bims-tumhet 2025-04-13 papers

Issue of 2025–04–13
five papers selected by
Sergio Marchini, Humanitas Research

Cancer Sci. 2025 Apr 09.

BRCA1 Promoter Methylation in Ovarian Cancer: Clinical Relevance and a Novel Diagnostic Approach Using Fragment Analysis.

Homologous recombination deficiency (HRD) tests, including MyChoice CDx, are companion diagnostics for poly (ADP-ribose) polymerase (PARP) inhibitors. BRCA1 promoter hypermethylation, a major HRD cause, may correlate with poorer prognosis. This study aimed to develop a simple, accurate method for detecting BRCA1 promoter hypermethylation and elucidate the characteristics of such cases. BRCA1 promoter methylation was analyzed using bisulfite sequencing (BIS-seq) in high-grade serous ovarian carcinoma specimens. We developed a newly developed BRCA1 methylation assay, BRCA1-Fragment Analysis of Methylation (BRCA1-FAM), which combines restriction enzyme digestion with fragment analysis. The accuracy of this assay was compared to the results of BIS-seq. We evaluated the relationship between BRCA1 promoter hypermethylation and prognosis and examined its association with BRCA1 expression and loss of heterozygosity. BRCA1 mutations and promoter methylation were mutually exclusive in the analyzed cases, with methylation observed in 28.9% (22/76) of primary debulking surgery cases. The BRCA1-FAM showed high sensitivity (91.3%) and specificity (100%) for detecting BRCA1 promoter hypermethylation, comparable to BIS-seq. Cases with BRCA1 promoter hypermethylation had significantly poorer progression-free survival (log-rank test, p = 0.048). Among these cases, 86.4% displayed abnormal BRCA1 immunostaining, with lower frequencies of BRCA1 loss of heterozygosity compared to those of other groups. BRCA1 promoter hypermethylation is associated with poor prognosis, underscoring the importance of its identification for HRD stratification. BRCA1-FAM is a simple and highly accurate method for evaluating BRCA1 promoter methylation. This approach may potentially enhance the precision of personalized therapies for ovarian cancer.

Keywords: BRCA1 ; DNA fragmentation; DNA methylation; homologous recombination deficiency; ovarian cancer

DOI: https://doi.org/10.1111/cas.70078

Clin Cancer Res. 2025 Apr 08.

Navigating Complexity: Perspectives on Risk Assessment in the Era of New Blood-based Tests for Early Cancer Detection.

In recent years there has been a surge in the development of new, blood-based, single- and multi-cancer detection tests (SCD and MCD), which can detect cancer signals prior to the onset of symptoms or clinical diagnosis of cancer. Recognizing the need for consensus definitions and standardized evidence development frameworks for these new types of blood test, the Early Detection and Screening (ED&S) Working Group of the Blood Profiling Atlas in Cancer (BLOODPAC) Consortium, a collaborative initiative dedicated to advancing standards and best practices, developed and published a lexicon for liquid-biopsy based SCD and MCD tests. During the preparation of the lexicon, the group recognized challenges regarding the definitions of key terms and concepts describing absolute and relative risk assessment of intended use populations for cancer screening tests. This article captures the working group's discussions on 1) risk assessment including considerations for adapting historical SCD risk terminology like "average risk" and "elevated risk" to MCD tests; 2) the implications of this terminology for describing intended use populations; 3) and the existing gaps in evidence for determination of absolute risks.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-4269

Biochim Biophys Acta Rev Cancer. 2025 Apr 04. pii: S0304-419X(25)00054-X. [Epub ahead of print]1880(3): 189312

Tertiary lymphoid structures achieve 'cold' to 'hot' transition by remodeling the cold tumor microenvironment.

Mengke Cui, Mengfan Zhou, Lu Zhou, Gan Zhou, Yingzi Liu.

Immune checkpoint blockade (ICB) therapies have demonstrated significant clinical efficacy in immune-infiltrated tumors such as melanoma and non-small cell lung cancer. However, "cold tumors"-including ovarian cancer, pancreatic cancer, and gliomas-exhibit insufficient immune infiltration, leading to poor therapeutic responses to ICBs and limited improvement in patient prognosis. Recent studies have shown that tumor-associated tertiary lymphoid structures (TLSs) can induce strong local immune responses within the tumor microenvironment (TME), serving as important biological markers for predicting ICB therapy efficacy. Notably, preclinical and clinical studies on cold tumors have confirmed that TLSs can potently enhance ICB efficacy through TME remodeling-a breakthrough that has attracted considerable attention. Here, we systematically examine the immunological profile of cold tumors and decipher the mechanistic basis for their impaired immune cell infiltration. We further delineate the distinctive features of tumor-associated TLSs in generating antitumor immunity and establish criteria for their identification. Significantly, we emphasize the unique capability of TLSs to reprogram the immunosuppressive tumor microenvironment characteristic of cold tumors. Based on these insights, we evaluate clinical evidence supporting TLS-mediated enhancement of ICB efficacy and discuss emerging strategies for exogenous TLSs induction.

Keywords: Cold tumor; Immune checkpoint blockade; Immunosuppressive; Tertiary lymphoid structures; Tumor Microenvironment

DOI: https://doi.org/10.1016/j.bbcan.2025.189312

Ann Oncol. 2025 Apr 03. pii: S0923-7534(25)00130-9. [Epub ahead of print]

Circulating tumor DNA Clearance as a Predictive Biomarker of Pathologic Complete Response in Patients with Solid Tumors Treated with Neoadjuvant Immune-Checkpoint Inhibitors: a Systematic Review and Meta-Analysis.

C Valenza, E F Saldanha, Y Gong, P De Placido, D Gritsch, H Ortiz, D Trapani, F Conforti, C Cremolini, S Peters, J Mateo, V Subbiah, H A Parsons, A H Partridge, G Curigliano.

BACKGROUND: In patients with solid tumors undergoing neoadjuvant immune checkpoint inhibitor (ICI) therapy, identifying biomarkers to predict pathologic complete response (pCR) preoperatively could enhance treatment modulation. Circulating tumor DNA (ctDNA) clearance is a potential predictor of pCR, though its analytical and clinical validity has yet to be established. This systematic review and meta-analysis aims to assess the role of ctDNA clearance as a predictor of pCR in patients with solid tumors treated with neoadjuvant ICIs.
MATERIALS AND METHODS: A systematic search of PubMed, EMBASE and conference proceedings up to 5 August 2024 was carried out to identify phase 1b, 2 or 3 clinical trials investigating ctDNA clearance and pCR in patients with solid tumors and detectable ctDNA, undergoing neoadjuvant therapy with ICIs. Using a bivariate model, we estimated the pooled sensitivity and specificity of ctDNA clearance in predicting pCR, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR), with 95% Confidence Intervals (CI).
RESULTS: Thirteen trials involving 380 patients with detectable ctDNA at baseline were included. ctDNA was assessed with a tumor-informed approach in 11 (85%) trials. Overall, 38% of patients achieved pCR and 73% had ctDNA clearance before/at the surgery. Pooled sensitivity was 0.98 (95% CI: 0.86, 1.00), specificity was 0.53 (95% CI: 0.37, 0.69), PLR was 2.09 (95% CI: 1.48, 2.93), NLR was 0.04 (95% CI: 0.01, 0.26), DOR was 57.36 (95% CI: 8.12, 405.12). Significant heterogeneity was observed across studies (I2 ∼70% for all metrics), indicating considerable variability in the diagnostic performance.
CONCLUSION: The lack of ctDNA clearance may identify patients unlikely to have a pCR. Instead, the confirmatory power of ctDNA clearance is limited by low specificity and high heterogeneity due to the variability of the assays, and warrants further study. Therefore, clinicians should not rely on the use of ctDNA clearance to inform treatment decisions in the neoadjuvant setting.

Keywords: circulating tumor DNA; ctDNA clearance; immunotherapy; pathologic complete response; solid tumors

DOI: https://doi.org/10.1016/j.annonc.2025.03.019

Oncol Res. 2025 ;33(4): 781-793

Use of DNA methylation patterns for early detection and management of lung cancer: Are we there yet?

Kontic Milica, Markovic Filip.

Detecting lung cancer early is crucial for improving survival rates, yet it remains a significant challenge due to many cases being diagnosed at advanced stages. This review aims to provide advances in epigenetics which have highlighted DNA methylation patterns as promising biomarkers for early detection, prognosis, and treatment response in lung cancer. Techniques like bisulfite conversion followed by PCR, digital droplet polymerase chain reaction, and next-generation sequencing are commonly used for detecting these methylation patterns, which occur early in the cancer development process and can be detected in non-invasive samples like blood and sputum. Key genes such as SHOX2 and RASSF1A have demonstrated high sensitivity and specificity in clinical studies, making them crucial for diagnostic purposes. However, several challenges remain to be overcome before these biomarkers can be widely adopted for use in clinical practice. Standardizing the assays and validating their effectiveness are critical steps. Additionally, integrating methylation biomarkers with existing diagnostic tools could significantly enhance the accuracy of lung cancer detection, providing a more comprehensive diagnostic approach. Although progress has been made in understanding and utilizing DNA methylation patterns for lung cancer detection, more research and extensive clinical trials are necessary to fully harness their potential. These efforts will help establish the robustness of methylation patterns as biomarkers and therapeutic targets, ultimately leading to better prevention, diagnosis, and treatment strategies for lung cancer. In conclusion, DNA methylation states represent a promising avenue for advancing early detection, accurate diagnosis, and management of lung cancer.

Keywords: DNA methylation; Early detection; Epigenetics; Hypermethylation; Lung cancer

DOI: https://doi.org/10.32604/or.2024.057231