bims-tumhet 2026-10-18 papers

JCO Precis Oncol. 2026 Oct;10(10): e2600484

PIK3CA Mutations in Advanced or Recurrent Endometrial Cancer: An Exploratory Molecular Profiling From the Phase II MITO END-3 Study.

PURPOSE: Immunotherapy with chemotherapy significantly improves progression-free survival in advanced endometrial cancer (EC), especially in microsatellite instability-high (MSI-H) cases. Despite this, for recurrent EC in the postimmunotherapy setting, new treatment options are urgently needed. The PI3K pathway is frequently altered in gynecologic cancers, including EC, representing a potential treatment target.
PATIENTS AND METHODS: In a preplanned translational analysis of the MITO END-3, we retrospectively analyzed the genomic abnormalities of 107 patients with samples eligible for next-generation sequencing (NGS) analysis (FoundationOne CDx) with a focus on PIK3CA mutational status.
RESULTS: In our analysis, the four most frequently mutated genes were TP53, PIK3CA, ARID1A, and PTEN. PIK3CA mutations were detected in 51.4% (55/107 patients) of tissue samples. A total of 68 different PIK3CA mutations were observed, of which 64 were considered pathogenic and four were classified as variants of unknown significance, with the co-occurrence of two different pathogenic mutations in 2 patients. The most frequent PIK3CA mutations were found in the kinase domain, most commonly H1047R (11/68) and H1047Y (3/68), and in the helical domain, including E545K (4/68) and E542K (3/68). Notably, 24 different PIK3CA mutations out of 68 reported in MITO END-3 are considered predictive of response to PI3K inhibition with alpelisib according to current literature in breast cancer. Interestingly, PIK3CA mutations were observed in all The Cancer Genome Atlas categories.
CONCLUSION: In this post hoc analysis from the MITO END-3 trial, we confirmed the high frequency of PIK3CA mutations in EC, establishing this tumor as an ideal candidate for testing of PI3K inhibitors in clinical trials.

DOI: https://doi.org/10.1200/PO-26-00484

Cell. 2026 Oct 15. pii: S0092-8674(26)01135-9. [Epub ahead of print]189(21): 6594-6612.e21

Comprehensive benchmarking of somatic mutation detection by the SMaHT Network.

Somatic Mosaicism across Human Tissues Network. Electronic address: abyzov.alexej@mayo.edu

Somatic mosaicism is increasingly recognized as a fundamental feature of human biology, yet the detection of somatic mutations remains challenging. The Somatic Mosaicism across Human Tissues (SMaHT) Network conducted large-scale benchmarking experiments involving cell lines and donor tissues to evaluate sequencing technologies, experimental approaches, and computational methods for detecting different types of somatic mutations, generating community resources with >1,000× short-read and 100-400× long-read data for nine analyzed samples. We determined effective strategies for utilizing short- and long-read sequencing for mutation detection and demonstrated that using donor-specific and pangenome-inferred diploid assemblies improved calling, extending mutation catalogs to challenging genomic regions. We benchmarked six duplex technologies and showed that single-cell sequencing resolves cell-type-specific mutational patterns and heterogeneity. Our results indicate that bulk, single-cell, and duplex analyses are complementary and that leveraging all three provides comprehensive characterization of mosaicism within tissues. Together, these findings provide the scientific and clinical communities with a roadmap for accurate genome-wide somatic mutation analysis.

Keywords: PTA; assembly; cell; duplex; human; lineage; mosaicism; mutation; post-zygotic; somatic

DOI: https://doi.org/10.1016/j.cell.2026.09.037

Gynecol Oncol. 2026 Oct 16. pii: S0090-8258(26)02157-8. [Epub ahead of print]214 110-118

Clinical implications of germline and somatic genetic testing in ovarian carcinoma: BRCA and beyond. The PERSONA-Ovary trial.

OBJECTIVE: The PERSONA-Ovary study evaluated germline pathogenic/likely-pathogenic variant prevalence, feasibility of unselected multigene testing integration in routine clinical care, and germline-somatic BRCA concordance in ovarian cancer patients.
METHODS: We conducted a prospective observational study of consecutive ovarian carcinoma patients treated at a tertiary-cancer care center, between July 2018 and September 2021. Germline multigene panel testing was performed using next-generation sequencing. Feasibility was assessed by informative rate and turnaround time. Germline-somatic concordance was assessed in patients with paired tumor BRCA results.
RESULTS: Among 320 patients, pathogenic/likely-pathogenic variants were identified in 95 (29.7%, 95% CI 24.7-35.0); 81 (85.3%, 95% CI 76.5-91.7) carried mutations in ovarian cancer susceptibility genes, including 60 with BRCA alterations (63.2%, BRCA1 n=43, BRCA2 n=17). Germline testing was informative in all patients (100%). Median turnaround time was 221days (IQR 173-284), improving significantly across study periods (p<0.001). Tumor BRCA testing was available in 298 patients (93.1%), with germline-somatic concordance of 94.0% (κ=0.82, 95% CI 0.72-0.90). A germline-first strategy with reflex tumor testing achieved complete detection with fewer assays than parallel testing; a tumor-first strategy required the fewest assays (366 vs 596) but missed two germline BRCA carriers (detection rate of 96.3%).
CONCLUSION: Unselected germline multigene panel testing was technically feasible and clinically informative in routine ovarian cancer care. Pathogenic/likely-pathogenic variants were identified in 29.7% of patients, supporting germline testing integration into contemporary ovarian cancer management. Although germline-first strategies maximize hereditary cancer detection, dedicated molecular workflows remain necessary to ensure clinically actionable turnaround times.

Keywords: BRCA1; BRCA2; Genetic testing; Germline mutation; Next generation sequencing; Ovarian cancer

DOI: https://doi.org/10.1016/j.ygyno.2026.10.006

Nat Med. 2026 Oct 14.

Personalized neoantigen-targeting cancer vaccines in ovarian cancer: a phase 1 trial.

Personalized neoantigen-targeting cancer vaccines in the adjuvant setting are of increasing interest across malignancies. Here we report the results of a phase 1 clinical trial testing the feasibility and safety of personalized neoantigen-targeting cancer vaccines for high-grade epithelial ovarian cancer. 'NeoVax' consisted of pools of synthetic long peptides targeting patient-specific neoantigens admixed with the immunostimulant poly-ICLC, was combined with delayed administration of anti-PD-1 antibody, and was tested in ten patients (one newly diagnosed patient (Cohort A) and nine patients at first recurrence (Cohort B)) with platinum-sensitive ovarian cancer following standard-of-care platinum doublet chemotherapy. Nine of 12 evaluable Cohort B patients were vaccinated (75%, 90% CI 47-93%) and 1 of 9 Cohort A patients (11%, 90% CI 0.6-43%). No unexpected safety signals were encountered and no patients discontinued treatment due to toxicity. Across patients, >70% selected targets remained detectable by noninvasive cell-free DNA analysis despite a median of 6.5 months from the time of diagnostic biopsy to vaccine administration, during which, patients received standard-of-care chemotherapy. Biomarker analysis was suggestive of biologic activity of the vaccine in six of ten patients and this was associated with broader tumor and vaccine-specific immune responses in blood and tumor following vaccination. Resistant tumor clones reflected diverse mechanisms affecting antigen presentation, indicative of immune-selective pressure exerted by vaccination. Overall, the interplay between the repertoire of antigens presented by the tumor and the breadth of induced immunity seemed to dictate clinical efficacy following vaccination. ClinicalTrials.gov identifier: NCT04024878 .

DOI: https://doi.org/10.1038/s41591-026-04717-8