bims-preonc 2025-01-26 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2025–01–26
eightteen papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Liquid biopsy in cancer management: Integrating diagnostics and clinical applications.
A Review of Circulating Tumor DNA (ctDNA) in Pancreatic Cancer: Ready for the Clinic?
Can circulating tumor DNA guide treatment de-escalation in metastatic lung adenocarcinoma harboring actionable genomic alterations?
Circulating tumor DNA (ctDNA) trajectories predict survival in trifluridine/tipiracil-treated metastatic colorectal cancer patients.
Multiple time points for detecting circulating tumor DNA to monitor the response to neoadjuvant therapy in breast cancer: a meta-analysis.
Whole-genome sequencing of cell-free DNA reveals DNA of tumor origin in plasma from patients with colorectal adenomas.
Circulating tumour DNA in early stage and locally advanced NSCLC: ready for clinical implementation?
Targeted detection of sequence variants in cell-free DNA from cerebrospinal fluid in pediatric central nervous system tumors.
Efficacy of ramucirumab combined with erlotinib or osimertinib in untreated EGFR-mutated NSCLC patients with asymptomatic brain metastases: insights from molecular biomarkers in the RELAY-brain trial.
Comprehensive Genome Profiling for Treatment Decisions in Patients with Metastatic Tumors: Real-World Evidence Meta-Analysis and Registry Data Implementation.
Epigenomics-guided precision oncology: Chromatin variants in prostate tumor evolution.
Cell-free tumor DNA analysis in advanced or metastatic breast cancer patients: mutation frequencies, testing intention, and clinical impact.
A prospective study of methylated ctDNA in patients undergoing treatment for liver metastases from colorectal cancer.
BRCA functional domains associated with high risk of multiple primary tumors and domain-related sensitivity to olaparib: the Prometheus Study.
Molecular and Immunohistochemical Classification of Extrapulmonary Small Cell Neuroendocrine Carcinomas: A Study of 181 Cases.
Osimertinib as a neoadjuvant therapy in resectable EGFR-mutant non-small cell lung cancer: a real-world, multicenter retrospective study.
Pembrolizumab in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) and non-MSI-H/non-dMMR advanced endometrial cancer: Phase 2 KEYNOTE-158 study results.
Exploring the Role of Health-care Professionals and Impact of Precision Medicine on Health Outcomes and Efficiency.

Pract Lab Med. 2025 Jan;43 e00446

Liquid biopsy in cancer management: Integrating diagnostics and clinical applications.

Shashwat Pandey, Preeti Yadav.

  Liquid biopsy is an innovative, minimally invasive diagnostic tool revolutionizing cancer management by enabling the detection and analysis of cancer-related biomarkers from bodily fluids such as blood, urine, or cerebrospinal fluid. Unlike traditional tissue biopsies, which require invasive procedures, liquid biopsy offers a more accessible and repeatable method for tracking cancer progression, detecting early-stage cancers, and monitoring therapeutic responses. The technology primarily focuses on analyzing circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and other cancer-derived genetic materials. These biomarkers provide critical information on tumor heterogeneity, mutation profiles, and potential drug resistance. In clinical practice, liquid biopsy has demonstrated its utility in identifying actionable mutations, guiding personalized treatment strategies, and assessing minimal residual disease (MRD). While liquid biopsy holds immense promise, challenges related to its sensitivity, specificity, and standardization remain. Efforts to optimize pre-analytical and analytical processes, along with the establishment of robust regulatory frameworks, are crucial for its widespread clinical adoption. This abstract highlights the transformative potential of liquid biopsy in cancer diagnosis, prognosis, and treatment monitoring, emphasizing its role in advancing personalized oncology. Further research, clinical trials, and regulatory harmonization will be vital in realizing its full potential in precision cancer care.

Keywords:  Cancer; Liquid biopsy; Personalized medicine; Tissue biopsy

DOI:  https://doi.org/10.1016/j.plabm.2024.e00446
J Gastrointest Cancer. 2025 Jan 21. 56(1): 50

A Review of Circulating Tumor DNA (ctDNA) in Pancreatic Cancer: Ready for the Clinic?

Purvi Jonnalagadda, Virginia Arnold, Benjamin A Weinberg.

  Pancreatic ductal adenocarcinoma is a devastating disease which is associated with an increase in cancer-related death in the USA. The minority of patients are cured by surgery alone and typically require adjuvant chemotherapy in order to improve clinical outcomes. Circulating tumor DNA (ctDNA) is an emerging technology whereby microscopic levels of minimal residual disease (MRD) can be detected in the bloodstream. Circulating KRAS mutations are frequently studied given that they are present in over 90% of pancreatic cancers. Other assays utilize whole exome sequencing and/or methylomics to detect MRD. We demonstrate that ctDNA has prognostic and predictive capabilities in patients with both resectable and unresectable pancreatic ductal adenocarcinoma. ctDNA opens the door to novel therapeutic options and is already being integrated into ongoing clinical trials.

Keywords:  Circulating tumor DNA (ctDNA); First-line metastatic; Minimal residual disease (MRD); Pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1007/s12029-024-01151-2
Transl Lung Cancer Res. 2024 Dec 31. 13(12): 3831-3834

Can circulating tumor DNA guide treatment de-escalation in metastatic lung adenocarcinoma harboring actionable genomic alterations?

Fabian Acker, Martin Sebastian.



Keywords:  Epidermal growth factor receptor (EGFR); circulating tumor DNA (ctDNA); de-escalation; liquid biopsy (LB); non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.21037/tlcr-24-861
Mol Oncol. 2025 Jan 22.

Circulating tumor DNA (ctDNA) trajectories predict survival in trifluridine/tipiracil-treated metastatic colorectal cancer patients.

Matthias Unseld, Stefan Kühberger, Ricarda Graf, Christine Beichler, Markus Braun, Nadia Dandachi, Ellen Heitzer, Gerald W Prager.

  Late-line treatment in metastatic colorectal cancer (mCRC) can improve prognosis. However, not every patient has a benefit and may experience severe side effects. Thus, predictive/prognostic biomarkers are urgently needed. We investigated the prognostic role of circulating tumor DNA (ctDNA) in mCRC patients before and during treatment with trifluridine/tipiracil (FTD/TPI). This noninterventional translational biomarker phase II study enrolled 30 mCRC patients (60% male, 40% female). Using a 77-gene panel, ctDNA was detectable in 90% of patients. Tumor levels were assessed based on aneuploidy (ichorCNA) as well as the highest variant allele frequency, and correlated with overall survival (OS). Uni- and multivariate survival analyses were performed with clinical variables. Longitudinal changes in tumor levels over time were analyzed with linear mixed and joint models. The median OS was 8.1 months, with a recorded disease control rate of 30%. High ctDNA levels (≥ 5%) were associated with inferior survival after undergoing FTD/TPI therapy. Elevated tumor level trajectories over time were associated with higher risks of death. Therefore, ctDNA can help identify patients who are unlikely to benefit significantly from this treatment in late-stage disease, thus preventing unnecessary treatments and their associated side effects, ultimately enhancing quality of life.

Keywords:  circulating tumor DNA; joint model; metastatic colorectal cancer; mixed model; molecular profiling; trifluridine/tipiracil

DOI:  https://doi.org/10.1002/1878-0261.13755
BMC Cancer. 2025 Jan 22. 25(1): 115

Multiple time points for detecting circulating tumor DNA to monitor the response to neoadjuvant therapy in breast cancer: a meta-analysis.

Shuyi Niu, Tie Sun, Mozhi Wang, Litong Yao, Tianyi He, Yusong Wang, Hengjun Zhang, Xiang Li, Yingying Xu.

   BACKGROUND: Not all breast cancer (BC) patients can benefit from neoadjuvant therapy (NAT). A poor response may result in patients missing the best opportunity for treatment, ultimately leading to a poor prognosis. Thus, to identify an effective predictor that can assess and predict patient response at early time points, we focused on circulating tumor DNA (ctDNA), which is a vital noninvasive liquid biopsy biomarker. We performed a meta-analysis to explore the predictive value of response by monitoring ctDNA at four time points of NAT using pathologic complete response (pCR) and residual cancer burden (RCB).
METHODS: By searching Embase, PubMed, the Cochrane Library, and the Web of Science until December 24, 2023, we selected studies concerning the relationship between ctDNA and response or prognosis. We analysed the results at the following various time points: baseline (T0), first cycle of NAT (T1), mid-treatment (MT), and end of NAT (EOT). pCR and RCB were used to evaluate the response as the primary endpoint. The secondary endpoint was to investigate the relationship between ctDNA and prognosis. Odds ratios (ORs) and hazard ratios (HRs) were used as effect indicators.
RESULTS: Thirteen reports from twelve studies were eligible for inclusion in this meta-analysis. The results demonstrated that ctDNA negativity was associated with pCR at T1 (OR = 0.34; 95% CI: 0.21-0.57), MT (OR = 0.35; 95% CI: 0.20-0.60), and EOT (OR = 0.38; 95% CI: 0.22-0.66). When RCB was used to evaluate responses, ctDNA negativity was associated with RCB-0/I at the MT (OR = 0.34; 95% CI: 0.21-0.55) and EOT (OR = 0.26; 95% CI: 0.15-0.46). Furthermore, ctDNA positivity at T1 predicted a worse prognosis for patients (HR = 2.73; 95% CI: 1.29-5.75). We also performed a subgroup analysis to more accurately assess the predictive value of ctDNA for triple-negative breast cancer.
CONCLUSIONS: Our meta-analysis suggested that the ctDNA status at the early stage of NAT can predict patient response, which provides evidence for adjusting personalized treatment strategies and improving patient survival.
PROSPERO REGISTRATION NUMBER: CRD42024496465.

Keywords:  Biomarkers; Breast cancer; Circulating tumor DNA; Neoadjuvant therapy; Prognosis; Response

DOI:  https://doi.org/10.1186/s12885-025-13526-0
Mol Oncol. 2025 Jan 20.

Whole-genome sequencing of cell-free DNA reveals DNA of tumor origin in plasma from patients with colorectal adenomas.

Amanda Frydendahl, Adam J Widman, Nadia Øgaard, Anushri Arora, Daniel Halmos, Jesper Nors, Johanne Ahrenfeldt, Tenna V Henriksen, Christina Demuth, Line Raaby, Mads H Rasmussen, Christina Therkildsen, Dan A Landau, Claus L Andersen.

  The presence of circulating tumor DNA (ctDNA) in patients with colorectal adenomas remains uncertain. Studies using tumor-agnostic approaches report ctDNA in 10-15% of patients, though with uncertainty as to whether the signal originates from the adenoma. To obtain an accurate estimate of the proportion of patients with ctDNA, a sensitive tumor-informed strategy is preferred, as it ensures the detected signal originates from the adenoma. Here, tumor-informed whole-genome sequencing-based ctDNA analysis (MRD-EDGESNV) was applied to two independent cohorts. Cohort 1, comprising 93 patients with stage III colorectal cancer (CRC) and 40 healthy individuals, was used to establish the signal threshold at 95% specificity. This threshold was then applied to Cohort 2, consisting of 22 patients with symptomatic and 20 with asymptomatic adenomas. In stage III, MRD-EDGESNV had an area under the curve of 0.98. ctDNA was detected in 50% and 25% of patients with symptomatic and asymptomatic adenomas, respectively. The median adenoma plasma tumor fraction was 5.9 × 10-5. These finding not only demonstrate the feasibility of ctDNA detection in patients with colorectal adenomas, but also provides an estimate of the necessary sensitivity required to detect these lesions, paving the way for future ctDNA-based screening strategies.

Keywords:  adenomas; circulating tumor DNA; colorectal cancer; early detection; whole‐genome sequencing

DOI:  https://doi.org/10.1002/1878-0261.13803
Nat Rev Clin Oncol. 2025 Jan 20.

Circulating tumour DNA in early stage and locally advanced NSCLC: ready for clinical implementation?

Nicola Normanno, Alessandro Morabito, Anna Maria Rachiglio, Vincenzo Sforza, Lorenza Landi, Emilio Bria, Angelo Delmonte, Federico Cappuzzo, Antonella De Luca.

Circulating tumour DNA (ctDNA) can be released by cancer cells into biological fluids through apoptosis, necrosis or active release. In patients with non-small-cell lung cancer (NSCLC), ctDNA levels correlate with clinical and pathological factors, including histology, tumour size and proliferative status. Currently, ctDNA analysis is recommended for molecular profiling in patients with advanced-stage NSCLC. In this Review, we summarize the increasing evidence suggesting that ctDNA has potential clinical applications in the management of patients with early stage and locally advanced NSCLC. In those with early stage NSCLC, detection of ctDNA before and/or after surgery is associated with a greater risk of disease recurrence. Longitudinal monitoring after surgery can further increase the prognostic value of ctDNA testing and enables detection of disease recurrence earlier than the assessment of clinical or radiological progression. In patients with locally advanced NSCLC, the detection of ctDNA after chemoradiotherapy is also associated with a greater risk of disease progression. Owing to the limited number of patients enrolled and the different technologies used for ctDNA testing in most of the clinical studies performed thus far, their results are not sufficient to currently support the routine clinical use of ctDNA monitoring in patients with early stage or locally advanced NSCLC. Therefore, we discuss the need for interventional studies to provide evidence for implementing ctDNA testing in this setting.

DOI: https://doi.org/10.1038/s41571-024-00985-w
Front Oncol. 2024 ;14 1513073

Targeted detection of sequence variants in cell-free DNA from cerebrospinal fluid in pediatric central nervous system tumors.

Katrina O'Halloran, Erin E Crotty, Eirini Christodoulou, Sarah E Leary, Alexandra Miller, Vera A Paulson, Christina M Lockwood, Ashley S Margol, Jaclyn A Biegel.

  The emergence of liquid biopsy technologies holds great promise in the cancer setting, including in pediatric central nervous system (CNS) tumors. In contrast to broad lower-depth sequencing, commonly referred to as low pass whole genome sequencing (WGS), targeted platforms with a higher depth of coverage have also been established. Here, we review targeted liquid biopsy techniques with applicability to pediatric CNS tumors. These include polymerase chain reaction (PCR), both droplet digital PCR and reverse transcription-based PCR, Sanger sequencing, and next-generation sequencing approaches that incorporate amplicon- and hybrid capture-based methods. The goal of this paper is to facilitate an understanding of these targeted techniques and provide a context for clinical relevance within disease categories, as well as a discussion on optimizing real-world implementation for pediatric CNS tumors.

Keywords:  cerebrospinal fluid; liquid biopsy; pediatric neuro-oncology; sequence variant; targeted sequencing

DOI:  https://doi.org/10.3389/fonc.2024.1513073
Invest New Drugs. 2025 Jan 23.

Efficacy of ramucirumab combined with erlotinib or osimertinib in untreated EGFR-mutated NSCLC patients with asymptomatic brain metastases: insights from molecular biomarkers in the RELAY-brain trial.

Hiroyasu Kaneda, Haruko Daga, Asuka Okada, Yuki Nakatani, Yoko Tani, Takako Oka, Kenji Sawa, Kazuko Sakai, Kazuto Nishio, Tomoya Kawaguchi.

   BACKGROUND: The RELAY-Brain trial examined the clinical utility and survival impacts of ramucirumab (RAM) combined with epidermal growth factor receptor (EGFR)-TKI in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) with brain metastases. Although RAM combined with erlotinib (ERL) is known to have clinical benefits, the benefits in patients with baseline brain metastases remain unclear. This report examined the long-term follow-up data (Japan Registry of Clinical Trials: jRCTs2051190027) of the same patients, analyzing relevant biomarkers from tumor and plasma samples.
PATIENTS AND METHODS: The six patients enrolled in the RELAY-Brain trial received RAM plus ERL or osimertinib (OSM). Our long-term follow-up observational study assessed patient survival, treatment status, and genetic biomarkers. Tumor and plasma samples were analyzed at baseline, during treatment, and at disease progression using next-generation sequencing and droplet digital PCR, to identify gene alterations and EGFR-TKI-resistant mutations.
RESULTS: After median follow-up of 44.2 months, the first site of disease progression in three of the patients was the brain metastases. In the RAM + ERL group, two patients with the T790M mutation subsequently received OSM. Progression-free survival (PFS) and overall survival ranged from 10.46 to 42.07 months and from 30.14 to 52.25 months, respectively. Gene alterations included TP53 mutations in three patients and ERBB2 and PIK3CA mutations in two. TP53 mutations were associated with shorter PFS.
CONCLUSION: RAM with ERL or OSM achieved significant clinical benefits for patients with EGFR-mutated NSCLC with asymptomatic brain metastases. These positive outcomes and the identification of related biomarkers support the therapeutic potential of these combinations.

Keywords:  Brain metastasis; EGFR mutation; Next-generation sequencing; Non-small-cell lung cancer; Ramucirumab; TP53 mutation

DOI:  https://doi.org/10.1007/s10637-025-01505-y
J Natl Cancer Inst. 2025 Jan 22. pii: djaf015. [Epub ahead of print]

Comprehensive Genome Profiling for Treatment Decisions in Patients with Metastatic Tumors: Real-World Evidence Meta-Analysis and Registry Data Implementation.

Ioannis Zerdes, Panagiotis Filis, Georgios Fountoukidis, Ali Inan El-Naggar, Foteini Kalofonou, Antonio D'Alessio, Athanasios Pouptsis, Theodoros Foukakis, George Pentheroudakis, Johan Ahlgren, Daniel Smith, Antonios Valachis.

BACKGROUND: Although precision oncology has rapidly been developed in recent years, its real-world impact and challenges in healthcare implementation remain underexplored. Through a meta-analysis of real-world evidence (RWE), we aimed at investigating the applicability and clinical impact of comprehensive cancer genome profiling (CGP) in cancer patients with metastatic solid tumors.
METHODS: We systematically searched Medline, Embase, and Web of Science for RWE studies on CGP and matched therapies in metastatic solid tumors (publication period: 2012-2023). Pooled proportions of actionable genomic alterations, patients treated with matched targeted therapies, treatment, and survival outcomes were calculated. Data from Swedish cancer registries were used as a case-study for nationwide CGP implementation.
RESULTS: Out of the 7218 identified studies, 144 were included in our analysis. 59.8% of CGP-tested patients had actionable genomic alterations, with 15.6% (95% Confidence Interval (CI) 13.4-18.2%) of them having received targeted therapy. Objective response was seen in 23.9% (95% CI 20.8-27.3%). Overall, CGP-guided treatment was correlated with prolonged progression-free survival (pooled Hazard Ratio (HR) = 0.63; 95% CI, 0.56-0.70; 18 studies) and overall survival (pooled HR = 0.60; 95% CI, 0.51-0.70; 21 studies) when compared to conventional treatment. Meta-regression time projections analyses showed that these rates will steadily increase by 2030.
CONCLUSIONS: Pooled analyses of RWE studies indicate that approximately one-fourth of the patients receiving CGP-matched treatment have an objective response. By utilizing meta-regression projections, our nationwide cancer registry case-study offers insights into the potential of precision oncology for patients with metastatic cancer and to inform future healthcare strategies.

DOI: https://doi.org/10.1093/jnci/djaf015
Int J Cancer. 2025 Jan 23.

Epigenomics-guided precision oncology: Chromatin variants in prostate tumor evolution.

Kira Furlano, Tina Keshavarzian, Nadine Biernath, Annika Fendler, Maria de Santis, Joachim Weischenfeldt, Mathieu Lupien.

  Prostate cancer is a common malignancy that in 5%-30% leads to treatment-resistant and highly aggressive disease. Metastasis-potential and treatment-resistance is thought to rely on increased plasticity of the cancer cells-a mechanism whereby cancer cells alter their identity to adapt to changing environments or therapeutic pressures to create cellular heterogeneity. To understand the molecular basis of this plasticity, genomic studies have uncovered genetic variants to capture clonal heterogeneity of primary tumors and metastases. As cellular plasticity is largely driven by non-genetic events, complementary studies in cancer epigenomics are now being conducted to identify chromatin variants. These variants, defined as genomic loci in cancer cells that show changes in chromatin state due to the loss or gain of epigenomic marks, inclusive of histone post-translational modifications, DNA methylation and histone variants, are considered the fundamental units of epigenomic heterogeneity. In prostate cancer chromatin variants hold the promise of guiding the new era of precision oncology. In this review, we explore the role of epigenomic heterogeneity in prostate cancer, focusing on how chromatin variants contribute to tumor evolution and therapy resistance. We therefore discuss their impact on cellular plasticity and stochastic events, highlighting the value of single-cell sequencing and liquid biopsy epigenomic assays to uncover new therapeutic targets and biomarkers. Ultimately, this review aims to support a new era of precision oncology, utilizing insights from epigenomics to improve prostate cancer patient outcomes.

Keywords:  chromatin variants; epigenomics; precision oncology; prostate cancer; tumor evolution

DOI:  https://doi.org/10.1002/ijc.35327
Precis Clin Med. 2025 Mar;8(1): pbae034

Cell-free tumor DNA analysis in advanced or metastatic breast cancer patients: mutation frequencies, testing intention, and clinical impact.

Hanna Huebner, Pauline Wimberger, Elena Laakmann, Eugen Ruckhäberle, Matthias Ruebner, Sarah Lehle, Sabrina Uhrig, Philipp Ziegler, Theresa Link, Carolin C Hack, Erik Belleville, Iris Faull, Marcus Hausch, Diethelm Wallwiener, Andreas Schneeweiss, Hans Tesch, Sara Y Brucker, Matthias W Beckmann, Peter A Fasching, Volkmar Müller, Tanja N Fehm.

   Background: Circulating cell-free tumor DNA (ctDNA) provides a non-invasive approach for assessing somatic alterations. The German PRAEGNANT registry study aims to explore molecular biomarkers and investigate their integration into clinical practice. In this context, ctDNA testing was included to understand the motivations of clinicians to initiate testing, to identify somatic alterations, and to assess the clinical impact of the results obtained.
Methods: Patients with advanced/metastatic breast cancer were prospectively enrolled in the Prospective Academic Translational Research Network for the Optimization of Oncological Health Care Quality in the Adjuvant and Advanced/Metastatic Setting (PRAEGNANT study; NCT02338167). The FDA-approved and CE-marked GUARDANT360 CDx test was used to assess somatic alterations. A ctDNA-analysis report was provided to the treating physician along with a questionnaire about the intent for testing and the clinical implications of test results.
Results: ctDNA from 49 patients was analyzed prospectively: 37 (76%) had at least one somatic alteration in the analyzed geneset; 14 patients (29%) harbored alterations in TP53, 12 (24%) in PIK3CA, and 6 (12%) in ESR1. Somatic mutations in BRCA1 or BRCA2 were detected in 3 (6%) and 4 (8%) patients, respectively, and 59% of patients had hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Questionnaires regarding test intentions and clinical impact were completed for 48 (98%) patients. These showed that ctDNA testing influenced treatment decisions for 35% of patients.
Discussion: The high prevalence of somatic alterations in TP53, PIK3CA, ESR1, and BRCA1/2 genes, identified by ctDNA genotyping, highlights their potential as biomarkers for targeted therapies. Detection of specific mutations affected treatment decisions, such as eligibility for alpelisib, and might further facilitate treatment with e.g. elacestrant or capiversatib in future treatment lines.

Keywords:  Clinical trial registration No.: NCT02338167; breast cancer; cell-free DNA; cfDNA; ctDNA; genetic testing

DOI:  https://doi.org/10.1093/pcmedi/pbae034
Eur J Surg Oncol. 2025 Jan 06. pii: S0748-7983(25)00014-9. [Epub ahead of print]51(5): 109586

A prospective study of methylated ctDNA in patients undergoing treatment for liver metastases from colorectal cancer.

Louise Raunkilde, Rikke Fredslund Andersen, Caroline Brenner Thomsen, Torben Frøstrup Hansen, Lars Henrik Jensen.

   BACKGROUND: Decision regarding local treatment of colorectal liver metastases (CRLM) is a multidisciplinary assessment, and liver intervention should be performed when the metastases are deemed resectable. There is no standard biomarker to aid neither this decision nor the postoperative treatment decisions. The present prospective, observational study aimed to investigate the potential clinical utility of a combined tumor-specific and organ-specific methylated circulating DNA assay in the perioperative setting of CRLM.
MATERIAL AND METHODS: The study included 56 cases with CRLM. Blood samples were drawn preoperatively and postoperatively. Multiplex methylation analysis of the markers NPY, KANK1, and GAL3ST3 (meth-ctDNA) was performed using droplet digital PCR.
RESULTS: The assay detected preoperative and postoperative meth-ctDNA in 37 % and 46 % of patients, respectively. Patients with negative preoperative meth-ctDNA had a longer median PFS compared to those with positive preoperative meth-ctDNA (HR = 2.2, 95 % CI 1.2-3.9, p < 0.01). In a multivariate analysis, preoperative negative meth-ctDNA was identified as a strong independent predictor of PFS (HR = 3.3, 95 % CI 1.5-7.2, p < 0.01). Similarly, patients with negative postoperative meth-ctDNA had longer median PFS (HR = 3.0, 95 % CI = 1.6-5.6, p < 0.001) and OS (HR = 4.1, 95 % CI 1.9-9.1, p < 0.001) compared to those with positive postoperative meth-ctDNA.
CONCLUSION: Preoperative meth-ctDNA may serve as an important biomarker to inform the multidisciplinary assessment and treatment planning of CRLM. Negative meth-ctDNA may indicate the optimal timing for liver intervention, whereas positive meth-ctDNA may indicate initiation or re-orientation of chemotherapy, or immediate local intervention. Our results confirm postoperative negative meth-ctDNA as a strong prognostic marker of survival.

Keywords:  DNA methylation; Liver metastases; Loco-regional treatment; Metastatic colorectal cancer; circulating tumor DNA

DOI:  https://doi.org/10.1016/j.ejso.2025.109586
ESMO Open. 2025 Jan 22. pii: S2059-7029(24)01846-5. [Epub ahead of print]10(2): 104076

BRCA functional domains associated with high risk of multiple primary tumors and domain-related sensitivity to olaparib: the Prometheus Study.

L Incorvaia, C Marchetti, C Brando, T D Bazan Russo, M Bono, A Perez, L Congedo, R Ergasti, L Castellana, L Insalaco, S Contino, V Gristina, A Galvano, D Fanale, G Badalamenti, A Russo, G Scambia, V Bazan.

   BACKGROUND: Germline pathogenic variants (gPVs) in the breast cancer susceptibility gene 1/2 (BRCA1/2) genes confer high-penetrance susceptibility to breast cancer (BC) and ovarian cancer (OC). Although most female BRCA carriers develop only a single BRCA-associated tumor in their lifetime, a smaller subpopulation is diagnosed with multiple primary tumors (MPTs). The genetic factors influencing this risk remain unclear. Further, in patients with BRCA-mutated tumors, there appears to be a variability in the effectiveness of olaparib treatment.
PATIENTS AND METHODS: This real-world, multicenter, observational study aimed to determine whether the location of BRCA gPVs within functional domains (FDs) is associated with the development of MPTs and the magnitude of olaparib benefit. The study population comprised consecutive patients with OC who underwent hereditary cancer genetic testing between May 2015 and March 2023. MPT history was assessed based on mutated genes (BRCA1 or BRCA2) and the location of the PVs within the FDs. Clinical outcomes of olaparib first-line maintenance therapy were evaluated according to BRCA1/2 FD location.
RESULTS: The frequency of MPT history in the overall population was 13.3% (118/882), and 20.4% in the BRCA-mutated subpopulation (68/333; P < 0.001). We observed a significant association between the DNA-binding domain (DBD) FD of BRCA2 and MPT. Specifically, 55.6% of BRCA2-mutated patients with PVs in the DBD had a history of BC as a second tumor. At a median follow-up of 48.5 months (95% confidence interval 10-70 months), the 48-month progression-free survival rates were 100.0% for patients with PVs in DBD, 91.7% for those with PVs in other FDs, and 36.4% for those with PVs in the RAD51-binding domain (RAD51-BD) of BRCA2 (P = 0.01). Results in the BRCA1 cohort were not statistically significant.
CONCLUSIONS: The results suggest that the location of PVs within BRCA FDs may influence the onset of multiple tumors and the benefit of olaparib in patients with BRCA-mutated OC. These findings could be relevant for cancer prevention efforts, particularly given the increasing number of cancer survivors. However, further understanding is needed before these results can inform clinical decisions.

Keywords:  BRCA; hereditary breast cancer; hereditary ovarian cancer; multiple tumors; olaparib; second tumor history

DOI:  https://doi.org/10.1016/j.esmoop.2024.104076
Lab Invest. 2025 Jan 16. pii: S0023-6837(25)00003-0. [Epub ahead of print] 104093

Molecular and Immunohistochemical Classification of Extrapulmonary Small Cell Neuroendocrine Carcinomas: A Study of 181 Cases.

Klára Pavlíčková, Jan Hojný, Petr Waldauf, Marián Švajdler, Pavel Dundr, Pavel Fabian, Eva Krkavcová, Jiří Dvořák, Romana Michálková, Iva Staniczková Zambo, Nikola Hájková, Miroslava Flídrová, Jan Laco, Helena Hornychová, Patricie Delongová, Jozef Škarda, Jan Hrudka, Radoslav Matěj.

Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Most patients with EP-SCNC have metastatic disease upon presentation, and their average overall survival (OS) is less than 12 months. Our study aimed to conduct a complex analysis of EP-SCNC. One hundred and eighty-one EP-SCNC tissue samples were subjected to a complex analysis. One hundred and fifty-five tumors were pure EP-SCNC, while 26 were combined tumors. Immunohistochemistry for ASCL1, NEUROD1, YAP1, POU2F3, Rb1, p53, cyclin D1, p16, PTEN, DLL3, PD-L1, CD56, synaptophysin, chromogranin A, and INSM1 was performed, and 128 samples were analyzed molecularly using next generation sequencing (NGS), comprising DNA and RNA analysis. Detailed results on immunohistochemical and molecular analyses were provided for each primary origin of EP-SCNC separately. Median survival for the whole cohort of patients was 8.94 months. Patient age (≥ 70 years), tumor mutational burden (TMB) < 15, and TP53 and BRCA2 mutations were negative prognostic factors. High expression of ASCL-1 was associated with shorter OS, whereas high expression of YAP1 was associated with longer OS. Patients with genitourinary tumors had significantly better OS than those with gastrointestinal tract EP-SCNC tumors. Rb1 expression loss was detected more often in genitourinary tract SCNCs. In contrast, p16 overexpression was found more often in genitourinary tract SCNCs. POU2F3 expression was detected more often in combined tumors, whereas NEUROD1 was detected more often in pure EP-SCNC. Regarding "druggable markers," DLL3 was expressed in 66% of tumors and PD-L1 in 17.4%. Detailed analyses of different prognostic and predictive markers are needed to better understand EP-SCNC biology and create more personalized therapy to improve patient prognosis.

DOI: https://doi.org/10.1016/j.labinv.2025.104093
Transl Lung Cancer Res. 2024 Dec 31. 13(12): 3344-3351

Osimertinib as a neoadjuvant therapy in resectable EGFR-mutant non-small cell lung cancer: a real-world, multicenter retrospective study.

Jialong Li, Youyu Wang, Zerui Zhao, Sihua Wang, Wanpu Yan, Xiaohui Chen, Tianxiang Chen, Pengfei Li, Sheng Wang, Qiang Fang, Lin Peng, Yongtao Han, Jian Tang, Xuefeng Leng.

   Background: Osimertinib, a third-generation tyrosine kinase inhibitor (TKI), has been authorized for use in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to evaluate the effectiveness and safety of neoadjuvant osimertinib in individuals with resectable locally advanced NSCLC harboring EGFR mutation.
Methods: Ten centers located in mainland China took part in a single-arm, real-world, multicenter retrospective study (registration number: ChiCTR2100049954). Enrollment included individuals with lung adenocarcinoma who had EGFR mutations. Following the administration of osimertinib, the patients underwent a surgical procedure for resection. The main endpoint was the objective response rate (ORR). The subsequent endpoint analyzed was the joint assessment of overall survival (OS) and disease-free survival (DFS).
Results: From July 31, 2018 to April 28, 2023, a total of 38 individuals were involved and received neoadjuvant osimertinib treatment. The ORR was 60.5% (23/38). Thirty-eight patients underwent surgery, and 36 (94.7%) underwent successful R0 resection. Out of 38 patients, sixteen (42.1%) experienced adverse events (AEs) due to treatment in the neoadjuvant phase, with none of them reaching grade 3. Skin irritation [14 (36.8%)], stomach upset [5 (13.2%)], mouth sores [1 (2.6%)] and increased liver enzyme levels [1 (2.6%)] were the common AEs of treatment. The follow-up period lasted an average of 24.9 months. The 1-year OS rate is 94.2%, while the 2-year OS rate is 89.2%. The 1-year DFS rate is 87.9%, and the 2-year DFS rate remains at 87.9%.
Conclusions: In the actual clinical setting, osimertinib displays encouraging possibilities as a neoadjuvant therapy for individuals with operable EGFR-mutated NSCLC, exhibiting adequate efficacy and an acceptable safety record. The phase III clinical trial of NeoADAURA is expected to provide further efficacy and safety results.

Keywords:  Neoadjuvant; epidermal growth factor receptor (EGFR); non-small cell lung cancer (NSCLC); osimertinib

DOI:  https://doi.org/10.21037/tlcr-24-541
Gynecol Oncol. 2025 Jan 22. pii: S0090-8258(24)01238-1. [Epub ahead of print]193 130-135

Pembrolizumab in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) and non-MSI-H/non-dMMR advanced endometrial cancer: Phase 2 KEYNOTE-158 study results.

David M O'Malley, Giovani M Bariani, Philippe A Cassier, Aurelien Marabelle, Aaron R Hansen, Ana De Jesus Acosta, Wilson H Miller, Tamar Safra, Antoine Italiano, Linda Mileshkin, Lili Yao, Alexander Gozman, Fan Jin, Michele Maio.

   OBJECTIVE: We report updated results with longer follow-up in patients with MSI-H/dMMR endometrial cancer (EC) in cohort D (advanced EC of any MSI/dMMR status) and cohort K (any MSI-H/dMMR advanced solid tumor, except colorectal) of the phase 2 KEYNOTE-158 study (NCT02628067) and the first results from patients with non-MSI-H/non-dMMR advanced EC (cohort D).
METHODS: Patients received pembrolizumab 200 mg Q3W for ≥35 cycles. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by central review. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
RESULTS: As of January 12, 2022, median (range) follow-up in the MSI-H/dMMR (n = 94) and non-MSI-H/non-dMMR (n = 96) groups was 54.5 (14.7-71.4) and 68.3 (64.3-71.9) months, respectively. The ORR (95 % CI) was 50 % (40 %-61 %) in the MSI-H/dMMR group; 15 patients (16 %) experienced a complete response, 32 (34 %) experienced a partial response. The ORR (95 % CI) in the non-MSI-H/non-dMMR group was 7 % (3 %-14 %); 7 patients (7 %) experienced a partial response, none experienced a complete response. The estimated 4-year DOR rates were 66 % and 56 %, respectively. Median PFS was 13.1 (95 % CI, 4.3-25.7) months in the MSI-H/dMMR group and 2.1 (95 % CI, 2.1-2.2) months in the non-MSI-H/non-dMMR group. Median OS was 65.4 (95 % CI, 29.5-not reached) and 11.1 (95 % CI, 8.1-15.3) months, respectively. Toxicity was manageable in both groups.
CONCLUSIONS: These results continue to support pembrolizumab as a standard-of-care option for MSI-H/dMMR advanced EC in patients with disease progression following prior systemic therapy who are not candidates for curative surgery or radiation.

Keywords:  Advanced endometrial cancer; DNA mismatch repair deficiency; Microsatellite instability-high; Pembrolizumab

DOI:  https://doi.org/10.1016/j.ygyno.2024.12.020
Contemp Clin Dent. 2024 Oct-Dec;15(4):15(4): 295-297

Exploring the Role of Health-care Professionals and Impact of Precision Medicine on Health Outcomes and Efficiency.

Saurabh RamBihariLal Shrivastava, Anup Mukund Marar, Prateek Sudhakar Bobhate, Ankit Badge.

  The inclusion of precision medicine in medical education represents a paradigm shift, as it is expected to transform the way in which health care will be delivered to patients in future. This shift is predominantly reported as precision medicine strongly advocates for the delivery of personalized care to patients after giving due consideration to the genetic makeup, biomarker level, etc., of the individual patient. Medical professionals are expected to discharge a wide range of roles since the introduction of precision medicine in the health-care industry. Training of medical students and health professionals in the domain of precision medicine is expected to significantly influence patient outcomes and enhance the efficiency of the health-care sector. In conclusion, precision medicine is expected to have a huge impact on medical professionals and the health sector, it is the need of the hour to strengthen its implementation process across medical colleges and health-care facilities.

Keywords:  Health care; medical education; precision medicine

DOI:  https://doi.org/10.4103/ccd.ccd_323_24