Hormone receptor-positive (HR+) breast cancer (BC) is characterized by a persistent risk of recurrence that continues for decades. Although many factors have been linked to recurrence, the clinical features associated with late relapse and patterns of distant metastases are less understood. Our study aimed to identify factors associated with early (< 5 years) and late (5–10 years) recurrence in a real-world cohort of HR+/human epidermal growth factor receptor type2-negative (HER2-) BC patients. Our study performed a retrospective analysis of stage I-III HR+/HER2- BC cases diagnosed between 1981 and 2022. Assessed variables included metastatic sites, early and late invasive recurrences. A total of 4,367 women with HR+/HER2- were included; 81.2

Summary Tumor-infiltrating lymphocytes (TILs) are widely used to assess antitumor immunity in breast cancer but may not reflect the functional competence of adaptive immune responses. We show that immune organization, reflected by tertiary lymphoid structures (TLS) and coordinated humoral and cellular immune programs, represents a distinct dimension of tumor immunity beyond lymphocyte abundance. By integrating histologic, transcriptomic, spatial, and immune receptor profiling analyses across multiple breast cancer cohorts, we show that immune organization is associated with greater immune repertoire diversity, evidence of therapy-induced clonal selection, and improved clinical outcomes, independent of immune infiltration. Transcriptomic measures of immune organization retained independent prognostic value across external cohorts, whereas measures of immune infiltration did not. Furthermore, treatment-induced increases in immune organization, but not immune infiltration, were associated with therapeutic response. These findings identify immune organization as a dynamic and clinically measurable state of adaptive antitumor immunity with implications for prognosis, treatment monitoring, and therapeutic development in breast cancer. One Sentence Summary Spatially organized immune responses, rather than lymphocyte abundance alone, define clinically relevant antitumor immunity in breast cancer.

5546 Background: Outcomes in high-grade serous ovarian carcinoma (HGSOC) may be influenced by systemic inflammation and the tumor immune microenvironment. We evaluated the prognostic impact of systemic inflammatory markers and intratumoral immune biomarkers, including FOXP3⁺ regulatory T cells and tumor-associated macrophages (CD68 and CD163), in the context of BRCA/HRD status. Methods: We conducted a retrospective cohort study of patients with HGSOC with available baseline systemic inflammatory markers and tumor immunohistochemistry. Systemic inflammation was assessed using neutrophil-to-lymphocyte ratio (NLR >3.5) and lactate dehydrogenase (LDH >220). Intratumoral FOXP3, CD68, and CD163 expression was evaluated by immunohistochemistry. BRCA/HRD status was coded as positive versus negative. Progression-free survival (PFS) and overall survival (OS) were analyzed using multivariable Cox proportional hazards models. Results: Twenty-nine patients were included, with 27 PFS events and 25 OS events. In multivariable analysis for PFS, elevated systemic inflammation was independently associated with worse outcomes: NLR >3.5 (HR 5.88, 95% CI 1.35–25.54; p=0.018) and LDH >220 (HR 6.70, 95% CI 1.33–33.74; p=0.021). Within the tumor microenvironment, higher intratumoral CD68 was associated with inferior PFS (HR 1.10, 95% CI 1.04–1.17; p=0.001), whereas higher CD163 was associated with improved PFS (HR 0.92, 95% CI 0.87–0.97; p=0.002). BRCA/HRD positivity was not independently associated with PFS. For OS, BRCA/HRD positivity was strongly protective (HR 0.14, 95% CI 0.03–0.60; p=0.008), while NLR >3.5 remained independently associated with worse OS (HR 4.27, 95% CI 1.17–15.68; p=0.028). High FOXP3 expression was associated with improved OS (HR 0.06; p=0.032). CD68 and CD163 showed borderline associations with OS. Conclusions: In this HGSOC cohort, baseline systemic inflammation was associated with inferior PFS, and elevated NLR predicted worse OS. Intratumoral immune biomarkers showed distinct prognostic patterns, suggesting that the balance and functional state of myeloid and regulatory immune compartments influence outcomes. BRCA/HRD positivity remained strongly favorable for OS. These findings support further investigation of integrated systemic and tumor immune profiling in larger, prospectively annotated cohorts.

e17597 Background: Health system inequities are major drivers of cancer outcomes in Latin America, where rapidly ageing populations intersect with fragmented access to specialized oncologic care. In high-grade serous ovarian cancer (HGSOC), older age and treatment within resource-limited health systems are associated with worse survival. Whether these associations reflect intrinsic tumour biology or are mediated by inequities in access to optimal care remains unclear. Global assessments have demonstrated variation in HGSOC outcomes by world region and Human Development Index, underscoring the role of health system capacity in shaping survival. Chile, with its segmented public–private health system, provides a natural setting to disentangle these effects. Methods: We conducted a retrospective cohort including 450 patients with HGSOC treated within the Chilean public or private health systems, with 20th years of follow up. The primary endpoint was overall survival (OS), defined as time from diagnosis to death from any cause. For independent prognostic factors we used Cox proportional hazards models integrating age (>65 vs ≤65 years), health system (public vs private), surgical strategy, FIGO stage, lactate dehydrogenase (LDH), and BRCA/HRD status. We evaluated whether age-related survival differences were attenuated after adjustment for health system and surgical strategy, conceptualized as proxies for access to specialized oncologic care. Attenuation was interpreted as consistent with mediation by access to care; however, formal causal mediation analyses were not performed. A propensity score model and inverse probability of treatment weighting (IPTW) were applied as sensitivity analyses. Results: Median OS was 48·2 months and median PFS was 13·8 months. In unadjusted analyses, OS differed significantly by age, stage, surgical strategy, LDH, BRCA/HRD status, and health system. In multivariable models, advanced stage, absence of primary cytoreductive surgery, elevated LDH, BRCA/HRD negativity, and treatment in the public health system were independently associated with worse OS, whereas age was not independently associated with OS after adjustment. IPTW analyses confirmed a robust association between primary cytoreductive surgery and improved OS (hazard ratio 0·29). The survival benefit of primary cytoreductive surgery was preserved across age groups. Conclusions: In this cohort, age-related survival differences in HGSOC were largely explained by inequities in access to optimal surgical care and comprehensive oncologic treatment rather than by chronological age or tumor biology. In segmented health systems such as those in Chile and much of Latin America, structural barriers to specialized care represent key determinants of survival.

The Explicit Health Guarantees program in Chile ensures diagnosis and treatment for breast cancer (BC). However, access to palliative care, including physical, psychological, social and spiritual dimensions of patients, remains limited. This study explored barriers and facilitators to implementing access to physical therapy, nutritional counselling and mental health support services in the context of oncology care. We performed a mixed-methods design combined analysis of 2019-2023 administrative data from the Southeastern Metropolitan Health Service with qualitative interviews and focus groups involving healthcare professionals and BC patients at one public hospital and one private center. We observed a decline in referrals to supportive care from 30.2% in 2019 to 11.9% in 2023. Participants identified a lack of referral protocols, staff shortages, limited infrastructure and fragmented coordination as major barriers. Facilitators included interdisciplinary collaboration, electronic referral systems and strong patient satisfaction. Both professionals and patients valued physical therapy most highly, while private-sector patients prioritised mental health and nutritional counselling. Our findings suggest that systemic and institutional gaps translate into an underutilisation of supportive care for BC in Chile. Strengthening referral systems, expanding staff, integrating supportive services into oncology pathways and raising awareness are essential to achieve a more person-centered cancer care.

The development of novel human epidermal growth factor receptor type-2 (HER2)-tar-geted therapies for HER2-positive breast cancer (HER2+ breast cancer (BC)) in recent decades has called fora reassessment of the benefit of including anthracyclines in neoadjuvant regimens, given their association with cardiotoxicity and secondary malignancies. Our study assessed the value of adding anthracyclines in a real-world cohort of early-stage HER2+ BC patients treated with trastuzumab with or without pertuzumab. We retrospectively evaluated 446 patients with early-stage HER2+ BC treated with neoadjuvant chemotherapy at two Chilean centers between 2010 and 2023. Patients received trastuzumab alone or trastuzumab plus pertuzumab, with anthracycline-containing or anthracycline-free regimens. Our primary endpoint was pathological complete response (pCR; ypT0/is ypN0). Secondary endpoints included invasive disease-free survival (iDFS) and overall survival (OS). Multivariate models assessed the predictive role of anthracyclines and pathological biomarkers (ER status, Ki67, HER2 amplification). Elevated Ki67, low ER expression and increased HER2 amplification were independent predictors of pCR. The addition of anthracyclines did not significantly improve pCR rates, even among patients treated with single HER2 targeted therapy (trastuzumab alone). With a median follow-up of 47 months, anthracyclines had no impact on iDFS (log-rank p = 0.19) or OS (p = 0.96). Subgroup and interaction analyses confirmed no benefit in other biomarkerdefined populations. Overall, anthracyclines did not improve response to treatment or survival in HER2+ BC, even without dual HER2 blockade. These findings support anthracycline-free regimens, even in health systems with limited access to dual HER2-blockade with pertuzumab.

Introducción La incidencia de cáncer de mama (CM) en mujeres jóvenes ha aumentado, pero existen pocos estudios que analicen factores pronósticos en este grupo etario. Métodos Estudio retrospectivo de pacientes con CM en etapas I–III, RH+/HER2–, diagnosticadas entre 2012 y 2021. Se compararon características clínico-patológicas y sobrevida libre de enfermedad invasiva (SLEi) entre mujeres<50 y =50 años. Resultados De 2 826 pacientes, 819 (29%) eran menores de 50 años. Estas mostraron mayores niveles de Ki67 y menor SLEi que las =50 años. La etapa III se asoció con peor SLEi en ambos grupos. Ki67 fue un predictor de recaída en =50 años (p=0,016), pero no en<50 años (p=0,454). Discusión y conclusión La etapa clínica fue un factor pronóstico clave, independiente de laedad. A pesar de su peor pronóstico y mayor índice de Ki67, este no fue pronóstico en<50 años, pero sí lo fue en =50 años, lo que subraya la necesidad de identificar biomarcadores específicos en este subgrupo.

Fatty acids (FAs) are bioactive dietary and metabolic molecules that participate in membrane architecture, energy homeostasis, inflammatory signaling, gene regulation and immune function, all of which intersect with breast cancer (BC) risk, progression and treatment response. In this narrative review we integrate epidemiological, clinical, translational and mechanistic evidence on the role of FAs in BC. Saturated, monounsaturated, trans- and polyunsaturated FAs (PUFAs) are treated as distinct biological exposures rather than interchangeable measures of total fat intake. Similarly, evidence from dietary assessment, circulating biomarkers, erythrocyte membrane composition, adipose tissue stores and tumor lipid signatures is interpreted separately, because each captures exposure and biology at a different level. BC subtypes differ in FA synthesis, uptake, oxidation, storage and remodeling: luminal tumors are frequently linked to hormone-regulated lipogenesis, human epidermal growth factor receptor 2 (HER2)-positive tumors to growth-factor-driven lipid metabolism, and triple-negative tumors to exogenous FA uptake, inflammatory lipid mediators and ferroptosis-related vulnerabilities. FA-derived mediators also shape immune-cell polarization, cytokine signaling and the tumor microenvironment, and dietary FAs may reshape the gut microbiota; the fiber-derived short-chain FAs it produces, distinct from dietary FAs, likewise help regulate immune and inflammatory tone. Clinical data suggest possible roles for fat-quality modification and selected n-3 PUFA interventions, but findings are heterogeneous and not yet sufficient to support routine biomarker-guided precision onco-nutrition. Candidate biomarkers, such as erythrocyte n-6:n-3 composition, require prospective validation before clinical implementation. FA biology thus represents a modifiable but complex axis in BC prevention, tumor biology and supportive care.

BackgroundPregnancy-associated breast cancer (PrBC) poses complex challenges in diagnosis and treatment, particularly when associated with biologically aggressive subtypes and extensive nodal involvement. Management must be individualized, integrating oncologic urgency, fetal safety, and limited validated evidence in this unique setting.Case SummaryWe present the case of a 36-year-old woman diagnosed during the second trimester of pregnancy with HER2-positive (HER2+), node-positive (cT2[m]N3a) breast cancer (BC). After a multidisciplinary team discussion, patient initiated anthracycline- and taxane-based neoadjuvant chemotherapy during gestation. Given its contraindication during pregnancy, anti-HER2 therapy was added postpartum, and surgery included nipple-sparing mastectomy with targeted axillary dissection (TAD) of clipped nodes. Pathology revealed minimal residual invasive disease in the breast and a complete axillary response, allowing omission of axillary lymph node dissection (ALND). Genomic profiling with HER2DX supported high-risk disease and informed systemic therapy with delayed anti HER2 therapy, and conservative axillary management (TAD without ALND) in cT2N3 PrBC, without compromising fetal outcome. The patient subsequently received adjuvant chest wall and nodal region radiotherapy plus trastuzumab-emtansine (T-DM1).ConclusionThis case underscores the value of personalized, multidisciplinary management in PrBC, particularly in patients with high-risk biologic features and advanced nodal disease. Integrating clinical judgment, genomic tools, and adaptive strategies, while accounting for gestational limitations, can optimize oncologic outcomes without compromising fetal safety.

Endometrial cancer incidence and mortality are rising globally, disproportionately affecting health systems facing diagnostic, therapeutic, and survivorship constraints. Rapid innovations-including the International Federation of Gynecology and Obstetrics (FIGO) 2023 staging, molecular classification, sentinel lymph node (SLN) mapping, evolving adjuvant strategies, immunotherapy, and digital tools-risk exacerbating inequities if implementation mismatches system readiness. This narrative review synthesizes key trials, international guidelines, and high-impact implementation studies published between 2010 and September 2025. We summarize contemporary evidence across staging, molecular pathology, imaging, surgery, radiotherapy, systemic therapy, survivorship, equity, and artificial intelligence (AI), translating this into a pragmatic, resource-stratified framework. A previously published principal-component-based structural-readiness clustering model encompassing 68 countries is applied-but not re-derived-to illustrate how health-system capacity shapes access to diagnostics, treatment, and innovation. Persistent gaps include limited availability of universal mismatch repair (MMR) and p53 immunohistochemistry, variable adoption of standardized SLN mapping, uneven radiotherapy access, restricted use of immunotherapy for mismatch-repair deficient (dMMR)/microsatellite instability high (MSI-H) tumors, and fragmented survivorship care. A minimum-core-optimal implementation ladder is proposed to guide diagnostic, surgical, radiotherapeutic, systemic-therapy, and survivorship priorities across varying resource levels. AI-supported quality assurance is discussed alongside essential requirements of local validation, bias mitigation, and robust governance. Rather than generating new empirical data, this review employs a cluster-informed, equity-oriented lens, applying previously validated system-level typologies to contextualize implementation gaps and support context-sensitive guideline adaptation.

Breast cancer is a heterogeneous disease that goes beyond traditional clinicopathological classifications. Identifying low and ultra-low levels of HER2 expression through immunohistochemistry, in tumors previously classified as HER2-negative, has led to a paradigm shift in patient management. This reclassification has expanded therapeutic options for a significant proportion of patients, with estimates indicating that over 60% of patients with horm one receptor-positive breast cancers fall into the HER2-low category. Trastuzumab deruxtecan, an antibody-drug conjugate, has demonstrated significant survival benefits in patients with advanced HER2-low breast cancer, who, in most cases, were previously cand idates solely for chemotherapy following hormonal treatment. However, this therapy is not exempt from toxicity, notably interstitial lung disease/pneumonitis, which can be severe and even fatal in some instances. Early detection of these toxicities and their interdisciplinary management a re crucial to optimize clinical outcomes in these patients. This article provides an overview of recent advancements in treating patients with HER2-low breast cancer, highlighting pivotal studies and emphasizing the importance of stringent monitoring for toxicities associated with new therapies.

Background: The identification of biomarkers for evaluating sensitivity to endocrine therapy in early breast cancer (EBC) is critical. Assessing the dynamic biological changes in the tumor caused by brief pre-operative endocrine therapy (POET) can guide decisions on reducing or intensifying treatment. In this study, we examined the molecular changes induced by short-term POET and their correlation with the treatment's effectiveness. Methods:This is a retrospective study of paired samples from patients (pts) with hormone receptor-positive and HER2-negative (HR+/HER2-) EBC treated at Hospital Clinic of Barcelona between 2014 and 2023 and from the letrozole arm of SOLTI-1501 VENTANA trial (Adamo et al. BCR 2019; NCT02802748). All pts received POET for 2 to 12 weeks prior to surgery, with tamoxifen or aromatase inhibitors (AI), administered according to menopausal status. RNA expression was assessed in baseline and surgery samples, including PAM50 and HER2DX signatures. Treatment response was defined as a value of Ki67≤10% at surgery. Logistic regression models explored the association between baseline gene expression and response. Gene expression changes were analyzed using paired SAM analysis and t-tests. Results: A total 111 pts with both baseline and surgery samples available were included. Median age was 63 years-old (61.8-66.4) and most of the tumors were cT1 (68.5%) and cN0 (97.3%) at diagnosis. 19 pts (17.1%) were premenopausal and 92 (82.9%) postmenopausal. The median baseline Ki67 was 18% (14-25%). After POET, the median Ki67 value was 4% (1-10). 81 pts (73%) reached Ki67≤10% at surgery and 41 (37%) Ki67≤ 2.7% (complete cell cycle arrest). At baseline, PAM50 molecular subtype distribution was: 79 pts (71.2%) Luminal A, 23 (20.7%) Luminal B, 4 (3.6%) HER2-enriched, 3 (2.7%) Normal-like, 2 (1.8%) Basal-like. At surgery, there were 82 (73.9%) Luminal A, 23 (20.7%) Normal-like, and 6 (5.4%) Basal-like tumors. In the univariate analysis, baseline clinicopathological variables associated with response were age (odds ratio [OR]=1.04, p=0.028), percentage of estrogen receptor (OR=1.03, p=0.025), Ki67 value (OR=0.95, p=0.003) and type of endocrine therapy (tamoxifen vs AI, OR=0.17, p<0.001). In terms of baseline gene expression, high Luminal A signature (OR=7.72, p<0.001) and luminal-related genes (e.g.: FOXA1 [OR=1.46, p=0.021] or ESR1 [OR=1.38, p=0.001]) were associated with response, while high Basal-like (OR=0.19, p=0.009), PAM50 proliferation (OR=0.30, p=0.005) and HER2DX proliferation (OR=0.24, p=0.037) signatures and proliferation-related genes (e.g.: MYBL2 [OR=0.58, p<0.003] or MKI67 [OR=0.71, p=0.004]) were associated with no response. After POET, all genes and signatures were up- or downregulated significantly. In particular, we observed a significant decrease of the PAM50 Luminal and proliferation signatures, as well as the HER2DX proliferation and luminal signatures, with an increase of the HER2DX immune (IGG) and HER2 amplicon signatures, both in responders and non-responders (FDR<5%). Conclusion: POET is a simple and secure treatment that can be administrated before surgery in HR+/HER2- EBC. The molecular profiling and dynamic evaluation of biological changes induced by POET could offer opportunities for a better understanding of the tumor´s sensitivity to endocrine therapy and could help guide and optimize treatment strategies in HR+/HER2- EBC. Citation Format: Raquel Gómez-Bravo, Barbara Adamo, Benjamin Walbaum, Esther Sanfeliu, Blanca González-Farré, Francesco Schettini, Olga Martínez-Sáez, Elia Seguí, Isabel García-Fructuoso, Paula Blasco, Oleguer Castillo, Ángela Aguirre, Valeria Sirenko, Pol Giménez, María Rey, Jordi Canes, Patricia Galván, Tomás Pascual, Maria Vidal, Adela Rodriguez Hernandez, Eva Ciruelos, Meritxell Bellet, Aleix Prat, Montserrat Muñoz, Fara Brasó-Maristany. Molecular effects of short pre-operative endocrine therapy in hormone receptor-positive and HER2-negative early breast cancer [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 P2-05-18.

OBJECTIVE:To evaluate if combining a prospective surveillance model (PSM) with a supervised multimodal exercise program prevents breast cancer-related lymphedema (BCRL) and its effect on the functional capacity and quality of life (QoL) of high-risk breast cancer (BC) patients undergoing treatment. DESIGN:Two-arm parallel superiority randomized controlled trial. SETTING:Outpatient physical therapy service in a public hospital. PARTICIPANTS:116 adult women (N=116; age ≥18y) diagnosed with stage I-III BC were enrolled. Inclusion criteria included recent surgery and indication for adjuvant chemotherapy. Exclusion criteria were significant arm volume difference, previous cancer, exercise contraindications, and extreme body mass index values. INTERVENTIONS:Participants were randomized into experimental (n=61) or control groups (n=55) in a 1:1 ratio. The experimental group received PSM with a supervised multimodal exercise program for 12 weeks. The control group received PSM alone. MAIN OUTCOME MEASURES:Arm volume, grip strength, 6-minute walk test, and QoL were blindly assessed at baseline, 3, 6, and 9 months. RESULTS:The combination of PSM with a supervised multimodal exercise program significantly reduced arm volume and body weight and improved grip strength, functional capacity, and the QoL of patients. CONCLUSIONS:Combining PSM and physical exercise reduces arm volume, prevents BCRL, and improves physical performance and QoL in high-risk patients. The combination of PSM and STRONG-B was superior to PSM alone, validating the study's superiority design.