Background Hepatocellular carcinoma (HCC) is the most common form of liver cancer and a major cause of cancer-related deaths worldwide. Despite the wealth of genomics data, treatment and prognosis are still dependent on clinical and pathological factors. The molecular heterogeneity characterizing HCC is denoted by the different etiology and the related array of signaling pathways involved in tumor initiation and progression. Aberrant activation of the Wnt/β-catenin pathway is among the most frequent alterations in HCC, and stems from somatic mutations, functional over-activity of the transcription machinery and epigenetic cues. Methods Targeted DNA and RNA sequencing were combined to investigate the Wnt/β-catenin pathway and the effects of its dysregulation in the TCGA HCC cohort. For external validation, an independent cohort of78 Caucasian patients affected by HCC was used. Results We have identified a Wnt/β-catenin-related transcriptional signature denoting pathway activity regardless of the presence of pathway-related activating mutations. This model predicts survival outcomes in two independent cohorts of HCC patients (TCGA cohort, N = 177; Rome cohort, N78) and is associated with distinctive immunogenomic features. Conclusions A non-genetic state recapitulating the transcriptional footprint associated with CTNNB1 mutation identifies wild-type HCCs characterized by unfavorable survival outcomes and immune-excluded tumor immune microenvironment.

BACKGROUND:Preclinical evidence suggests that BRCA1/2-mutated tumors may rely on RANKL signaling for survival and proliferation. RANKL inhibition with denosumab could disrupt tumor-bone microenvironment crosstalk and potentially limit metastatic progression. We evaluated the association between denosumab and real-world progression-free survival (rwPFS) in germline BRCA1/2-mutated hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) with bone metastases. METHODS:We performed a retrospective, multicenter study across 24 Italian hospitals including HR+/HER2- bone mBC patients treated in first- or second-line with a CDK4/6 inhibitor plus endocrine therapy. rwPFS was estimated by Kaplan-Meier and compared with log-rank tests. Center-stratified multivariable Cox models adjusted for clinically relevant covariates were used to assess the association between denosumab exposure and rwPFS. Effect modification by BRCA status was evaluated using a denosumab×BRCA1/2 mutation status. RESULTS:Among 1399 patients, 46 harbored germline BRCA1/2 mutations (13 BRCA1, 33 BRCA2), and 21 of these patients received denosumab. Among patients not receiving denosumab, BRCA1/2-wild-type/unknown patients had better rwPFS than BRCA1/2-mutated patients (median 28 vs 13 months; hazard ratio (HR) 0.48, 95% CI 0.32-0.73; p = 0.001). Among BRCA1/2-wild-type/unknown patients, denosumab use did not affect rwPFS (HR 0.98, 95% CI 0.85-1.12). Conversely, denosumab use was associated with longer rwPFS among patients with BRCA1/2 mutations (median 35 months, 95% CI 24-NR vs 13 months, 95% CI 9-27; HR 0.34, 95% CI 0.16-0.74; p = 0.006), with no significant difference between BRCA1 and BRCA2-mutated subgroups. Multivariable analysis confirmed the rwPFS benefit of denosumab in BRCA1/2-mutated patients (adjusted HR 0.45, 95% CI 0.21-0.99; p = 0.048). CONCLUSION:In this real-world cohort, denosumab use was associated with longer rwPFS in germline BRCA1/2-mutated HR+/HER2- mBC with bone metastases.

Platinum-containing neoadjuvant chemotherapy increases pathological complete response (pCR) rates in triple-negative breast cancer (TNBC), but predictive biomarkers remain incompletely defined. In the multicenter NeoCarbo cohort, we assessed a carboplatin-containing neoadjuvant regimen and examined whether germline homologous recombination deficiency (HRD) and baseline tumor DNA damage response (DDR) activation predict pCR and outcomes. Stage I-III TNBC patients at three centers received carboplatin (AUC6 q3w×4) plus weekly paclitaxel (×12), followed by dose-dense epirubicin/cyclophosphamide (q2w×4) and surgery. The primary endpoint was pCR (ypT0/is ypN0); secondary endpoints were disease-free survival (DFS) and overall survival (OS). Germline HRD was defined by pathogenic/likely pathogenic variants in BRCA1/2 and other homologous recombination genes, and DDR activation was assessed centrally by phospho-DDR immunohistochemistry. Among 128 patients, pCR occurred in 77 (60.2%; 95% CI 51.1-68.7%). HRD status was available in 80 patients (28 HRD-positive), with pCR rates of 78.6% in HRD-positive versus 57.7% in HRD-negative tumors (Fisher p = 0.086). In a bivariable analysis restricted to patients with complete biomarker data, HRD positivity independently predicted pCR (adjusted OR 2.68; 95% CI 1.16-6.85; p = 0.027), whereas DDR tertiles were not independently associated with pCR. At a median follow-up of 60.4 months, pCR was associated with improved DFS (HR 0.29; 95% CI 0.12-0.72; p = 0.008) and OS (HR 0.30; 95% CI 0.12-0.81; p = 0.017). Grade ≥3 toxicity occurred in 14.4% during carboplatin-paclitaxel and 18.9% during epirubicin-cyclophosphamide, predominantly hematologic. These findings support high pCR rates with this regimen and suggest that HRD may identify patients more likely to achieve pCR, whereas baseline tumor phospho-DDR lacked predictive value; future evaluation may require dynamic DDR assessment in larger studies.

BACKGROUND:Bone-only HR+/HER2 - metastatic breast cancer generally has a favourable prognosis, but some patients develop visceral metastases. We aimed to quantify visceral conversion and identify reproducible baseline correlates during CDK4/6 inhibitor (CDK4/6i) therapy. METHODS:This multicentre retrospective cohort included 692 patients treated with palbociclib, ribociclib, or abemaciclib plus endocrine therapy as first- or second-line treatment across 24 Italian centres. Visceral conversion was analysed in a competing-risks framework, with skeletal progression or death without prior visceral conversion as competing events. Eighteen baseline candidate predictors derived from a 35-variable dataset were evaluated using Fine-Gray modelling, ridge penalisation, bootstrap stability assessment, and cause-specific Cox sensitivity analyses. RESULTS:Over a median follow-up of 31 months, 162 patients (23.4%) developed visceral conversion after a median of 17.0 months. Cumulative incidence was 8.8%, 17.5%, and 24.5% at 12, 24, and 36 months, respectively; median overall survival after visceral conversion was 18.0 months. Progesterone receptor (PR) expression was the most stable tumour-biological correlate, with complete sign concordance and a median absolute coefficient rank of 1 across 500 bootstrap resamples. In the mutually adjusted Fine-Gray model, higher PR expression was associated with lower visceral-conversion risk (sHR per 10-percentage-point increase, 0.929; 95% CI, 0.889-0.971; p = 0.0012), with consistent direction across complementary analyses. However, stand-alone PR prediction remained modest (24-month IPCW AUC, 0.585; Brier score, 0.142; IPA, 1.1%; O:E, 1.00), limiting individual-level clinical utility. CONCLUSIONS:Broad baseline-variable profiling identified PR expression as the most reproducible tumour-biological correlate of visceral conversion, although its stand-alone predictive performance was modest.

Breast cancer, the most frequently diagnosed cancer in women globally, is a heterogeneous disease with distinct subtypes requiring distinct therapeutic approaches. Regardless of molecular subtyping, breast cancer stem cells significantly contribute to tumor heterogeneity, distant dissemination, and therapeutic resistance. The Hippo pathway is a key regulator of organogenesis and tissue development, and its deregulation is common in breast cancer and linked to cancer stem cell features across several cancer types. Dysfunctional pathway activity leads to the aberrant activation of Hippo downstream effectors, the Yes‐associated protein (YAP) and its paralog transcriptional co‐activator with PDZ‐binding motif (TAZ), which promote epithelial‐to‐mesenchymal transition, growth factor‐independent proliferation, and maintenance of the breast cancer stem cells' niche. This review summarizes the regulation of the Hippo pathway, emphasizing its significant role in coordinating stemness‐related mechanisms in breast cancer. An overview of how the Hippo pathway fuels stemness in triple‐negative breast cancer, the most aggressive BC subtype, is then provided. We also discuss how the activation of stem cell‐like properties, driven by dysregulation of the Hippo pathway, contributes to the development of resistance to current therapies across the spectrum of breast cancer subtypes.

BACKGROUND:The introduction of CDK4/6 inhibitors (CDK4/6i) has improved outcomes in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (mBC), including in patients with bone metastases. Assessing their comparative effectiveness in real-world settings is crucial. METHODS:This retrospective, multicenter cohort study (January 2019-December 2023; median follow-up 39 months) evaluated the real-world progression-free survival (rwPFS) of abemaciclib, ribociclib, and palbociclib combined with endocrine therapy (ET) in HR+/HER2- mBC patients with bone metastases. Overall survival (OS) was a secondary exploratory endpoint. A total of 1399 patients with ECOG PS 0-1 and at least 12 months of follow-up were included. Analyses used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) to adjust for confounding. RESULTS:Palbociclib showed shorter rwPFS (22 months) compared to abemaciclib (32 months; HR = 1.47, p = 0.001) and ribociclib (35 months; HR = 1.49, p < 0.001). No significant difference was observed between abemaciclib and ribociclib. OS was also lower with palbociclib (47 months) versus abemaciclib (60 months; HR = 1.77, p < 0.001) and ribociclib (64 months; HR = 1.69, p = 0.001). Results were consistent after PSM and IPTW adjustment. CONCLUSION:Ribociclib and abemaciclib may provide superior rwPFS and OS compared to palbociclib in HR+/HER2- mBC patients with bone metastases.

Background: In high risk early triple negative breast cancer (TNBC), the integration of pembrolizumab into chemotherapy regimens has enhanced clinical outcomes in neadjuvant setting. However, there is a paucity of data regarding its efficacy in routine clinical settings, and the therapeutic response in germline mutation carriers remains inconclusive. This retrospective study aims to describe outcomes and safety in patients (pts) with early TNBC who received neoadjuvant pembrolizumab in a real-world context. Methods: Clinical, pathological and germaline evaluation data of patients with early TNBC treated with neoadjuvant chemio/immunotherapy were retrospective collected from 10 italian referral hospitals. CTCAE v5 guidelines were used for toxicity grading. Logistic regression assessed the effect of clinical variables on AEs and response, adjusting for covariates. Results: One hundred twenty one (121) patients (pts) were included, with a median age of 50 years (26-79). Body mass index (BMI) was <18.5 in 3 pts, from 18.5 to 24.9 in 75, 25-29.9 in 21, >30 in 17 and not available (NA)in 4, respectively. 74 pts had stage II TNBC and 47 stage III. G3 disease was reported in 93 pts, G2 in 18 and not known in 10, respectively. Nodal status was N0 in 59 pts, N1-N2 in 59, and NA in 3 pts. Overall, 19% of pts fell into clinical T2 or higher TNBC (n=24). G3 or greater AEs in the combined phases were experienced by 28% of pts (n=35) and AEs led to discontinuation in 12% of cases (n=15). 74/121 pts received up to 8 Pembrolizumab cycles. Germline alterations were detected in 26 pts (21%). Among them, 19 patients presented BRCA1/2 germline mutations, while 7 pts showed other than-BRCA germline alterations (1 PALB2, 1 MRE11, 1 RAD51, 1 TINF2, 1 FANCD2, 1 ATM and 1 BRIP1, respectively). Globally 94/121 patients received surgery and, of them, 56 achieved pCR (60%). In germline mutated subgroup, pCR rate was 80% (n=20/25). In the pts population that received surgery, the presence of germline mutations was significantly associated with higher probability of pCR (OR 3.6, p=0.01). At multivariate analysis, correlation between pCR and germline alterations was confirmed (p=0.02). No significant association was found between pCR and toxicity and other variables [stage, nodal status, grading, BMI class, treatment discontinuation and pembrolizumab cycles number (p>0.05)]. Conclusions: Efficacy of neoadjuvant pembrolizumab plus chemotherapy was confirmed in our Italian real-world population. Toxicity and discontinuation rate were comparable with that previously reported. Carrier pts with germline alterations, both BRCA1/2 and other than-BRCA1/2, showed a significant higher pCR rate when compared to wild type population. Citation Format: Andrea Botticelli, Simona Pisegna, Simone Scagnoli, Armando Orlandi, Daniele Alesini, Giuliana D'Auria, Domenico Bilancia, Marianna Giampaglia, Francesco Pantano, Ilaria Portarena, Matteo Vergati, Patrizia Vici, Agnese Fabbri, Federica Mazzuca, Francesca Salvatori, Giorgia Arcuri, Carla Maria Gullotta, Francesca Sofia Di Lisa, Denise Drittone, Paolo Sciattella, Alessandra Fabi. IMPACT OF GERMLINE MUTATIONS ON pCR IN TRIPLE NEGATIVE BREAST CANCER PATIENTS TREATED WITH PEMBROLIZUMAB PLUS CHEMOTHERAPY: THE TIGER STUDY [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-11-29.

Introduction:Evaluation of every breast cancer (BC) patient by multidisciplinary team and application of guidelines are very important to ensure the best treatment and achieve the best outcome. Methods:The multicenter prospective observational BRIDE study enrolled, from 01/2018 to 02/2021, 1633 BC patients from 19 Italian cancer centers. To evaluate the clinical and biopathological characteristics of BC patients with pathological stage I-II-III treated with surgery followed by adjuvant systemic therapy, type of therapies delivered, outcome and adherence to guidelines, an analysis of 1123 patients out of 1633 patients enrolled in BRIDE study was conducted. Results:The 1123 patients with stage I-II-III BC had a median age of 61.2 years (Q1-Q3: 50.6-71.7); 70.2% were postmenopausal, 92.1% had ECOG PS 0, 68.4% pT1 disease, 70.7% pN0, 91.7% pathological stage I-II; 68.9% underwent conservative breast surgery and 79.8% sentinel lymph node biopsy alone. According to phenotypic subgroup, 80.6% of patients had a HER2-negative/HR-positive, 10.4% HER2-positive/HR-positive, 6.4% triple negative and 2.6% HER2-positive/HR-negative BC. In clinical practice, the phenotypic tumoral subgroup influenced oncologists in the choice of the type of adjuvant systemic therapy (p<0.0001) according to ESMO and AIOM Guidelines. Adjuvant radiotherapy was administered to 85.5% patients undergoing breast-conserving surgery. At the median follow up of 41.4 months (Q1: 35.3 months - Q3: 57.9 months), the DFS at 48 months was 92.8%, with different rates in the phenotypic subgroups. The adherence to AIOM Guidelines in clinical practice was ≥ 70% for the four evaluated quality indicators of treatment process. Discussion:In patients with pathological stage I-II-III BC, the phenotypic subgroup influenced the oncologists' decision on the choice of type of adjuvant systemic therapy, as also indicated by international and national guidelines. In our patients, the DFS rate at 24 and 48 months after surgery was 95.4% and 92.8% respectively. The adherence to the AIOM Guidelines in clinical practice was high but having both quality indicators (shared at international and national level) to evaluate the quality of care in BC and standardized threshold levels to evaluate adherence to guidelines is very important today because this type of evaluation will increase in the coming years.

Background: mTNBC is an aggressive subtype of breast cancer with poor prognosis, so treatment primarily aims to prolong patients (pts) survival and improve their quality of life. SG is a new antibody-drug conjugate that incorporates the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 (TOP1) inhibitor payload, that increased overall survival (OS) in pretreated mTNBC. Based on the results of ASCENT pivotal study, SG was approved in Italy since August 2022 for mTNBC pts, pretreated with at least 2 previous lines of chemotherapy. To date, very fragmentary real-world data are available. In order to study safety and efficacy of SG outside of a registrative trial, the SARELIFE study was designed. Patients and Methods: This is an observational, retrospective and prospective study, whose primary objective was to evaluate the safety of SG in a real-world population. The secondary objectives included: treatment adherence, safety of concomitant radiation therapy (RT) and drug-drug interactions (DDI), response rate according to RECIST v1.1 criteria, progression free survival (PFS) and OS. Treatment-related adverse events (AEs) were categorized and graded according to NCI-CTCAE v5.0. Data were analysed for safety, activity and survival outcomes, and the results were reported using descriptive statistics. Results: Since August 2023 to July 2024, 121 women were enrolled from 27 Italian centres. Median age was 59 years (range: 31-86). PS (ECOG) was 0-1 in 89.7% of pts; 12% had ≥ 2 comorbidities; 10.4% of pts were gBRCAmut carriers; 23.1% were metastatic at the diagnosis. Visceral metastases (mts) were present in 62.6% of pts, the commonest metastatic site was lung (40.9%), 12.2% had brain mts. Median number of prior treatment lines was 2 (range: 0-8): 29.3% of pts had received >2 prior lines of therapy, 26.7% had been treated with immunotherapy and 9.5% with PARP inhibitors. For the safety analysis, 116 pts were considered: 68.1% experienced at least one AE of any grade. The most frequent were: neutropenia (51.9%, G3/G4: 24.1%), fatigue (45.6%, G3/G4: 3.8%), nausea (44.3%), diarrhoea (32.9%, G3: 5.1%), anaemia (27.8%, G3: 6.3%) and febrile neutropenia (6.3%, G4: 3.8%). 1 case of G3 pneumonitis was recorded. No G5 AEs observed. Median time to the onset of the first AE is 21 days. Dose reductions were needed for 43 pts. Median time to first dose reduction: 39 days (range 7 -161). 4 pts discontinued SG due to toxicities. UGT1A1 status was evaluated in 18 pts: 4 were (*28/*28), 6 were (*1/*28). In the (*28/*28) group only 1 case of G3 anaemia was reported. Interestingly, 21 pts received RT during SG treatment, including 10 concurrent treatments, but no additional AEs occurred. Data analyses on DDI are still ongoing. With a median follow-up of 11.5 months, the median PFS was 5.9 months (95%CI: 4.5-6.8), while the median OS was 14.1 months (95%CI: 11-16.3) these data were consistent with those reported in the ASCENT study (mPFS: 5.6 months; mOS: 12.1 months). Best response was evaluable in 95 pts: 25.2% obtained partial response (PR), 1% complete response (CR), 40% stable disease (SD) and 31.5% progression disease (PD). Conclusions: SARELIFE offers an interesting overview on the performance of SG in an unselected real-world mTNBC population. Of note, in our study was included also a small percentage of pts with PS (ECOG): 2, excluded in the ASCENT trial. No new safety signals were reported. Survival outcomes are surprisingly good. Concomitant RT appears safe, although few pts underwent to both treatments. Citation Format: Elena Florio, Giovanna Catania, Elisa Gallerani, Giuliana D'Auria, Paola Tagliabue, Andrea Botticelli, Rita Chiari, Federica Villa, Alessandra Chirco, Monica Giordano, Mirco Pistelli, Francesco Verderame, Annalisa Bramati, Agnese Latorre, Simonetta Chiara Stani, Patrizia Vici, Icro Meattini, Beatrice Tedesco, Azzurra Irelli, Serena Madaro, Giusy Ricciardi, Laura Roazzi, Luigi Rossi, Luigia Stefania Stucci, Sara Zanelli, Barbara Tagliaferri, Lorenzo Ruggieri, Ottavia Amato, Anna Gambaro, Davide Dalu, Alessio Midali, Francesca Galli, Eliana Rulli, Nicla La Verde. SARELIFE study: Safety and efficacy of Sacituzumab Govitecan (SG) in pretreated metastatic triple negative breast cancer (mTNBC): a multicentric, real-life study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-12-07.

A comparative analysis of Denosumab (DMAB) and Zoledronic Acid (ZA) was conducted in a real-world cohort of 864 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer with bone metastases, who were undergoing CDK4/6 inhibitors plus endocrine therapy. We evaluated the time to first skeletal-related events (SREs), progression-free survival (PFS), and overall survival (OS). To adjust for confounding variables, we utilized propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) methodologies. In the unadjusted cohort, ZA was associated with a longer time to first SRE compared to DMAB (HR = 0.77, 95 % CI: 0.61-0.98, p = 0.031). Similar results were obtained in both the PSM (HR = 0.69, 95 % CI: 0.52-0.92, p = 0.011) and IPTW cohorts (HR = 0.74, 95 % CI: 0.63-0.87, p < 0.001), with ZA-treated patients showing an extended time to first SRE compared to those treated with DMAB. No differences in PFS and OS were observed between the two cohorts.

Early breast cancer (EBC) treatment has evolved from radical surgery to a multidisciplinary approach, integrating radiotherapy, chemotherapy, targeted therapy, and hormone therapy with surgery to ensure the best possible outcome. Despite these advancements, hormone receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2-Negative (HER2−) EBC still faces high recurrence rates after endocrine therapy. A panel of oncologists from Central-Southern Italy discussed the profile of ribociclib as an adjuvant therapy, based on the results of the NATALEE study, focusing on efficacy, safety, patient profiles, and regional challenges in treatment access. The experts identified ribociclib as suitable adjuvant treatment for stage II and III HR+/HER2− EBC patients, including those without lymph node involvement but with biologically aggressive disease. In their view, ribociclib could be an interesting option for patients not eligible for chemotherapy due to contraindications. Key challenges in translating the evidence on ribociclib in EBC into clinical practice include treatment duration, patient follow-up, and adverse events management. Strategies to address these challenges range from telemedicine and support from local clinics to tailored communication to improve adherence. Ribociclib is expected to significantly impact adjuvant treatment for HR+/HER2− EBC by addressing broader patient needs and potentially improving long-term outcomes through enhanced adherence and personalized management strategies.

Background: This study aims to investigate the prognostic value of lymph node ratio (LNR) and log odds of positive lymph nodes (LODDS) in patients with locally advanced, nonmetastatic (Stage II-III) triple-negative breast cancer (TNBC). Methods: In this observational, monocenter, retrospective study, patients who underwent breast surgery for locally advanced TNBC were analyzed. Clinical-pathological features of interest were collected. The log-rank statistics method and the Cox proportional hazard analysis were used to identify prognostic factors. Disease-free survival (DFS) and overall survival (OS) curves were evaluated by the Kaplan-Meier method, using the log-rank test to compare survival between groups. Results: Between 2011 and 2016, 82 patients were included in the study. The median follow-up was 33 months. Cox's univariate analysis showed that T stage, positive lymph nodes, LODDS, and LNR were statistically significant prognostic factors for DFS (P < 0.05). In the Multivariate Cox analysis, LNR was the only independent prognostic factor for DFS (P < 0.0001). Conclusions: LNR and LODDS can provide additional prognostic value for DFS and OS in locally advanced TNBC. Moreover, LNR had a better prognostic value compared with LODDS. These data should be considered in the overall care strategy of these patients, especially in the decisions on possible adjuvant therapy.

PURPOSE:We report the 6-year results of a phase 2 study on hypofractionated radiation therapy targeting the primary and regional lymph nodes in 10 fractions. METHODS AND MATERIALS:A schedule of 34 Gy/10 fractions/2 weeks to the whole breast/chest wall and the draining lymph nodes was used. Both acute and late toxicities were collected. All patients but those who underwent mastectomy without reconstruction or with temporary expander were asked to rate their cosmetic outcome according to the Harvard scale. Toxicity was assessed weekly during radiation therapy (RT) and then at each follow-up (fup) examination. Cancer-related endpoints were evaluated from the date of RT start to the diagnosis of local relapse/distant metastases or the last fup. RESULTS:From February 2015 to March 2019, 59 women (median age, 60 years and IQR, 48.3-68.8 years) with stage II to IIIA breast cancer who underwent axillary dissection and conservative surgery (83%) or mastectomy (17%) were accrued. One patient was lost to fup immediately after the end of RT. At the median fup of 77.11 months (range, 24-102 months), the cumulative incidence of any grade locoregional late toxicity estimated with the Kaplan-Meier method is 43.4% (95% CI) (30.0% and 46.1% for patients undergone mastectomy and lumpectomy, respectively). Peak-2 events have been observed for fibrosis (1 patient, 1.7%), telangiectasia (1 patient, 1.7%), and lymphoedema (1 patient, 1.7%). One patient (1.7%) experienced grade 3 breast retraction at 36 months fup. The cosmetic outcome resulted in being excellent, good, fair, and poor in 61.7%, 25%, 7.6%, and 5.7%, respectively. At 72 months, the specific-disease-free survival was 96.5%; distant metastasis-free survival and overall survival rates were 88% and 94.4%, respectively. CONCLUSIONS:Our results support the activity of a 10-fractions hypo-RT schedule targeting the primary site as well as the draining lymph node stations after surgery for locally advanced breast cancer.

Background. Optimal therapy after breast conserving surgery (BCS) in older adults with low-risk early breast cancer (BC) is controversial. This study compares the effects of radiation therapy (RT) and endocrine therapy (ET) as exclusive treatments on health-related quality of life (HRQoL) and ipsilateral breast tumour recurrence (IBTR) rate in women aged ≥70 years with stage I luminal-like BC. Methods. EUROPA (NCT04134598) is a phase 3, randomized, controlled trial. Women with early luminal-like BC (ER/PgR ≥10%, HER2 negative, Ki-67 index ≤20%, pT1ab N0/Nx, any grade or pT1c, grade 1-2), were 1:1 randomized after BCS to receive exclusive ET or exclusive RT. Central randomization was stratified by G8 health status (≤14 vs >14) and age at baseline (70–79 vs ≥80 years). The study coprimary endpoints are 2-year HRQoL as assessed by the global health status (GHS) scale of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and 5-year IBTR rate. Secondary endpoints are locoregional recurrence (LRR), contralateral BC (CBC), distant metastases (DM), BC specific- (BCSS), and overall-survival (OS) rates, adverse events, individual scale scores from QLQ-C30, QLQ-BR45, QLQ-ELD14 EORTC modules up to 5 years after treatment. We present the pre-planned interim HRQoL analysis results after at least 152 patients reached the 2-year HRQoL assessment. Data were analysed by intention to treat, using repeated mixed-effects methods. Results. Between Feb 2021 and June 2024, 734 patients were enrolled and 731 randomly assigned to receive RT (n=365) or ET (n=366); 78.9% of the planned 926 patients from 21 centres. In the current interim analysis, the RT and ET arms included 104 and 103 patients, respectively. Age distribution was similar across treatment arms (74% aged 70-79 and 26% aged 80+ years); G8 scores were comparable (40% ≤14 and 60% scoring >14). At baseline, RT arm (n=104) had a mean GHS score of 71.9 (SD 19.05), while ET arm (n=99) had a mean score of 75.5 (SD 19.34). RT arm showed mean changes of -1.1 (24-month, SD 18.80) as compared to -10.0 (24-month, SD 25.80) of ET arm. Significant factors influencing GHS score changes were treatment type (p=0.045) and baseline GHS value (p<0.0001). Concerning adjusted mean GHS score reductions, for RT arm the mean changes were -3.77 (3-month; p=0.0452), -0.59 (6-month; p=0.7420), -4.33 (12-month; p=0.0333), and -3.40 (24-month; p=0.1314). For ET arm, mean changes were -6.45 (3-month; p=0.0015), -5.38 (6-month; p=0.0043), -6.60 (12-month; p=0.0025), and -9.79 (24-month; p<0.0001). The adjusted mean differences between RT and ET arms at 24 months showed a significant difference of 6.39 favouring RT arm (95%CI 0.14 to 12.65; p=0.0453). ET resulted in a more significant decline at 24 months in most of the functional and symptom scales of the QLQ-C30 questionnaire compared to RT. No IBTR, LRR, or DM events were reported in either group. CBC events occurred in 2 RT arm patients (1.9%) and 1 ET arm patient (1%). Deaths were 4 (3.8%) in RT arm and 2 (1.9%) in ET arm, none BC-related. Conclusions. ET patients had significantly reduced HRQoL over 24 months compared to RT patients. These findings will help shared decision-making while awaiting final study results. Citation Format: Icro Meattini, Maria Carmen De Santis, Luca Visani, Marta Scorsetti, Alessandra Fozza, Bruno Meduri, Fiorenza De Rose, Elisabetta Bonzano, Agnese Prisco, Valeria Masiello, Eliana La Rocca, Ruggero Spoto, Carlotta Becherini, Gladys Blandino, Luca Moscetti, Riccardo Ray Colciago, Francesca Martella, Lorenzo Vinante, Sara Ramella, Marco Gatti, Sara Pedretti, Patrizia Vici, Nadia G. Di Muzio, Alice Pastorino, Maria Cristina Leonardi, Ivica Ratosa, Jure Verbancic, Riccardo A. Audisio, Etienne Brain, Saverio Caini, Marije Hamaker, Orit Kaidar-Person, Matteo Lambertini, Livia Marrazzo, Calogero Saieva, Tanja Spanic, Vratislav Strnad, Sally Wheelwright, Philip M. P. Poortmans, Lorenzo Livi, on behalf of the EUROPA trial Investigators. Exclusive endocrine therapy or radiation therapy in women aged 70+ years with luminal-like early breast cancer (EUROPA): preplanned interim analysis of a randomized phase 3 trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS2-01.

The attempt to exploit molecular subtyping for risk stratification in breast cancer patients has been only partially successful with a limited application in the clinical practice. In the BREMIR study, we aimed to identify a panel of miRNAs as prognostic biomarkers for breast cancer. We first confirmed the association of previously linked miRNAs with critical clinical parameters, then adopted a discovery-driven approach to identify novel biomarkers. miRNA expression was analyzed using the Affymetrix Gene Chip 4.0 array in a discovery cohort of 34 patients (3 with synchronous metastases, 14 who developed metastases after 10 years, and 17 who remained metastasis-free) and 6 controls. RT-qPCR validated selected miRNAs in an extended cohort (n = 223) with a median follow up of 6.6 years. A stepwise logistic regression model incorporating miRNA levels and clinicopathological features was developed to predict metastasis risk. Additionally, miRNA expression was assessed in plasma extracellular vesicles (EVs) using digital PCR in an independent cohort (n = 39). In silico enrichment analyses explored the functional role of relevant miRNAs in metastasis development. Eight differentially expressed miRNAs were identified in the discovery cohort. In the extended cohort, miR-3916 and miR-3613-5p were the most effective in distinguishing patients who developed metastases. Higher miR-3916 expression was associated with reduced metastasis risk (OR = 0.42, 95