bims-tumhet 2026-08-16 papers

Issue of 2026–08–16
four papers selected by
Sergio Marchini, Humanitas Research

ESMO Open. 2026 Aug 14. pii: S2059-7029(26)02184-8. [Epub ahead of print]11(8): 108242

Homologous recombination deficiency testing implementation in the routine clinical setting: real-life experience and lessons learned.

P Romero-Lozano, M Gómez-Rey, M Vila-Casadesús, A Martin, G Buono, V Bach, A Onieva, M Ricart, N Deltiempo, E Castillo, L Fariñas, S Aguilar, E Garralda, R Dienstmann, P Nuciforo, J Tabernero, C Garcia-Duran, A Vivancos.

BACKGROUND: Homologous recombination deficiency (HRD) is a critical biomarker for predicting response to poly (ADP-ribose) polymerase (PARP) inhibitors in high-grade serous ovarian cancer (HGSOC). Hence, genomic scar-based HRD testing must be implemented in routine clinical labs. This study aims to obtain a head-to-head comparison of some of the applications available for HRD status determination in a real-world clinical cohort to guide HRD testing standardization.
MATERIALS AND METHODS: HRD scores were obtained from HGSOC formalin-fixed, paraffin-embedded samples from the Molecular Prescreening Program at Vall d'Hebron Institute of Oncology (VHIO) using two approaches: VHIO-HRD (n = 229) and shallow sequencing-based HRD score (LSTsh-HRD; n = 123). Large-scale transitions (LST), telomeric allelic imbalance (TAI), and genomic loss of heterozygosity (LOH) were calculated using data from a custom hybrid-capture panel (VHIO-HRD score), and LST was determined from shallow whole-genome sequencing of a genomic library (LSTsh-HRD score). Validation was obtained by benchmarking against established and commercially available platforms. Tumor fraction (TF) was estimated using several computational tools.
RESULTS: Optimized HRD status cutoff for VHIO-HRD (LSTVHIO-HRD + TAIVHIO-HRD + LOHVHIO-HRD) was set to ≥47 based on comparison with commercially available tools, whereas HRD status cutoff for LSTsh-HRD was predefined at ≥20. Despite differences in chemistry and scoring metrics, strong concordance in HRD classification was observed across assays. TF strongly influenced HRD performance, with optimal sensitivity at TF ≥0.4 for VHIO-HRD and ≥0.2 for LSTsh-HRD.
CONCLUSIONS: We validated that HRD scar quantification can be implemented across testing laboratories using assays with different library preparation chemistries and biomarker calculation algorithms. TF is a critical determinant of accurate HRD scoring; LSTsh-HRD quantification offers improved sensitivity in low-cellularity contexts, and VHIO-HRD enables status classification across the continuum of score values in samples with TF ≥0.4. A multiplatform, standardized HRD testing strategy may enhance biomarker-driven patient selection for PARP inhibitor therapies in HGSOC and other HRD-associated tumors.

Keywords: genomic scarring; high-grade serous ovarian cancer; homologous recombination deficiency; real-world molecular diagnostics; tumor fraction

DOI: https://doi.org/10.1016/j.esmoop.2026.108242

Int J Gynecol Cancer. 2026 Jun 20. pii: S1048-891X(26)00354-3. [Epub ahead of print] 104823

Somatic BRCA1 and BRCA2 detection in homologous recombination deficiency testing: concordance of four sequencing workflows with the Myriad myChoice companion diagnostic.

OBJECTIVE: To assess concordance of tumor BRCA1/BRCA2 variant detection across four sequencing workflows benchmarked against the Myriad myChoice companion diagnostic in newly diagnosed ovarian cancer.
METHODS: Within the MITO16A/MaNGO-OV2 trial, 100 formalin-fixed paraffin-embedded ovarian cancer samples were analyzed across four workflows in the Italian network: one academic modular workflow (Agilent OneSeq/VarDict) and three commercial platforms (Oncomine Comprehensive Assay Plus/Ion Reporter, SOPHiA DDM, and TruSight Oncology 500/DRAGEN). BRCA1/BRCA2 calls were compared with myChoice as the reference. Variant classification, quality metrics, and copy number findings were centrally curated. Concordance was assessed at the sample level, and discordant cases underwent manual review to identify technical or interpretive drivers.
RESULTS: Two samples failed myChoice testing and were excluded, leaving 98 evaluable cases. Complete agreement across all workflows and the reference assay was observed in 86 of 98 samples (87.8%). The 12 discordant cases (12.2%) fell into four recurrent categories: limited detection of exon-level copy number alterations, low-frequency variants in formalin-fixed paraffin-embedded specimens, differences in reporting of variants of uncertain significance, and transcript or nomenclature inconsistencies. An illustrative sample with dual BRCA1/BRCA2 pathogenic variants highlighted the impact of local coverage and filtering thresholds. No workflow showed systematic over-calling or under-calling.
CONCLUSIONS: Tumor BRCA1/BRCA2 results showed moderate cross-platform concordance, with clinically relevant discordances driven mainly by technical and interpretive factors. Greater standardization of tumor BRCA1/BRCA2 testing is needed to support consistent reporting, treatment decisions, and referral for hereditary cancer assessment.
TRIAL REGISTRATION: EudraCT 2012-003043-29; NCT01706120.

Keywords: Cross-platform Concordance; Next-Generation Sequencing Workflows; Ovarian Cancer; Tumor BRCA1/BRCA2 Testing

DOI: https://doi.org/10.1016/j.ijgc.2026.104823

Pathol Oncol Res. 2026 ;32 1612465

Molecular classification of endometrial carcinoma: clinical utility of an NGS panel with targeted detection of 116 cancer-related genes.

Lingfeng Chen, Zhijie You, Xunbin Yu, Yijuan Wu, Xin Chen, Jie Lin.

Background: This study aimed to evaluate the efficacy of a single-test, targeted DNA next-generation sequencing (NGS) panel in classifying endometrial carcinoma (EC) into molecular subtypes and to compare its performance with that of the established Sanger sequencing + immunohistochemistry (Sanger + IHC) molecular classification.
Methods: Targeted DNA NGS was performed on 131 samples using the clinically validated AmoyDx® Comprehensive Panel, and a commercially available targeted AmoyDx EC Panel covering POLE, TP53, and MSI was used for 63 samples.
Results: The concordance between the NGS and Sanger + IHC classifications was 93.8% (182/194 cases), with a kappa value of 0.908. The exclusion of seven discordant POLE mutations improved concordance to 97.4% (kappa = 0.962). NGS identified 30 POLE mutations compared to 23 detected by Sanger sequencing, which missed low-frequency variants. Microsatellite instability (MSI) analysis and mismatch repair (MMR) immunohistochemistry (IHC) results were highly concordant (97.9%). However, NGS-based TP53 mutation detection showed moderate agreement with the p53 IHC results (kappa = 0.688). Mutations associated with targeted therapy trials, including PTEN (76.3%), PIK3CA (50.4%), and ARID1A (35.9%), were found in 131 EC samples.
Conclusion: These findings indicate that NGS-based molecular classification aligns well with Sanger + IHC molecular classification and offers higher sensitivity than Sanger sequencing, thereby improving the identification of mutations associated with targeted therapy trials. This enhances the prognosis and treatment planning for patients with advanced EC.

Keywords: NGS; Sanger sequencing; endometrial carcinoma; immunohistochemistry; molecular classification

DOI: https://doi.org/10.3389/pore.2026.1612465

Oncol Lett. 2026 Oct;32(4): 436

Current status and targeted therapies in endometrial cancer: Molecular classification-driven treatment strategies (Review).

Xinyu Li, Jie Liu, Fang Huang, Xinyue Deng, Mingxuan Chen, Wen Mou, Wenxia Liu.

Endometrial cancer (EC) is one of the most common gynecological malignancies worldwide. Although numerous patients are diagnosed at an early stage with favorable outcomes, advanced and metastatic disease remains associated with limited therapeutic options and poor prognosis. Advances in molecular characterization have reshaped the understanding of EC pathogenesis and enabled the development of classification-driven treatment strategies. The present review summarized current standard therapies, including surgery, chemotherapy and radiotherapy, and highlighted the growing role of molecularly targeted treatments. The integration of pathogenetic, histopathological and molecular classifications provides a framework for identifying actionable alterations. Key oncogenic signaling pathways, including PI3K/AKT/mTOR and RAS/RAF/MEK/ERK, were discussed in the context of therapeutic targeting and precision medicine. In addition, emerging strategies, particularly immunotherapy and combination approaches, were addressed. A deeper understanding of molecular heterogeneity may facilitate individualized treatment selection and improve clinical outcomes in patients with EC.

Keywords: endometrial carcinoma; immunotherapy; molecular classification; oncogenic signaling; precision medicine; targeted therapy; therapeutic resistance

DOI: https://doi.org/10.3892/ol.2026.15791