Hospital Universitari Arnau de Vilanova

Abstract HER2DX is a genomic test developed to guide treatment decisions in newly diagnosed HER2-positive (HER2+) breast cancer. It analyzes the expression of 27 genes grouped into 4 biological signatures: immune/immunoglobulin (IGG), luminal differentiation, proliferation, and HER2 amplicon expression. The test provides three distinct outputs: a prognostic relapse risk score, a pathologic complete response (pCR) likelihood score, and a quantitative ERBB2 mRNA score. This study investigates the relationship between HER2DX-derived outputs and standard histopathologic features in early-stage HER2+ breast cancer. The standardized HER2DX genomic test provided by Reveal Genomics was performed on paraffin tumor samples from newly diagnosed patients with early-stage HER2+ breast cancer, treated across 24 hospitals from January 2022 to June 2025. Histopathologic evaluation of hematoxylin-eosin-stained slides included tumor grade, stromal tumor-infiltrating lymphocytes (TILs) percentage, spatial TIL distribution, and presence of tertiary lymphoid structures (TLS). Hormone receptor (HR) status and Ki67 proliferative index were assessed locally by immunohistochemistry (IHC), while HER2 status was determined using IHC and in situ hybridization. Associations between HER2DX scores and pathologic features were assessed using appropriate statistical tests for continuous variables and categorical comparisons. HER2DX scores and their underlying biological signatures were analyzed in 410 HER2+ tumors. HR+ disease represented 75.7% of cases. The distribution of tumor grade, HER2 IHC status, HR status, Ki67 index, stromal TILs, TLS, and TIL spatial patterns is summarized in the Table. The HER2DX pCR score was significantly associated with all histopathologic features evaluated, the relapse-risk score five of these features (including Ki67 and TILs), and the HER2DX ERBB2 score with HER2 and HR status. Higher stromal TIL levels were moderately correlated with the IGG signature (r=0.59, p<0.001), and the inflamed TIL distribution was associated with increased IGG signature expression and higher HER2DX pCR scores (p<0.001). TLS presence also correlated with elevated IGG signature expression (p<0.001). HR+ tumors exhibited higher luminal signature expression (p<0.001), while HER2 IHC 3+ tumors had increased HER2 amplicon signature and HER2DX ERBB2 scores (p<0.001). Finally, higher Ki67 levels were moderately correlated with the proliferation signature (r=0.50, p<0.001). The HER2DX genomic test shows significant associations with multiple histopathologic features in early-stage HER2+ breast cancer, although no single feature can fully explain the outputs of the test. These findings support the notion that HER2DX integrates complex biological and histological dimensions, offering complementary information that may enhance personalized treatment decision-making. Citation Format: E. Sanfeliu, A. Martinez-Romero, M. Marín-Aguilera, S. Cobo, B. González-Farré, E. Hernandez, P. Jares, J. Puig-Butillé, M. Muñoz, R. Gómez-Bravo, M. Tapia, C. Tebar, C. Saura, S. Escrivà-de-Romaní, J. Soberino, J. Cortés, S. Morales, K. Amillano, L. Paré, P. Villagrasa, W. Buckingham, F. Pardo, J. Parker, F. Brasó-Maristany, E. Ciruelos, R. Sánchez-Bayona, O. Martinez-Sáez, J. Cejalvo, A. Prat. Biologic and Pathologic Correlations of the HER2DX Genomic Test in HER2+ Disease [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-10-24.

Abstract Background: Accurate HER2 status assessment is crucial for guiding treatment decisions in breast cancer. MammaTyper® is a CE-marked in-vitro diagnostic device utilizing real-time quantitative PCR (qRT-PCR) to quantify mRNA transcripts of ERBB2, ESR1, PGR, and MKI67. It provides an objective and standardized classification of breast cancer into intrinsic subtypes (Luminal A, Luminal B, HER2-enriched, and Triple-Negative), offering prognostic and predictive information that complements traditional immunohistochemistry (IHC). MammaTyper®'s high reproducibility and sensitivity are particularly valuable when subjective interpretation of IHC presents challenges. Objective: This study aimed to analyses whether the MammaTyper® platform improves the classification of HER2-equivocal breast cancer cases and to assess its concordance with FISH-based methods. Methods: We analysed 93 breast cancer patients. Estrogen receptor (ER) and progesterone receptor (PR) status, along with Ki67 index, were determined by IHC. HER2 status was initially assessed by IHC and FISH. MammaTyper® was then performed to classify intrinsic subtypes and determine HER2 status based on ERBB2 mRNA levels. Concordance between MammaTyper®, IHC, and FISH was evaluated. Results: Of the 93 patients, 83 (89%) were ER-positive, 42 (45%) PR-positive, and 51 (55%) had a high Ki67 index by IHC. Forty-two cases (45%) were classified as HER2-positive by IHC and FISH. MammaTyper® confirmed HER2-positivity in 25 (60%) of these cases. Among the 51 HER2-negative cases by IHC and FISH, MammaTyper® was positive in only 8 (15%). The overall concordance between MammaTyper® and the IHC/FISH combined assessment was 73%. Specifically, concordance was 60% for IHC/FISH-positive cases and 84% for IHC/FISH-negative cases. Of the 32 cases classified as HER2-positive by MammaTyper®, 23 (71%) had a HER2 FISH ratio of ≥2. Conversely, among the 55 cases classified as HER2-negative by MammaTyper®, 17 (31%) had a HER2 FISH ratio of ≥2. MammaTyper® showed a 72% concordance with IHC for HER2 phenotype determination, identifying a lower proportion of HER2-positive tumors (34%) compared to IHC (45%). This concordance was notably higher (84%) in HER2-negative cases. Conclusion: MammaTyper® demonstrates substantial concordance with IHC and FISH for HER2 status determination, particularly in HER2-negative cases. It identifies a smaller subset of HER2-positive tumors compared to IHC, suggesting its potential to refine the selection of patients for HER2-targeted therapies. Further clinical utility should be assessed by correlating MammaTyper® results with treatment response and survival outcomes. Citation Format: A. VELASCO, I. URDANIBIA, G. RODRIGUEZ, N. TUSET, G. ARIADNA, S. MORALES. Improving HER2 Status Assessment in Breast Cancer with MammaTyper®: Focus on Equivocal Cases [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-04-02.

Exposomic determinants substantially influence the variability of molecular IgE-mediated sensitization in allergic rhinitis and conjunctivitis across bioclimatic regions, underscoring their relevance in precision allergology. This study aimed to characterize molecular sensitization profiles in Spanish patients with respiratory allergy from distinct geographic and climatic areas. A cross-sectional, multicenter study was performed in 12 Spanish cities. The study population comprised 291 patients diagnosed with allergic rhinitis and/or conjunctivitis according to the modified ARIA/DECA criteria. Participants underwent skin prick testing with standardized allergen extracts and multiplex molecular IgE analysis. Clinical, demographic, and regional bioclimatic variables were integrated to define exposomic sensitization patterns. Patients previously treated with allergen immunotherapy or biologics were excluded. Regional pooled sera were analyzed by ELISA and IgE immunoblotting to validate molecular data and identify IgE binding to nonrecombinant or poorly characterized allergenic components. Distinct regional sensitization profiles were identified. Grass pollen allergens predominated in oceanic and continental climates, while olive and cypress pollens were more frequent in Mediterranean areas. Sensitization to house dust mite, particularly Dermatophagoides pteronyssinus and Blomia tropicalis, was highly prevalent in subtropical and humid zones. Molecular assays confirmed skin test findings and identified major allergenic molecules, including Phl p 1, Ole e 1, Der p 1, and Der p 2, along with region-specific components such as Der p 23, Cup a 1, Alt a 1, and Pla a 2. This multicenter exposomic study demonstrated that climatic diversity modulates allergen sensitization in Spain, supporting region-tailored precision diagnostic and therapeutic strategies in respiratory allergy.

Exudative pleural effusion often presents diagnostic challenges, with up to 25% of cases remaining undiagnosed after thoracentesis or closed pleural biopsy. Semi-rigid thoracoscopy is a widely used minimally invasive diagnostic method. However, its diagnostic yield is limited by small and superficial biopsy samples due to the lack of mechanical power, particularly in cases of thickened pleura or suspected mesothelioma. We had designed and developed a dual-function semi-rigid thoracoscope and semi-rigid forceps to improve sampling quality and depth. However, their diagnostic performance and safety, particularly compared with that of conventional semi-rigid thoracoscopy is still unclear. This randomised controlled trial will enrol a total of 522 adults with exudative pleural effusions of unclear aetiology that remain undiagnosed after the initial investigations from 10 sites in China. Participants will be randomised (1:1:1) to undergo thoracoscopy using either a conventional semi-rigid thoracoscope (with flexible forceps) or a novel dual-function semi-rigid thoracoscope (with either semi-rigid forceps alone or a combination of flexible and rigid forceps). The primary outcome is diagnostic yield. Secondary outcomes include the biopsy success rate, incidence of procedure-related complications, biopsy specimen size and depth, histological interpretability, and adequacy of tissue for molecular marker analysis. We hypothesize that the dual-function semi-rigid thoracoscopy with semi-rigid forceps will achieve higher diagnostic yield than conventional semi-rigid thoracoscopy due to the larger and deeper sampling. If this hypothesis is validated, dual-function semi-rigid thoracoscopy could be a novel option for performing pleural biopsy for patients with unknown exudative pleural effusion. This study has been registered at www.clinicaltrials.gov (ID: NCT06744725; Registration Date: 2024-12-19).