bims-ovdlit 2026-09-06 papers

Issue of 2026–09–06
five papers selected by
Lara Paracchini, Humanitas Research

Am J Surg Pathol. 2026 Sep 01.

Folate Receptor Alpha Expression Across the Spectrum of Serous Tubal Lesions: An Adjunct Biomarker for Distinguishing Serous Tubal Intraepithelial Carcinoma From Serous Tubal Intraepithelial Lesions.

Yan Feng, Rujia Fan, Zhigang Yao, Zeng Yuan, Ruijiao Zhao, Yuxin Liu, M Ruhul Quddus, Oluwole Fadare, Jayanthi Lea, Beihua Kong, Wenxin Zheng.

Folate receptor alpha (FRα) is highly expressed in tubo-ovarian high-grade serous carcinoma (HGSC), but its expression in serous tubal intraepithelial carcinoma (STIC) and earlier tubal lesions has not been systematically characterized. We evaluated FRα expression across the spectrum of fallopian tube lesions and assessed its potential as an adjunctive diagnostic biomarker. Immunohistochemistry was performed on 408 tubal epithelial samples from 262 patients, including 52 normal fallopian tube samples, 110 secretory cell expansions (SCE), 88 secretory cell outgrowths (SCOUT), 72 serous tubal intraepithelial lesions (STIL), and 56 STICs. An additional 30 HGSCs were included for comparison. FRα expression was assessed using the percentage score ≥2+ (PS2+) system. Associations with germline BRCA status and age were evaluated. FRα expression was detectable in normal fallopian tube epithelium but usually below the high-expression threshold. In contrast, expression was increased in STIC and HGSC, with high PS2+ scores in 73.2% and 76.7% of cases, respectively. Earlier tubal lesions showed predominantly low or negative/very low expression. No significant difference in FRα expression was observed between STIC and HGSC. BRCA-mutated STIC and HGSC showed higher FRα expression than their BRCA nonmutated counterparts, whereas earlier lesions showed no such association. In normal fallopian tube epithelium, FRα expression decreased with age. These findings demonstrate that FRα upregulation is established at the STIC stage and maintained in invasive HGSC. Diffuse high-level expression is uncommon in STIL and earlier lesions, suggesting that FRα may serve as an adjunct biomarker for distinguishing STIC from morphologically overlapping lesions. When interpreted in conjunction with morphology, p53, and Ki-67, FRα may improve diagnostic confidence along the STIL-to-STIC spectrum. The early and sustained upregulation of FRα in STIC also raises interesting questions regarding the timing of FRα-targeted interventions.

Keywords: Serous tubal intraepithelial lesion (STIL); folate receptor alpha (FRα); high-grade serous carcinoma (HGSC); serous tubal intraepithelial carcinoma (STIC); tubal epithelial alterations

DOI: https://doi.org/10.1097/PAS.0000000000002612

Klin Onkol. 2026 ;39(Supplementum 1): 17-25

Multicancer early detection (MCED) tests - an overview of technologies and clinical evidence.

T Büchler, M Zubaľ, M Svoboda, J Halámková.

Early detection of cancer is one of the key factors influencing patient prognosis and overall cancer-related mortality. However, current population--based screening programs are limited to only a few selected diagnoses, and many highly lethal malignancies still lack an effective option for early detection. Multicancer early detection (MCED) tests represent a new group of blood-based screening methods aimed at identifying the presence of early-stage cancer across multiple primary sites through a single peripheral blood sample. They mainly rely on the analysis of circulating tumor DNA, including its methylation and fragmentation characteristics, or on combinations with protein markers or the detection of circulating tumor cells. These tests offer high specificity and are able to estimate the most likely site of origin of the tumor, which is crucial for guiding subsequent diagnostic workup. At present, the largest body of evidence is available for methylation-based and multiomic platforms. Prospective studies conducted so far in asymptomatic individuals suggest that MCED tests may enable the detection of cancers at clinically relevant stages, with a relatively low false-positive rate and an acceptable burden of follow-up investigations. At the same time, important limitations remain particularly lower sensitivity in the earliest stages of disease, the absence of standardized diagnostic algorithms following a positive result, and the lack of evidence for an effect on cancer-specific mortality and the incidence of advanced-stage disease. MCED tests therefore cannot yet be considered a replacement for established organ-specific screening programs. However, they appear to be a promising complement to current screening strategies, particularly for the detection of cancers for which no established screening exists. Their future clinical role will depend on the results of large prospective and randomized studies demonstrating their true benefit for both the population and healthcare systems. In addition to strong evidence of clinical benefit, widespread implementation into clinical practice will also require standardization of downstream diagnostic pathways and careful health-economic evaluation.

Keywords: Circulating tumor DNA; DNA methylation; circulating tumor DNA; early cancer detection; liquid biopsy

DOI: https://doi.org/10.48095/ccko2026S17

ESMO Gastrointest Oncol. 2026 Sep;13(Pt B): 100407

The role of circulating tumor DNA (ctDNA) to detect minimal residual disease in locally advanced gastroesophageal carcinoma: the BUTTERFLY study.

Background: Despite advances in perioperative and neoadjuvant strategies, patients with locally advanced gastroesophageal cancers remain at high risk of recurrence after curative intent treatment. No validated biomarkers are available to detect minimal residual disease (MRD) or to guide post-operative risk-adapted management. Circulating tumor DNA (ctDNA) has emerged as a noninvasive tool for disease monitoring; single-parameter or tumor-informed assays, however, may lack sensitivity in low-tumor burden settings. Multimodal, tumor-agnostic approaches may overcome these limitations.
Methods: The BUTTERFLY study is a prospective, multicenter observational study enrolling patients with stage II-III gastric, gastroesophageal junction, or esophageal cancer treated with perioperative chemotherapy or neoadjuvant chemoradiotherapy followed by surgery. It evaluates the diagnostic performance and prognostic value of an academic, tumor-agnostic, multimodal ctDNA assay for MRD detection and prognostic stratification. Serial plasma samples are collected from baseline through post-operative follow-up and at relapse. Cell-free DNA is analyzed using the Agnostic Liquid Biopsy Multimodal Advancement (ALMA) platform, integrating tumor fraction estimation, somatic copy number alterations, fragmentomic features, single-nucleotide variants, and whole-genome methylation profiling. Multimodal features are combined with clinical variables using machine learning-based models to enhance MRD detection and relapse risk stratification. The primary endpoint includes sensitivity and specificity of ALMA-defined ctDNA/MRD status at the 4-8 weeks after surgery landmark, whereas secondary endpoints assess diagnostic performance at other time points and associations between ctDNA status and dynamics with disease-free survival, overall survival, treatment response, and lead time to recurrence.
Future perspectives: If validated, this tumor-agnostic, multimodal ctDNA approach may enable earlier molecular relapse detection and support personalized post-operative management strategies.

Keywords: circulating tumor DNA (ctDNA); gastroesaophageal cancer; minimal residual disease (MRD); perioperative setting

DOI: https://doi.org/10.1016/j.esmogo.2026.100407

Fam Cancer. 2026 Aug 29. pii: 84. [Epub ahead of print]25(3):

The evolution of hereditary cancer genetic counselling: mainstreaming, service redesign and patient experience in Lynch syndrome.

Kelly Kohut, Sarah Cable, Alekhya Ashokan, Stefania Vicari, Hannah Ditchfield, Julie Young, Ben Bux, Fiona Lalloo.

Genetic counselling for hereditary cancer predisposition has evolved substantially over more than three decades, driven by advances in genomic technologies and the growing use of tumour and germline testing. These developments have expanded access to hereditary cancer testing, treatment and prevention, while also introducing new clinical, psychosocial and system-level challenges. This review examines the transition from traditional specialist-led genetic counselling to mainstreamed testing pathways. Using Lynch syndrome as a paradigm, we explore how service redesign, personalised risk communication and patient experience intersect in contemporary hereditary cancer care. This invited review synthesises clinical, academic and patient perspectives on the evolution of hereditary cancer genetic counselling. Lived experiences of Lynch syndrome were incorporated through patient and public involvement contributors involved in manuscript development and interpretation. Mainstreamed testing has expanded access to genomic information and strengthened opportunities for cascade testing and prevention within families. However, it has also increased testing volumes, complexity of results interpretation and reliance on non-genetics clinicians. As a result, effective care requires close coordination between genetics and cancer services, alongside support for shared decision-making, family communication and psychosocial needs. This review uniquely integrates clinical evidence and lived experience to highlight how mainstreaming has transformed the delivery of hereditary cancer genetic counselling but not the need for specialist genetics expertise. Lynch syndrome illustrates how genomics can be integrated into routine cancer care while maintaining personalised counselling and family-centred follow-up. These principles are relevant across hereditary cancer predispositions and inform the future development of genetic counselling services.

Keywords: Genetic counselling; Genetic testing; Lynch syndrome; Mainstreaming; Patient and public involvement (PPI); Shared decision-making

DOI: https://doi.org/10.1007/s10689-026-00597-6

JAMA Otolaryngol Head Neck Surg. 2026 Sep 03.

Tissue-Informed ctDNA Assay Performance in Head and Neck Squamous Cell Carcinoma.

Ryan M Sicard, Peter V Cooke, Alyssa Steinbaum, Diana Shaari, Alicia B Yang, Ethan Gomez, Daniel O Kraft, Michael Berger, Marita S Teng, Mohemmed N Khan, Krzystoff J Misiukiewicz, Elisabet Pujadas, Richard Bakst, Kunal Sindhu, Eric M Genden, Raymond Chai, Scott A Roof.

Importance: Liquid biopsy is emerging as a strong biomarker for detecting and monitoring head and neck squamous cell carcinoma (HNSCC). The strongest evidence for circulating tumor DNA (ctDNA) in HNSCC comes from studies of tissue-agnostic assays detecting human papillomavirus (HPV)-associated HNSCC. In HPV-negative HNSCC, the lack of broadly shared variational targets precludes the use of tissue-agnostic ctDNA approaches. An emerging alternative, tissue-informed assays, leverage patient-specific tumor variant profiles to enable individualized ctDNA detection in the blood.
Objective: To measure the detection characteristics of a commercially available tissue-informed assay when compared to the standard criterion for tissue biopsies, both in the pretreatment and surveillance settings of HPV-positive and HPV-negative HNSCC.
Design, Setting, and Participants: This was a retrospective cohort study of adults with HNSCC who received a tissue-informed ctDNA assay as part of their oncologic treatment at a large, urban tertiary care center from December 2024 to March 2026. Data analysis was conducted from March to April 2026.
Exposure: Tumor tissue specimen, collected by fine-needle aspiration or surgical biopsy, used to create an individualized ctDNA assay for subsequent ctDNA blood tests.
Main Outcomes and Measures: For the pretreatment analysis: test detection rate, miss rate, and insufficient tissue rate. In the surveillance setting: sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) on a per-test and per-patient basis.
Results: The pretreatment cohort comprised 77 patients (mean [SD] age, 65.0 [12.6] years; 28 female [36%] and 49 male [64%] individuals) and the surveillance cohort, 107 patients (mean [SD] age, 65.0 [12.1] years; 28 female [26%] and 79 male [74%] male individuals). The median (IQR) time since treatment conclusion for patients in the surveillance cohort was 18 (11-39) months. Tissue-informed ctDNA was detected in 71 of 77 patients (92.2%) in the initial pretreatment setting. In the surveillance setting, the assay demonstrated a per-test sensitivity of 95.2% (20 of 21 patients; 95% CI, 83.3%-100%), specificity of 100% (157 of 157 patients; 95% CI, 100%-100%), PPV of 100% (20 of 20 patients; 95% CI, 100%-100%), and a NPV of 99.4% (157 of 158 patients; 95% CI, 97.9%-100%). On a per-patient level, the sensitivity was 94.4% (17 of 18 patients; 95% CI, 72.7%-99.9%), specificity was 100% (89 of 89 patients; 95% CI, 95.9%-100%), PPV was 100% (17 of 17 patients; 95% CI, 80.5%-100%), and NPV was 98.9% (89 of 90 patients; 95% CI, 93.0%-99.8%).
Conclusions and Relevance: In this cohort study, tissue-informed ctDNA assay showed excellent test creation ability in the pretreatment setting and performance metrics in the surveillance setting. Reasons for a failure rate of 7.8% in the pretreatment cohort remain unclear. These metrics support the feasibility of using this assay as a promising ctDNA approach for disease monitoring in HNSCC.

DOI: https://doi.org/10.1001/jamaoto.2026.2469