Oryzon Genomics (Spain)

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.

This study describes the clinical and genetic features of Meesmann epithelial corneal dystrophy (MECD) in two unrelated families and reports new genotype-phenotype associations. Ten patients from a Lebanese family (n = 4) (Family 1) and a Spanish family (n = 6) (Family 2) underwent ophthalmologic evaluation, in vivo confocal microscopy (IVCM), anterior segment optical coherence tomography (AS-OCT) with epithelial thickness mapping (ET-map), and targeted next-generation sequencing (NGS) using a custom-designed 133-gene panel associated with anterior segment dystrophies. In Family 1, a novel homozygous KRT12 c.1181T>C (p.Leu394Pro) variant was identified in the symptomatic proband and his clinically asymptomatic brother, while both parents, who were first cousins, were heterozygous for this nucleotide variant. The proband also carried the heterozygous KRT3 c.250C>T (p.Arg84Trp) variant, which has been previously reported but, to our knowledge, has not been described in co-occurrence until now. In addition, the proband showed a complex phenotype with signs of MECD and epithelial basal membrane alterations consistent with epithelial basement membrane dystrophy (EBMD). In Family 2, four affected members carried the KRT3 c.1492G>A (p.Glu498Lys) variant in heterozygosity, which has been previously described. The elderly members affected showed typical signs of MECD and EBMD. To our knowledge, these concomitant alterations have not been previously described with genetical confirmation. In conclusion, this study provides the first evidence that the co-occurrence of variants in two Meesmann corneal dystrophy-associated genes (KRT3 and KRT12) can jointly account for the disease phenotype. We also highlight the association of MECD with EBMD in both families. Characterization using IVCM and AS-OCT ET-Map provides a deeper understanding of the morphological changes and phenotypic variability in MECD, confirming the utility of this multimodal imaging approach for diagnosis and management.

633 Background: epNECs and SCLC are aggressive with poor prognosis where chemoresistance limits treatment benefit. Iada is an oral inhibitor of lysine-specific demethylase 1 (LSD1) via its flavin adenine dinucleotide cofactor. Preclinical data suggest LSD1 inhibition may reverse chemoresistance. We conducted an investigator-initiated, multicenter, phase II study of Iada plus P. Methods: With IRB approval, the study planned to accrue 42 pts in epNEC and SCLC cohorts. Treatment: Iada 150 μg oral (5day on/2 day off weekly) + P 80 mg/m² IV weekly in 21 day cycles. Eligible pts: metastatic/unresectable epNEC or SCLC, 1–3 prior lines, must include platinum. Primary endpoint: ORR. Secondary: G3+ toxicity, PFS, OS, clinical benefit rate (CBR), duration of response (DoR). Exploratory: cytokine/immune profiling, tumor and blood epigenomic/genomic analyses. Protocol preplanned futility analysis was at 12 pt for NEC and 16 pt for SCLC. Results: Between January 2023 and July 2024, twenty pts were enrolled into 2 cohorts, epNEC (N=10) and SCLC (N=10) with 17 evaluable; 65% males, median age 67 years. Rate of any G3+ toxicity was 64% (9 hematologic, 1 hypocalcemia were drug related). Iadademstat 150 μg initial lead-in dose was decreased to 100 μg given 5d on/2d off to reduce myelosuppression. Preliminary results for efficacy are summarized in the table. The study stopped early given low probability of reaching the threshold for no-futility after enrolling 10 pts in each cohort. Both doses reached the intended 80% LSD1 target engagement, and there were no apparent drug interactions with P. Correlative studies are underway. Conclusions: Iada 100 μg in combination with P 80 mg/m² was feasible and achieved consistent LSD1 target engagement, but efficacy was insufficient to meet the prespecified threshold. This investigator-initiated study is the first prospective clinical trial to evaluate LSD1 inhibition as a strategy to overcome chemoresistance in epNEC and SCLC, and correlative analysis will provide critical pharmacodynamic and epigenetic insights to guide future therapeutic development. Clinical trial information: NCT05420636 . Cohort N evaluable PR (n,%) SD (>6 wk) (n,%) PD (n,%) CR+PR+SD (n,%) PFS (m) OS (m) DoR (m) NEC 9/10 0 3 (33.3%) 6 (66.7%) 3/9 (33.3%) 1.6 4.4 2.07 SCLC 8 / 10 1 (12.5%) 2 (25%) 5 (62.5%) 3/8 (37.5%) 1.3 8.4 3.15

Weekly paclitaxel and trastuzumab (APT regimen) represents the standard treatment for most stage I HER2+ breast cancer (BC) patients based on results of the single arm phase II APT trial. Confirmation of long-term outcomes in real-world cohorts is of interest. This retrospective study included patients with early HER2 + BC (pT ≤ 3 cm; pN0/N1mic) treated with APT regimen. This study included 276 patients; most presented hormone receptor (HR) positive (75%, N = 207) and grade 3 tumors (65.6%, N = 181). The majority had pT ≤ 2 cm (92.4%, N = 255), no nodal involvement (93.1%, N = 257), with only 19 patients (6.9%) presenting N1mic. Anatomical stage was: IA 86.2% (N = 238), IB 6.2% (N = 17), and IIA 7.6% (N = 21). At a median follow-up of 4.4 years, 3-year recurrence free survival (RFS) was 97.3% (95% CI 95.1–99.5), 3-year distant relapse free survival (DRFS) was 98.2% (95% CI 96.4–100), and 3-year invasive breast cancer free survival (IBCFS) rate was 97.1% (95% CI 94.7–99.5). A statistically significant difference in RFS was observed according to anatomical stage ( p < 0.001). This real-world study confirms that APT regimen is associated with excellent outcomes in stage IA HER2 + BC patients, while caution is warranted for patients with stage IB or IIA disease.

Chronic dermatological conditions such as acne vulgaris, androgenetic alopecia (AGA), and alopecia areata (AA) affect hundreds of millions worldwide and contribute substantially to quality-of-life impairment. Despite the availability of systemic retinoids, anti-androgens, and JAK inhibitors, therapeutic responses remain heterogeneous and relapse is common, underscoring the need for biologically grounded stratification. Over the past decade, large genome-wide association studies and functional analyses have clarified disease-specific and cross-cutting mechanisms. In AA, multiple independent HLA class II signals and immune-regulatory loci such as BCL2L11 and LRRC32 establish antigen presentation and interferon-γ/JAK–STAT signalling as central drivers, consistent with clinical responses to JAK inhibition. AGA is driven by variation at the androgen receptor and 5-α-reductase genes alongside WNT/TGF-β regulators (WNT10A, LGR4, RSPO2, DKK2), explaining follicular miniaturisation and enabling polygenic risk prediction. Acne genetics highlight an immune–morphogenesis–lipid triad, with loci in TGFB2, WNT10A, LGR6, FASN, and FADS2 linking follicle repair, innate sensing, and sebocyte lipid metabolism. Barrier modulators such as FLG and OVOL1, first described in atopic dermatitis, further shape inflammatory thresholds across acne and related phenotypes. Together, these findings position genetics not as an abstract catalogue of risk alleles but as a map of tractable biological pathways. They provide the substrate for patient-stratified interventions ranging from JAK inhibitors in AA, to endocrine versus morphogenesis-targeted strategies in AGA, to lipid- and barrier-directed therapies in acne, while also informing cosmetic practices focused on barrier repair, sebaceous balance, and follicle health.

Vafidemstat is a brain-penetrant, orally bioavailable, small molecule irreversible inhibitor of the histone lysine-specific demethylase KDM1A (also known as LSD1), which corrects memory deficits and behavior alterations including aggression and social interaction deficits in preclinical models. Here, we report the results of REIMAGINE, a phase IIa, single-center, open-label, one-arm basket trial that evaluated the safety and efficacy of vafidemstat on aggression in adult patients with borderline personality disorder (BPD), attention-deficit/hyperactivity disorder (ADHD), and autistic spectrum disorder (ASD). Participants received 1.2 mg/day of vafidemstat for 8 weeks. Vafidemstat was shown to be safe and well tolerated, and no drug-related clinically significant adverse events were observed. Furthermore, all neuropsychiatric scales assessed showed notable efficacy signals, whether assessing agitation/aggression (Clinical Global Impression for Severity [CGI-S] and Clinical Global Impression for Improvement [CGI-I] and Neuropsychiatric Inventory [NPI] questionnaire for Agitation-Aggression [NPI-AA]), overall patient functioning (total NPI), or disease-specific features (Attention-Deficit/Hyperactivity Disorder Rating Scale [ADHD-RS] and Borderline Personality Disorder Checklist [BPDCL]). Statistically significant improvements were observed in the aggregated data (all participants) and for each of the three disease groups independently. Changes were evident within the first 2 weeks of treatment. In summary, the REIMAGINE study supports that vafidemstat is safe, well tolerated, and causes a significant and consistent reduction in agitation/aggression and nonaggression features in BPD, ADHD, and ASD. These data support continuing the development of vafidemstat as a new treatment option for these psychiatric disorders.