner, CCDC6 showed higher PD-L1, while global transcriptomes were otherwise similar to KIF5B. Conclusions: In RET+ aNSCLC, TP53 mutation is prognostic for inferior outcomes on SRIs but not predictive of differential benefit versus CH±ICI. Fusion partner carries both prognostic and predictive relevance; CCDC6 is associated with a more indolent course and greater relative benefit from SRI. External profiling supports an inflammatory microenvironment in TP53-mutant disease, reinforcing biologically distinct—and clinically meaningful—subsets within RET-driven lung cancer. Citation Format: Daniela Miliziano, Julia K. Rotow, Meghanne Lomibao, Tolulope Adeyelu, Arianna Marinello, Helena Bote-de Cabo, Jamie Feng, Andrea De Giglio, Mariana Brandão, Florian Guisier, Michael Duruisseaux, Christina Falcon, Massimiliano Cani, Francesca Colamartini, Barliz Waissengrin, Isabelle Monnet, Anna Eisert, Emilio Bria, Amin H. Nassar, Ayesha Aijaz, Patricia Iranzo, Colin R. Lindsay, Elizabeth Fabre, Vladmir Cordeiro de Lima, Judith Raimbourg, Laura Mezquita, Nicolas Minatta, Sophie Cousin, Katarzyna Szymczak, Vincent Fallet, Clarisse Audigier-Valette, Helene Doubre, Philippe Rochigneux, Annarita Avanzo, Antonio Calles, Marco Tagliamento, Diego Cortinovis, Balazs Halmos, Nicholas Girard, Andrew Elliott, Jair Bar, Alessio Cortellini, Diana N. Ionescu, Frances A. Shepherd, Fabrice Barlesi, Karen L. Reckamp, David Planchard, Benjamin Besse, Alexander Drilon, Mihaela Aldea. Prognostic and predictive effects of TP53 co-mutations and RET fusion partners in RET-rearranged advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2434.

PURPOSE:Dabrafenib plus trametinib is a standard first-line treatment for BRAF V600E-mutated non-small cell lung cancer (NSCLC). The LiBRA study aimed to explore the role of liquid biopsy in detecting and monitoring BRAF V600E mutation, assessing its potential to predict treatment response and emerging resistance. MATERIALS AND METHODS:This prospective multicenter study enrolled patients with BRAF V600E-mutated NSCLC treated with first-line dabrafenib plus trametinib. Plasma samples were collected at baseline (t0), after 4 weeks (t1), and longitudinally until disease progression (PD). BRAF V600E was monitored by digital droplet PCR (ddPCR). Next-generation sequencing (NGS) was performed at t0 and PD to identify resistance mechanisms. RESULTS:Forty patients were enrolled. Dabrafenib plus trametinib achieved an overall response rate of 42.5%, with a median progression-free survival (PFS) and overall survival (OS) of 8.3 and 21.1 months, respectively. At t0, BRAF V600E was detectable by ddPCR in 24 (62%) of 39 patients. Among 21 shedders evaluated at t1, 17 (81%) cleared the mutation. Higher baseline BRAF V600E allele frequency was associated with shorter PFS (hazard ratio [HR], 1.09, P = .013) and OS (HR, 1.10, P = .010), whereas clearance at t1 correlated with longer PFS (8.3 v 1.4 months, P < .001) and OS (10.5 v 2.2 months, P < .001). Biological PD anticipated radiologic/clinical PD by a median of 4.9 weeks (IQR, 1.4-9.8). Baseline EGFR and MET CNVs were associated with shorter PFS and OS. Resistance mechanisms at PD included NRAS, KRAS, TP53 mutations and MET, EGFR, ERBB2 CNVs. CONCLUSION:The LiBRA study supports liquid biopsy as a prognostic and monitoring tool in BRAF V600E-mutated NSCLC undergoing targeted therapy.

HER2-positive/hormone-receptor-positive breast cancer represents approximately 10% of all breast cancer cases and constitutes a distinct biological entity with unique therapeutic challenges. The complex crosstalk between HER2 and estrogen receptor signaling pathways contributes to both primary and acquired resistance to anti-HER2 therapies, and the convergence of these pathways on cell cycle regulation, particularly through the cyclin D1-CDK4/6-Rb axis, has provided a compelling rationale for combining CDK4/6 inhibitors with anti-HER2 therapy. This scoping review aimed to map preclinical and clinical evidence evaluating combinations of CDK4/6 inhibitors with HER2-targeted therapy in HER2+/HR+ disease. Eligible sources included preclinical models and clinical studies assessing CDK4/6 inhibitor-based combinations with anti-HER2 therapy, identified through searches of PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov. Data were charted and synthesized descriptively according to PRISMA-ScR guidelines. Preclinical studies have demonstrated synergistic antitumor activity when CDK4/6 inhibitors are combined with trastuzumab, pertuzumab, or newer HER2-targeted agents across multiple HER2+ breast cancer models. In the metastatic setting, phase II trials including MonarcHER and PATRICIA II have shown encouraging efficacy signals, while the phase III PATINA trial demonstrated a clinically meaningful 15.2-month progression-free survival benefit with palbociclib plus anti-HER2 therapy and endocrine therapy. In the neoadjuvant setting, trials including NA-PHER2 and MUKDEN-01 demonstrated marked Ki67 suppression and promising pathologic responses, supporting the exploration of chemotherapy de-escalation strategies. Despite these advances, key challenges remain including the identification of predictive biomarkers, optimal treatment sequencing, and the integration of emerging HER2-targeted agents such as trastuzumab deruxtecan. Novel CDK4/6 inhibitors including dalpiciclib and next-generation agents are expanding therapeutic options, while combination strategies incorporating CDK7 inhibition represent future therapeutic frontiers. The evolving landscape of HER2+/HR+ breast cancer treatment increasingly emphasizes precision medicine approaches that leverage cell cycle control mechanisms to overcome resistance and improve patient outcomes across all disease stages.

12040 Background: Exercise (EX) is associated with improved survival, symptom control, and management of treatment-related side effects in patients (pts) with cancer. However, evidence from large, real-world cohorts including unselected pts across different phases of the disease trajectory remains limited. This study aimed to evaluate the feasibility and effectiveness of a tailored EX program implemented in routine clinical practice. Methods: A three-month, bi-weekly supervised EX program was offered to consecutive cancer pts referred at the University Hospital of Verona, regardless of treatment status. The program included moderate-intensity aerobic exercise (10–30 minutes/session) and resistance training (2–3 sets of 8–12 repetitions; six exercises). The primary endpoint was feasibility, assessed by recruitment rate, adherence, and dropout. Secondary endpoints included cardiorespiratory fitness (six-minute walking test, 6MWT), muscular strength (handgrip strength test, HST), waist-hip ratio (WHR), and quality of life (QoL), measured using the EORTC QLQ-C30. Pre- and post-intervention outcomes were analyzed using descriptive statistics and paired Student’s t-tests. Results: A total of 2276pts were recruited (92% recruitment rate) with a median age of 57±12 years. The most frequent tumor types were upper gastrointestinal cancers (34%) and breast cancer (31,8%). 84% of patients were receiving systemic treatments, and 47% had metastatic disease. Overall, 156 pts completed the intervention (dropout rate 31%, mainly due to disease progression), with an adherence rate of 84%. Significant improvements were observed in WHR (−1.2%, p = 0.03), 6MWT (+25 m, p < 0.001), and HST (+1.9 kg, p < 0.01). QoL significantly improved in physical, role, emotional, and social functioning (all p < 0.01), along with reductions in fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, and diarrhea. Global QoL and financial difficulties also significantly improved. Conclusions: In a real-world, unselected cohort of cancer pts across different treatment phases, a tailored EX program is feasible and associated with meaningful improvements in physical function and QoL. These findings support the integration of structured exercise programs into routine oncology care beyond controlled clinical trial settings. Clinical trial information: NCT04226508 .

Antibody-drug conjugates (ADCs) represent a major advance in breast cancer therapy, with trastuzumab deruxtecan and sacituzumab govitecan emerging as leading agents targeting distinct tumor antigens and employing different linker-payload designs. Trastuzumab deruxtecan is a second-generation HER2-directed ADC composed of trastuzumab linked via a cleavable tetrapeptide linker to the camptothecin derivative exatecan, a highly potent topoisomerase I inhibitor. Its high drug-to-antibody ratio (DAR 8:1), membrane-permeable payload, and efficient lysosomal release confer strong antitumor activity, including a robust bystander effect in HER2-low tumors. By contrast, sacituzumab govitecan is a TROP-2-targeted ADC conjugated through a hydrolysable CL2A linker to SN-38, the active metabolite of irinotecan. Sacituzumab govitecan features a high DAR (7.6:1) and allows extracellular as well as intracellular release of SN-38, enhancing bystander killing in tumors with heterogeneous TROP-2 expression, while maintaining a favorable toxicity profile due to the lower intrinsic potency of SN-38 relative to exatecan. Since both these ADCs are conjugated to topoisomerase I inhibitors, concerns about potential cross-resistance regarding their sequencing in clinical practice are being raised, and currently there is a lack of predictive biomarkers providing a rational basis for their sequential administration. Resistance mechanisms exhibit significant heterogeneity: resistance to trastuzumab deruxtecan has been associated with mutations in TOPO I and SLX4, impaired lysosomal function, and efflux via ABC transporters. In contrast, resistance to sacituzumab govitecan is linked to overexpression of multidrug resistance proteins, particularly BCRP-mediated efflux. Clinically, trastuzumab deruxtecan has shown substantial efficacy in both HER2-positive and HER2-low breast cancer, whereas sacituzumab govitecan has demonstrated efficacy across triple-negative and hormone receptor-positive/HER2-negative breast cancers. Collectively, these agents highlight how variations in target antigen, linker chemistry, and payload potency impact ADC activity, therapeutic index, and potential strategies for sequential treatment in advanced breast cancer.

Response Evaluation Criteria In Solid Tumors (RECIST 1.1) and circulating tumor DNA (ctDNA) recapitulate and anticipate response to treatment, respectively. However, ctDNA-RECIST (cRECIST) and ctDNA-guided End of Treatment (cEoT) are not applied routinely. To provide proof-of-concept for RECIST1.1/cRECIST integration, HER2-positive metastatic breast cancer patients (n = 50) were enrolled in the multi-center prospective GIM21 study to receive Trastuzumab-emtansine (T-DM1). CT scans (113 tumor lesions) were longitudinally assessed for classical Objective Responses (ORs: progressive disease/stable disease/partial response/complete response; PD/SD/PR/CR) applying default RECIST 1.1 cut-offs (SD/PD ≥ 20

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality globally. While multi-modal artificial intelligence (AI) models offer significant predictive potential, their translation into routine clinical practice is delayed by the “black box” nature of complex algorithms and the fragmentation of heterogeneous data. We present LANTERN-XGB, a hierarchical machine learning workflow designed to bridge this gap by generating interpretable “digital human avatars” for precision oncology. The methodology employs a multi-stage scalable tree boosting system (XGBoost) architecture utilizing shapley additive explanations (SHAP) for rigorous hierarchical feature selection, missing value management, and patient-specific decision support. The workflow was developed and benchmarked using a retrospective cohort of 437 patients with clinical N0 NSCLC, followed by validation on a prospective dataset (n = 100) and an independent external dataset (n = 100). The pipeline integrates diverse data modalities to predict occult lymph node metastasis (OLM). LANTERN-XGB identified a robust consensus signature driven by non-linear interactions among CT textural fragmentation, PET metabolic heterogeneity, tumor density distribution, and systemic clinical modulators. Exploratory transcriptomic pathway analysis (GSVA) revealed that high-risk predictions strongly correlate with systemic molecular dysregulation, such as the enrichment of immune-inflammatory signaling and metabolic stress pathways. The model achieved robust discrimination in external validation (AUC ≈ 0.77), performing comparably to state-of-the-art nomogram benchmarks. Crucially, the LANTERN-XGB framework demonstrated superior utility in handling diagnostic ambiguity; local force plots allowed for the correct reclassification of “borderline” prediction by visualizing feature interactions that standard linear models fail to capture. LANTERN-XGB provides a validated, open-source framework that successfully balances predictive power with clinical transparency. By empowering clinicians to visualize and verify the logic behind AI predictions, this workflow offers a pragmatic path for integrating reliable multi-modal avatars into daily medical decision-making.

e14538 Background: Circulating monocytes (CM) may acquire immunosuppressive activity (IA) and contribute to resistance to immune checkpoint inhibitors (ICIs), while the ICIs impact on CM function is not fully clarified. We previously reported that ICIs can downregulate cellular FLICE-inhibitory protein (c-FLIP), a mediator of CM IA, in non-progressing non–small cell lung cancer (NSCLC) patients (pts). Methods: Pts with advanced NSCLC treated with first-line ICIs, alone (I) or with chemotherapy (CI), were prospectively enrolled at the University of Verona. Blood samples were collected at baseline (T0) and after 3 months (T1). Pts were classified as responders (R; PFS ≥6 months) or non-responders (NR; PFS < 6 months). CM were isolated and co-cultured with anti-CD3/CD28–activated healthy donor PBMCs to assess IA by flow cytometry. Group comparisons used unpaired t tests (p < 0.05). c-FLIP interactome was analysed by liquid chromatography–mass spectrometry in nuclear and cytoplasmic fractions of FLIP-overexpressing monocytes. RNA-seq libraries were performed with TruSeq RNA Prep Kit v2 and sequenced with NovaSeq 6000. Results: From 2021 to 2025, 80 pts were enrolled: 57 evaluable for CD3⁺ T-cell proliferation at T0, 40 receiving CI (70.2 %) and 17 receiving I (29.8%). Between CI-treated pts, 21 (52.5%) were classified as R and 19 (47.5%) as NR. CM from R pts showed higher IA than NR (p = 0.03). At T1, considering specifically pts receiving CI, CM from R pts showed reduced IA after treatment (p = 0.04), whereas IA increased in NR (p = 0.03). Based on RNA-seq analysis, transcriptional profile of CM from R is affected by CI (T1 vs T0, fdr (padj) < 0.1; up-regulated genes: 587, down-regulated genes: 476). Gene-set enrichment analysis revealed a strong modulation of lipid metabolism (MLXIPL, SPHK1, NR1D1) and biological processes related to cell-differentiation (FOSL2, NR4A1, MAFB). Analysis of nuclear and cytoplasmic c-FLIP interactome identified lactate dehydrogenase A (LDH-A) as a c-FLIP–interacting protein in both compartments. According to TCGA analysis, high LDH-A expression in the tumor microenvironment was associated with worse survival in lung adenocarcinoma (p < 0.0001). Accordingly, in our cohort of CI-treated patients, R had significantly lower baseline LDH levels than NR (p = 0.0071). Conclusions: CI reshapes circulating monocytes in NSCLC, reducing IA and modifying transcriptional profiles associated with CM differentiation in responders. Moreover, LDH levels could serve as an immunologically plausible and easy-to-use tool to select pts. Clinical trial information: 1839CESC.

BACKGROUND:Immune checkpoint inhibitor (ICI) monotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with PD-L1 ≥ 50%; however, up to 30% of patients experience early progression or death, including cases of hyperprogressive disease (HPD). High baseline levels (≥ 30.5%) of circulating CD10- low-density neutrophils (LDNs) have been associated with increased HPD occurrence. Emerging evidence suggests that combining ICI with platinum-based chemotherapy (PCT) may mitigate the risk of HPD. Currently, no prospective studies have addressed HPD prevention in this context. PATIENTS AND METHODS:HYPERBOLIC (NCT07274384) is a phase 2, randomized, open-label, multicenter, international trial evaluating whether adding 3 cycles of PCT to first-line cemiplimab reduces HPD rate in stage IV NSCLC with PD-L1 ≥ 50% and CD10- LDNs (identified by flow cytometry as CD15⁺CD11b⁺ within the PBMC fraction, with immature cells defined by loss of CD10) ≥ 30.5%. Seventy-four patients will be randomized (1:1 ratio) to receive cemiplimab alone or cemiplimab plus 3 PCT cycles, followed by cemiplimab maintenance. Randomization will be stratified by Lung Immune Prognostic Index. The first computed tomography scan at week 7 after treatment start will assess HPD occurrence, defined as RECIST v 1.1. disease progression with a delta tumor growth rate (ΔTGR) ≥ 50% and/or TGR ratio ≥ 2. The primary endpoint will be the combined rate of HPD and early death (death within 12 weeks with no radiological evaluation). Secondary endpoints will be HPD rate according to alternative definitions, overall survival, progression free survival, objective response rate, and safety. An extensive translational research platform will include spatial transcriptomics of tumor tissue, single-cell RNA sequencing of PBMCs, circulating-free DNA and plasma factors profiling, and saliva/stool microbiome genomics and metabolomics, to longitudinally explore tumor-host dynamic interactions during treatment. CONCLUSION:to our knowledge, HYPERBOLIC is the first prospective, biomarker-driven trial investigating early treatment escalation based on HPD risk in PD-L1-high NSCLC.

Abstract Background: Taletrectinib is a next-generation, CNS-active, selective ROS1 TKI approved by the US FDA for the treatment of patients (pts) with locally advanced/metastatic ROS1+ NSCLC. In two Phase 2 studies, TRUST-I (NCT04395677) and TRUST-II (NCT04919811), taletrectinib showed robust efficacy, including intracranial (IC) activity and efficacy against G2032R mutations, and a tolerable safety profile in TKI-naïve and TKI-pretreated pts with ROS1+ NSCLC (Pérol M, et al. J Clin Oncol 2025). Here we report updated data in TKI-pretreated pts with ∼3 years of follow-up. Methods: The study designs of TRUST-I and TRUST-II have been previously reported (Pérol M, et al. J Clin Oncol 2025). The efficacy population included pts from TRUST-I and TRUST-II with ≥1 measurable baseline lesion per RECIST v1.1 by independent review committee. The safety population included pts with ROS1+ NSCLC from Phase 1 and 2 studies who received ≥1 dose of taletrectinib 600 mg once daily. Results: As of Aug 31, 2025, the pooled efficacy analysis included 113 TKI-pretreated pts (66 from TRUST-I [prior crizotinib]; 47 from TRUST-II [37 prior crizotinib, 10 prior entrectinib]). With a median (m) follow-up of 35.8 months (mo), confirmed ORR was 55.8% (95% CI 46.1-65.1), mDOR was 16.6 mo (95% CI 10.7-24.9), mPFS was 9.7 mo (95% CI 7.6-12.0), and mOS was 29.8 mo (95% CI 23.2-46.0). Responses were observed in pts with G2032R mutations (8/13; ORR 61.5% [95% CI 31.6-86.1]) and with CNS metastases (IC-ORR 65.6% [95% CI 46.8-81.4]). Data by trial are shown in the Table. Safety was similar between TKI-pretreated pts and the safety population (n=363). Conclusion: With longer follow-up, taletrectinib maintained durable responses in TKI-pretreated pts, including activity against CNS metastases and G2032R mutations, with a tolerable safety profile. These data support taletrectinib as an effective and tolerable treatment option for pts with ROS1+ NSCLC after prior TKI therapy. Citation Format: Geoffrey Liu, Jorge Nieva, Lyudmila Bazhenova, Chang-Min Choi, Qitao Yu, Shunichi Sugawara, Noriko Yanagitani, Filippo de Braud, Huijie Fan, Enriqueta Felip, Emilio Bria, Maurice Pérol, Feiwu Ran, Wei Wang, Xianyu Zhang, Michael Chen, Caicun Zhou. Taletrectinib in tyrosine kinase inhibitor (TKI)-pretreated patients with ROS1+ non-small cell lung cancer (NSCLC): Updated data from TRUST-I and TRUST-II [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT244.

e12673 Background: The role of neoadjuvant chemotherapy (NACT) in stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer remains controversial due to low pathological complete response (pCR) rates. Recent evidence from the NATALEE trial subgroup analysis presented at San Gallen 2025 identified prior NACT as an independent negative prognostic factor for invasive disease-free survival (iDFS) in HR+/HER2- early breast cancer, raising concerns about the optimal sequencing of systemic therapy in this population. Whether NACT or adjuvant chemotherapy (ACT) provides better survival outcomes in HR+/HER2- breast cancer is an ongoing debate with significant clinical implications. Methods: Six hundred fifty-five patients (pts) with HR+/HER2- locally advanced breast cancer at stage II-III undergoing NACT (429 pts) or ACT (226 pts) between 2005 and 2021 were identified from Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome. Propensity score matching (PSM) was employed to create cohorts with balanced baseline characteristics across different categories (age, menopausal status, grading, stage, Ki67, ER, PgR, HER2). The efficacy of NACT and ACT in terms of overall survival (OS) and real-world invasive disease-free survival (rwiDFS) was evaluated using Kaplan-Meier analysis and the Cox proportional hazards model. Results: Using PSM, a total of 432 pts was ultimately included in the study (216 vs 216). OS was significantly longer for ACT versus NACT (NR vs 229 months mOS, 96.8% vs 90.6% survival rate at 5 years, HR 0.58, 95% CI 0.36-0.95, p = 0.03). The rwiDFS was longer for ACT versus NACT (NR vs 135 months, 91.6% vs 74.8% survival rate at 5 years, HR 0.63, 95% CI 0.43-0.92, p = 0.017). Patients who underwent ACT had significantly better OS compared to those who did not achieve pCR after NACT (HR 0.56, 95% CI 0.38-0.82, p = 0.016), while no significant difference was observed compared to patients who achieved pCR after NACT (HR 1.81, 95% CI 0.9-3.6, p = NS). Conclusions: In stage II-III HR+/HER2- breast cancer, NACT was associated with inferior OS and rwiDFS compared to ACT, consistent with NATALEE trial findings identifying NACT as an adverse prognostic factor. NACT should be reserved for selected cases requiring downstaging. While neoadjuvant CDK4/6 inhibitors have shown limited efficacy in replacing chemotherapy, emerging oral SERDs and PROTACs may improve pCR rates and bridge the efficacy gap in this subtype.

BACKGROUND:In hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC), the prognostic significance of estrogen receptor (ER), progesterone receptor (PgR), and HER2 immunohistochemical expression levels in patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) remains unclear. The CYCLHER study was designed to evaluate treatment outcomes and identify biologically driven prognostic factors. METHODS:CYCLHER (NCT06243432) is a retrospective, multicenter study conducted across 16 Italian oncology centers. Patients with HR+/HER2- mBC who received first-line endocrine therapy (ET) plus CDK4/6i between November 2016 and May 2023 were included. ER, PgR and HER2 status were assessed on metastatic or primary tumor samples. The primary endpoint was real-world progression-free survival (rwPFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and attrition rate. Optimal cut-off values for ER and PgR expression were determined using Cut-off Finder v1.0. RESULTS:Among 597 eligible patients, median rwPFS was 28.1 months at a median follow-up of 41 months. HER2-low status emerged as a negative prognostic factor, being independently associated with shorter rwPFS compared to HER2-0 (p = 0.02). ER ≥ 87% and PgR ≥60% were associated with improved rwPFS, DCR, and 5-year OS rates. A prognostic score derived from the three biomarkers identified four groups with significantly different rwPFS outcomes (global log-rank p < 0.0001). The first-to-second line attrition rate was 16.2% (95% CI 12.4-20.0). The identified biomarkers did not significantly impact treatment outcomes in the second-line setting. CONCLUSIONS:CYCLHER confirms the prognostic relevance of ER, PgR, and HER2 expression in patients with HR+/HER2-mBC treated with CDK4/6i. HER2-low status was associated with poorer outcomes, supporting its potential role as a negative prognostic marker. The proposed score may facilitate personalized treatment strategies and enhance risk stratification in clinical practice.

Background/Objectives: Alterations of the phosphatidylinositol 3-kinase catalytic subunit alpha gene (PIK3CA) are identified in approximately 2-4% of non-small cell lung cancer (NSCLC) cases; however, their biological and clinical relevance in NSCLC remains incompletely understood. This study aimed to comprehensively characterize the clinical and molecular features, as well as outcomes, of patients with PIK3CA-altered NSCLC across different disease stages. Methods: We conducted a retrospective multicenter analysis of 62 patients with histologically confirmed early-stage or advanced NSCLC-harboring PIK3CA alterations (mutations and/or gene amplifications) treated between 2015 and 2022 at three Italian institutions. Demographic, clinical, pathological, and molecular variables were systematically collected and analyzed. Results: PIK3CA mutations accounted for the majority of alterations (90.3%), while amplifications represented 9.7%. The most frequent mutations involved exon 9 (66.1%), predominantly E545K and E542K, followed by exon 20 (16.1%). Most patients were current or former smokers, and concomitant oncogenic alterations were detected in 59.7% of cases, most commonly KRAS mutations. A history of prior malignancy was reported in 24.6% of cases. In the metastatic setting, adenocarcinoma histology was associated with significantly longer overall survival (OS) compared with non-adenocarcinoma histologies (18.4 vs. 5.5 months; p = 0.02). Patients with PD-L1-negative tumors demonstrated a numerically longer OS than those with PD-L1-positive tumors; however, this difference did not reach statistical significance (19.1 vs. 5.4 months; p = 0.05). No statistically significant survival differences were observed according to specific PIK3CA mutation subtypes or treatment strategies. Conclusions: PIK3CA-altered NSCLC represents a molecularly heterogeneous and clinically understudied subgroup, frequently characterized by co-occurring oncogenic alterations. In this study, no definitive prognostic or predictive role for PIK3CA alterations could be established. Nevertheless, these findings provide a descriptive real-world characterization of this molecular subset and support the need for validation in larger, prospectively designed, molecularly stratified studies.

BackgroundFollowing the ADAURA study results, showing that adjuvant osimertinib was associated with significant improvement in disease-free survival among patients with stage IB-IIIA epidermal growth factor receptor mutation positive (EGFRm+) non-small cell lung carcinoma (NSCLC), an Early Access Program (EAP) was activated in Italy to provide preapproval access to osimertinib.MethodsThe ELBA observational retrospective cohort study aims to describe the characteristics, diagnostic workup, mutation testing, and treatment patterns of the patients included in the ADAURA EAP. The retrospective observation period was from the day of the first procedure leading to the pathological diagnosis of NSCLC (index date) to osimertinib initiation and data were obtained from medical records or other original documents available at the sites.ResultsOverall, 71 patients were evaluable, mainly females (73.2%), with mean (SD) age of 67.5 (8.7) years. Age-adjusted Charlson Comorbidity Index scored 2 or 3 for 74.7% of patients without considering lung cancer. Forty-six (66.7%) out of 69 evaluable patients with available data were discussed at the multi-disciplinary team meeting. The median (25th-75th percentiles) time from the initial diagnostic suspicion to the index date was 52.0 (30.0-67.0) days and from index date to EGFR test prescription 20.0 (0.0-42.0) days. Among patients with available data (N = 69), the tests were mostly single-gene polymerase chain reaction mutation-specific test (63.8%) and next-generation sequencing (33.3%). Primary tumor surgery was mostly lobectomy (n/N=63/71, 88.7%). Pathological staging was IB for 21.1% of patients, II for 43.7% and III for 35.2%. Adjuvant chemotherapy prior to osimertinib was administered in 32.4% of patients. Osimertinib was started after a median (25th-75th percentiles) time from tumor resection of 2.9 (2.1-4.9) months.ConclusionsThe ELBA Study showed an evolving landscape in biomarker-driven and molecular targeted therapies in early-stage NSCLC management towards the integration of mutational testing into clinical practice, with a growing focus on an optimal definition of adjuvant treatment.

12100 Background: Patients with cancer frequently experience psychological impairments, including anxiety, depression, and emotional distress, which may significantly affect quality of life and overall well-being. Third-generation cognitive-behavioral interventions such as Mindfulness-Based Cognitive Therapy-Cancer (MBCT-Ca), Acceptance and Commitment Therapy (ACT) and Compassion Focused Therapy (CFT) have shown potential benefits in reducing psychological burden, although evidence of their efficacy remains limited. This study aimed to evaluate the efficacy of a structured third-generation cognitive behavioral therapy (CBT) intervention in reducing psychological symptoms in patients (pts) with cancer undergoing active cancer treatment. Methods: A third-generation CBT intervention was delivered twice a month. The eight individual 45-minute sessions included psychoeducation, behavioral activation, relaxation and breathing techniques, present-moment awareness, self-compassion, problem-solving, and assertiveness training. Psychological outcomes were assessed using the Hospital Anxiety and Depression Scale (HADS) and Distress Thermometer (DT) at baseline (T0) and post- psychological intervention (T1). Descriptive statistics, Student t-test and Chi-square test were performed. Results: Overall 341 pts were recruited. The mean age was 65.8 years ( SD = 11.80); 60% (n = 204) were women. Most patients were married or partnered 82% (n = 279). Regarding education level, 65% (n = 221) had higher education, 29% (n = 100) secondary education, and 6% (n = 20) primary education.. At baseline psychological assessment, 4.4% of patients (n = 15) had early-stage disease (stage I–II), 50.7% (n = 173) had locally advanced disease (stage III), and 44.9% (n = 153) had advanced-stage disease (stage IV). The most represented cancer sites were gastrointestinal cancer 55.7% (n = 190), followed by lung 11.7% (n = 41) and breast cancer 10.6% (n = 36). Chemotherapy was the most frequently administrated treatment 74% (n = 254), followed by targeted therapy 10% (n = 35) and immunotherapy 10% (n = 34). At T0, clinically significant levels of anxiety, depression, and distress were reported in 33.2%, 31.3%, and 86,9% of patients, respectively. A total of 313 patients completed the intervention (dropout rate 8.2%, mainly due to disease progression), resulting in an adherence rate of 91.8%. At three-months follow up (T1), significant reductions in clinically relevant symptoms were observed for anxiety (-24.6%, p < 0.001), depression (-24.0%, p < 0.001), and distress (-30.0%, p < 0.001). Conclusions: These findings support the routine use of validated psychological screening tools in oncology and highlight the clinical value of structured CBT-based psycho-oncological interventions delivered by trained professionals to improve psychological well-being in patients with cancer.

Introduction: Lung cancer, the leading cause of cancer-related mortality worldwide, is a heterogeneous malignancy comprising distinct histological and molecular subtypes, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases and adenocarcinoma (ADC) representing the most prevalent histotype. An emerging pathological feature of NSCLC, spread through air spaces (STAS)-defined as the extension of tumor cells into the lung parenchyma beyond the main tumor margin-has been associated with worse disease-free and overall survival and has been proposed as a possible predictor of recurrence to guide surgical extent. Concurrently, recent comprehensive genomic profiling of early-stage NSCLC has highlighted the need to interpret multi-omics data and their relationship with pathological variables, including IASLC histological subtypes, to better personalize treatment strategies. In this context, we investigated the overall distribution of STAS and its association with tumor mutational profiles and IASLC histological subtypes in a large real-world cohort of lung adenocarcinoma patients from the LANTERN project. Materials and Methods: In a prospective, multicenter observational study (March 2023-December 2024), 271 NSCLC patients were enrolled, and clinicopathological, immunohistochemical, and genomic data were collected; comprehensive genomic profiling was performed using the TruSight Oncology 500 assay to analyze 523 cancer-related genes, tumor mutational burden (TMB), and microsatellite instability; and STAS was assessed according to IASLC criteria. Adenocarcinoma accounted for roughly 90% of the cases, with a median age of 69 years and a predominance of stage IV disease (49.5%). STAS was evaluable in 162 cases and was detected in 17.9% of tumors. Results: STAS-positive tumors showed a higher trend towards locally advanced and advanced disease; no differences were observed in sex, age, smoking status, tumor mutational burden, or PD-L1 expression. Additionally, STAS-positive tumors showed a higher association with micropapillary, mucinous, and papillary patterns, whereas the acinar pattern was more frequent in STAS-negative tumors. The most frequently mutated genes were TP53, KRAS, EGFR, and STK11, with no significant differences between groups; ROS1 alterations were absent in STAS-negative tumors but detected more frequently in STAS-positive cases. Conclusions: Overall, these findings indicate that STAS positivity is associated with high-risk histological subtypes and advanced disease, suggesting its importance as a marker of tumor aggressiveness and emphasizing the need for its systematic evaluation in lung adenocarcinoma to better guide surgical planning and patient risk assessment.