bims-ovdlit 2026-10-04 papers

Int J Gynecol Pathol. 2026 Sep 28.

Interobserver Variability in Diagnosing STIC With Frequent Underdiagnosis of Early High-grade Serous Carcinoma: Insights From a Multicenter Review From the CANSTIC Study.

Sarah E J Khan, Martin Köbel, Elisabeth Spénard, Lien Hoang, Katherine Grondin, Marcus Q Bernardini, Marjan Rouzbahman.

It has become widely accepted that most cases of tubo-ovarian high-grade serous carcinoma (HGSC) arise from precursor lesions in the fallopian tube called serous tubal intraepithelial carcinoma (STIC). This study evaluated the interobserver reproducibility of STIC diagnosis and its diagnostic boundaries from a multicentre Canadian cohort study. The multicentre CANSTIC study included patients with isolated STIC diagnosed between 1998 and 2020 across 15 Canadian centres. A blinded panel of 4 subspecialized gynecologic pathologists independently reviewed scanned slides (hematoxylin and eosin, p53, and Ki67) from 57 cases and met for a consensus meeting. Diagnoses were grouped as HGSC, STIC, and serous tubal intraepithelial lesion/other. The initial interobserver agreement for the diagnostic categories was moderate (Fleiss's kappa =0.495, 95% CI: 0.269-0.675; Cohen's kappa =0.492, 95% CI: 0.226-0.758, percent agreement 83.3%). A concordant diagnosis among all 4 reviewers was initially reached in 68% (39/57; 95% CI: 55.5%-79.0%), which increased to 91% (52/57; 95% CI: 81.1%-96.2%) after the consensus meeting. Consensus or majority (3 of 4 reviewers) was considered the final diagnosis; this resulted in STIC in 79% (45/57; 95% CI: 66.7-87.5), in agreement with the original diagnosis. Nine percent of cases were downgraded to serous tubal intraepithelial lesion/other (5/57; 95% CI: 1.8%-14.4%), while 12% were upgraded to HGSC (7/57; 95% CI: 6.1%-23.2%). Six patients developed HGSC clinically (11%; 95% CI: 4.9%-21.1%), of whom 3 had a review diagnosis of HGSC and 3 of STIC. This study shows suboptimal interobserver reproducibility for a diagnosis of STIC, despite consideration of ancillary p53/Ki67 testing. This study offers guidance to increase interobserver reproducibility in this challenging area, particularly in avoiding an underdiagnosis of HGSC.

Keywords: Fallopian tube; High-grade serous carcinoma; Ovary; Serous tubal intraepithelial carcinoma

DOI: https://doi.org/10.1097/PGP.0000000000001218

JAMA. 2026 Sep 28.

Diagnostic Delays Associated With a Screening Trial of a Multicancer Early Detection Test-Reply.

Sean Mann, Pedro Nascimento de Lima, Beth Ann Griffin.

DOI: https://doi.org/10.1001/jama.2026.15538

JAMA. 2026 Sep 28.

Diagnostic Delays Associated With a Screening Trial of a Multicancer Early Detection Test.

Michael Froehner.

DOI: https://doi.org/10.1001/jama.2026.15536

Nat Genet. 2026 Sep 29.

Genetics and treatment history influence clonal hematopoiesis risk after PARP inhibitor therapy.

DOI: https://doi.org/10.1038/s41588-026-02749-x

JAMA Oncol. 2026 Oct 01.

Rethinking Treatment Intensification in Poorly Chemosensitive Ovarian Cancer: A Review.

Importance: Despite the integration of bevacizumab and poly(ADP-ribose) polymerase inhibitors into first-line treatment of advanced high-grade serous ovarian cancer, survival remains poor for the substantial subset of patients whose tumors respond insufficiently to platinum-based chemotherapy and who, therefore, frequently do not achieve complete cytoreductive surgery (the 2 red flags population). This Review examines the rationale, current evidence, and emerging strategies for systemic treatment intensification-or chemosensitization-aimed at improving tumor response before initiating maintenance therapy.
Observations: Achieving minimal residual disease before maintenance depends on 2 key determinants: surgical completeness and intrinsic tumor chemosensitivity. Pragmatic indicators of chemosensitivity-KELIM (modeled cancer antigen 125 elimination rate constant K), pathological chemotherapy response score, and radiologic response-are now cited in European Society for Medical Oncology-European Society of Gynaecological Oncology and American Society of Clinical Oncology guidelines, while BRCA/homologous recombination deficiency status may not reliably predict neoadjuvant carboplatin-paclitaxel response. Across post hoc analyses of phase 3 trials (ICON-7, GOG-0218, ICON-8, ICON-8B, VELIA, and IMagyn050), patients with poorly chemosensitive disease may have derived greater benefit from intensification strategies. Weekly dose-dense paclitaxel was associated with improved survival in the 2 red flags subgroup of ICON-8. Bevacizumab, added either to standard postoperative chemotherapy or to neoadjuvant dose-dense chemotherapy, showed signals of greater benefit on both progression-free and overall survival in high-risk and poorly chemosensitive subsets. In contrast, poly(ADP-ribose) polymerase inhibitor and immune checkpoint inhibitor combinations showed meaningful activity only in selected subgroups, supporting further evaluation of innovative DNA repair-targeting agents and immunotherapeutic approaches in these populations.
Conclusions and Relevance: Early identification of poorly chemosensitive advanced high-grade serous ovarian cancer enables a response-adapted first-line strategy in which treatment intensification is selectively offered to patients most likely to benefit-an approach now being prospectively evaluated in the phase 3 SALVOVAR and phase 1/2 RegeNovar trials. This framework provides a clinically actionable platform to test novel therapies aimed at increasing complete interval cytoreduction rates and improving survival in a population with otherwise limited options.

DOI: https://doi.org/10.1001/jamaoncol.2026.3875

Gynecol Oncol. 2026 Sep 22. pii: S0090-8258(26)02139-6. [Epub ahead of print]214 15-21

Survival associated with recommended risk-reducing interventions for individuals with pathogenic variants in BRCA1/2.

Isabel Beshar, David Viveros-Carreno, Nuria Agusti, Roni Nitecki Wilke, J Alejandro Rauh-Hain.

Individuals with pathogenic variants in BRCA1 and BRCA2 face increased risks of breast and ovarian cancer and are recommended to follow lifelong cancer prevention strategies to reduce their cancer-related morbidity and mortality. Many of these strategies, including annual imaging, risk-reducing surgery, and select medication, have been shown to reduce cancer incidence or shift diagnosis toward early-stage disease. However, survival benefits of these commonly recommended interventions have been more difficult to demonstrate, and the quality of evidence supporting survival varies substantially across interventions. In this narrative review, we use the 2026 National Comprehensive Cancer Network (NCCN) guidelines as a framework to identify current breast and ovarian cancer risk-management strategies and evaluate the strength and certainty of the evidence supporting the potential survival benefit of each recommendation. We address methodological challenges that complicate interpretation of survival-associated outcomes, including limitations of observational study design and biases that restrict causal inference. We demonstrate that risk-reducing salpingo-oophorectomy has the most consistent evidence supporting improved overall survival, whereas evidence for breast cancer interventions may be limited by competing preventive strategies and concerns for self-selection and immortal time bias. Recognizing these differences may facilitate informed shared decision-making between patients and providers and identify priorities for future prospective research in hereditary breast and ovarian cancer.

Keywords: BRCA; Breast cancer; Breast imaging; Ovarian cancer; Risk-reducing mastectomy; Risk-reducing salpingo-oophorectomy; cancer prevention

DOI: https://doi.org/10.1016/j.ygyno.2026.09.014

Cancer Discov. 2026 Oct 01. 16(10): 1973-1991

Immunologic Consequences of Genomic Instabilities.

Emily Alouani, Jean-David Fumet, Paul Johannet, Aurélien Marabelle, Benoit Rousseau.

Genomic instability manifests in two distinct ways based on DNA alteration scale, differentially affecting the tumor-immune microenvironment. Mutational instability involves excessive accumulation of small-scale alterations, such as substitutions and indels, from defective DNA repair or aberrant mutagenic processes, generating neoantigens and increased immunogenicity. Chromosomal instability encompasses large-scale alterations in which cells gain, lose, or rearrange chromosomes, resulting in aneuploidy and immune evasion through chronic innate activation and myeloid remodeling. This review outlines differences between mutational and chromosomal instability and discuss how their interplay shapes tumor immunogenicity and response to immunotherapy. Understanding these opposing mechanisms could inform immunotherapeutic approaches in cancer.
SIGNIFICANCE: Mutational and chromosomal alterations exert opposing effects on antitumor immunity. Hypermutated tumors can generate abundant neoantigens that prime adaptive immunity and sensitize tumors to checkpoint blockade. In contrast, chromosomal instability triggers chronic innate immune signaling that is paradoxically immunosuppressive, in part through myeloid cell and T-cell dysfunction. Integrating both processes into a unified framework could help uncover mechanisms of immune evasion and guide personalized immunotherapeutic strategies.

DOI: https://doi.org/10.1158/2159-8290.CD-25-2063

Nat Genet. 2026 Sep 28.

Germline homologous recombination deficiency influences TP53-mutant clonal hematopoiesis fitness during platinum and PARP inhibitor treatment.

Poly(ADP-ribose) polymerase inhibitors (PARPi) are commonly used in tumors with homologous recombination deficiency (HRD) but are associated with an increased risk of therapy-related myeloid neoplasms (tMN). Clonal hematopoiesis (CH) driven by DNA damage response (DDR) mutations is the origin of most tMN. Here, to better understand the causes of tMN following PARPi therapy, we studied the relationship between PARPi use and CH. We observed a high frequency of DDR CH following PARPi therapy, largely explained by prior carboplatin exposure. Among patients with serial blood sampling, DDR CH expanded during carboplatin and to a lesser extent, during PARPi treatment. Surprisingly, this expansion was largely reduced in patients with germline HRD. We validated these findings in a mouse model of Trp53-mutated CH. Our findings suggest that the increased risk of tMN following PARPi is largely influenced by prior oncologic therapies, including carboplatin, and may vary by germline HRD status.

DOI: https://doi.org/10.1038/s41588-026-02752-2

NPJ Precis Oncol. 2026 Jul 23. pii: 361. [Epub ahead of print]10(1):

MammaTrace - a tumor naïve cell-free DNA methylation test for minimal residual disease in breast cancer.

David N Buckley, Alex J Kalfa, Gerald Gooden, Juan Pablo Lewinger, Marissa Pacheco, Jessica Gayton, Darcy Spicer, John Carpten, Daphne Stewart, Heinz-Josef Lenz, Chanita Hughes Halbert, Caryn Lerman, Joyce O'Shaughnessy, Barbara Pockaj, Bodour Salhia.

Metastatic breast cancer (MBC) remains an incurable disease with a 5-year overall survival below 25%. Metastases often emerge from subclinical, disseminated tumor cells that persist after primary therapy, referred to as minimal residual disease (MRD). Detecting MRD is critical for identifying patients at high risk of recurrence and enabling timely intervention. We constructed MammaTrace, a plasma-only, tumor-naive cfDNA methylation assay for MRD surveillance in breast cancer. Candidate differentially methylated regions (DMRs) associated with metastasis and recurrence were identified directly from plasma cfDNA using whole genome bisulfite sequencing (WGBS) of MBC, healthy controls, and treatment-naive patients with stage I-III breast cancer who either developed recurrence or remained disease-free. These DMRs were incorporated into a targeted capture panel and used to train a binary classification model. The assay was evaluated in an independent longitudinal cohort of 107 early-stage breast cancer (EBC) patients treated with curative intent, with serial plasma samples collected prior to recurrence. MammaTrace demonstrated strong performance in distinguishing MBC from healthy samples, achieving a ROC AUC of 0.96. For MRD detection in EBC samples collected more than 9 months after surgery, MammaTrace achieved a sensitivity of 91% and specificity of 83% (AUC = 0.88). A positive MammaTrace score preceded clinically confirmed recurrence by a median of 457 days, providing substantial lead time for therapeutic intervention. MammaTrace enables detection of MRD in breast cancer patients, providing substantial lead time prior to clinical recurrence. This approach may improve risk stratification and support earlier therapeutic intervention to delay or prevent metastatic progression.

DOI: https://doi.org/10.1038/s41698-026-01595-8