bims-preonc 2025-02-23 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2025–02–23
ten papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

ctDNA detection in cerebrospinal fluid and plasma and mutational concordance with the primary tumor in a multicenter prospective study of patients with glioma.
Circulating tumor DNA in endometrial cancer: clinical significance and implications.
Molecular counting enables accurate and precise quantification of methylated ctDNA for tumor-naive cancer therapy response monitoring.
Clinical Utility of Liquid-based Comprehensive Genomic Profiling (CGP) in Gastrointestinal Stromal Tumors (GIST).
Longitudinal evaluation of circulating tumor DNA in patients undergoing neoadjuvant therapy for early breast cancer using a tumor-informed assay.
A review on intrathecal administration of medications for leptomeningeal metastases in solid tumors.
Selpercatinib in RET Fusion-Positive Non-Small Cell Lung Cancer: Final Safety and Efficacy, Including Overall Survival, From the LIBRETTO-001 Phase I/II Trial.
Pembrolizumab in microsatellite-instability-high and mismatch-repair-deficient advanced solid tumors: updated results of the KEYNOTE-158 trial.
Real-world effectiveness and tolerability of sotorasib in patients with KRAS G12C-mutated metastatic non-small cell lung cancer: The IFCT-2102 Lung KG12Ci study.
Assessing germline TP53 mutations in cancer patients: insights into Li-Fraumeni syndrome and genetic testing guidelines.

Ann Oncol. 2025 Feb 18. pii: S0923-7534(25)00064-X. [Epub ahead of print]

ctDNA detection in cerebrospinal fluid and plasma and mutational concordance with the primary tumor in a multicenter prospective study of patients with glioma.

S Cabezas-Camarero, R Pérez-Alfayate, V García-Barberán, M L Gandía-González, P García-Feijóo, I López-Cade, V Lorca, I Casado-Fariñas, M A Cerón, M Paz-Cabezas, M J Sotelo, M García Conde, H Roldán Delgado, Y Sánchez Medina, I Díaz-Millán, P Pérez-Segura.

   BACKGROUND: Cerebrospinal fluid (CSF) stands as an easily accessible reservoir for circulating tumor DNA (ctDNA) analysis in patients with CNS tumors, although evidence is still limited. Our aim was to prospectively evaluate the feasibility of detecting ctDNA for mutational analysis in CSF and plasma in patients with glioma.
METHODS: Prospective study of patients with gliomas diagnosed at four third-level hospitals in Spain. A customized next-generation sequencing (NGS) 8-gene panel (IDH1, IDH2, ATRX, TP53, PTEN, PIK3CA, EGFR, BRAF) was used in paired CSF, plasma and tumor samples. Mutation concordance occurred when the same pathogenic gene variant was detected in tumor and ctDNA. The prognostic value of ctDNA and that of its median variant allele frequency (mVAF) were analyzed.
RESULTS: Between February 2017 and March 2020, 37 patients with glioma were enrolled. Among 32 patients with analyzable CSF samples: new diagnosis (n=23); relapse (n=9). WHO 5th Ed: IDH-mut astrocytoma (n=10), IDH-mutant oligodendroglioma (n=6), IDH-wildtype glioblastoma (n=16). CSF-ctDNA-positive (ctDNA+): 19/32 (59%). CSF-ctDNA-negative (ctDNA-): 13/32 (41%). No. of mutations in CSF: 1 (10/19), 2 (7/19), 3 (2/19). Frequency of CSF-ctDNA mutated genes: EGFR (8/19: 42%), PTEN (7/19: 37%), TP53 (6/19: 32%), IDH1 (5/19: 26%), PIK3CA (4/19: 21%). Tumor-CSF mutation concordance: 16/19 (84%). Progression-free and overall survivals were significantly shorter in patients with ctDNA+ ≥ mVAF compared to ctDNA+ < mVAF. No association was found between ctDNA in CSF and distance to closest CSF reservoir, tumor size or IDH status. ctDNA was detected in 2 out 14 (14%) individual plasma samples, in both cases concordant with the primary tumor.
CONCLUSION: CSF is a reliable reservoir for ctDNA analyses in patients with gliomas. ctDNA is detectable in plasma although at a lower rate. Larger, prospective studies should be conducted to refine the potential role of liquid biopsy in this disease.

Keywords:  cerebrospinal fluid; ctDNA; glioma; liquid biopsy; next generation sequencing; variant allele frequency

DOI:  https://doi.org/10.1016/j.annonc.2025.02.005
Int J Gynecol Cancer. 2025 Jan 23. pii: S1048-891X(25)00179-3. [Epub ahead of print] 101656

Circulating tumor DNA in endometrial cancer: clinical significance and implications.

Ilaria Capasso, Camilla Nero, Gloria Anderson, Marzia Del Re, Emanuele Perrone, Francesco Fanfani, Giovanni Scambia, Giuseppe Cucinella, Andrea Mariani, Grace Choong, Evelyn Reynolds.

  Circulating tumor DNA (ctDNA) is a promising non-invasive tool that has been demonstrated to be a clinically useful biomarker in several tumor types for risk stratification, prognosis, and early detection of recurrence. However, there are limited data on the clinical utility of ctDNA in endometrial cancer (EC) compared with other solid tumors. The evolution of EC management through the integration of molecular characterization into the treatment algorithm has intensified the need to develop more effective predictive biomarkers to optimize treatment and reduce clinical toxicities. Given its non-invasive nature and its ability to represent and complement tumor multiclonal spatial and temporal heterogeneity, ctDNA could act as a valid surrogate for tissue sampling. In addition to plasma ctDNA detection being associated with clinicopathologic features of tumor aggressiveness at pre-operative assessment, an association with reduced disease-free survival and overall survival has been observed in patients with detectable ctDNA. Moreover, the half-life of ctDNA is significantly shorter than CA125, and plasma levels are reported to be completely cleared from the blood within 1 week from surgical debulking. Therefore, ctDNA may serve as a dynamic biomarker for occult microscopic residual disease when assessed within the first 4 to 8 weeks after eradicative surgery. Few studies have reported high sensitivity of ctDNA in detecting disease recurrence at longitudinal follow-up, although there are limited data comparing ctDNA and traditional serum biomarkers (CA125 and HE4) in identifying recurrence. In the perspective of personalized oncology, ctDNA may potentially help improve adjuvant therapeutic management by escalating/de-escalating treatment based on ctDNA detection after surgery, during maintenance, or in the recurrent/metastatic setting, in addition to acting as a sensitive biomarker for early detection of recurrence. Several challenges hinder the use of ctDNA in EC, including the lack of standardized protocols, the low mutational burden, tumor heterogeneity, and background normal DNA, which limit assay sensitivity and specificity. In addition, the high cost of ctDNA analysis, particularly, next-generation sequencing, restricts its accessibility. Future trials should focus on cost-effective approaches to ensure sustainability and efficient resource allocation.

Keywords:  Circulating Tumor DNA; Endometrial Cancer; Liquid Biopsy

DOI:  https://doi.org/10.1016/j.ijgc.2025.101656
Sci Rep. 2025 Feb 18. 15(1): 5869

Molecular counting enables accurate and precise quantification of methylated ctDNA for tumor-naive cancer therapy response monitoring.

Patrick Peiyong Ye, Robb Viens, Katherine E Shelburne, Sydne Scot Langpap, Xavier S Bower, Jonathan Jiahui Shi, Wen Zhou, Jan Christian Wignall, Joyce Jiawei Zhu, Brian D Woodward, Hatim Husain, David S Tsao, Oguzhan Atay.

Personalized cancer treatment can significantly extend survival and improve quality of life for many patients, but accurate and real-time therapy response monitoring remains challenging. To overcome logistical and technical challenges associated with therapy response monitoring via imaging scans or assays that track the variant allele fraction (VAF) of somatic mutations in circulating tumor DNA (ctDNA), we developed a tumor-naive liquid biopsy assay that leverages Quantitative Counting Template (QCT) technology to accurately and precisely quantify methylated ctDNA (Northstar Response™). The assay achieves < 10% coefficient of variation at 1% tumor fraction, which is 2 × lower than tumor-naive, targeted-panel approaches using VAF. The assay accurately distinguishes 0.25% absolute changes in contrived tumor fraction (AUC > 0.94) and performs well in 12 solid tumor types. Finally, in a small cohort of patients with lung, colorectal, or pancreatic cancer, the assay detected changes in ctDNA methylation that correlate with clinical outcomes. With its precise quantification of ctDNA methylation, Northstar Response is a novel tool for therapy response monitoring with the potential to inform clinical decision making for cancer treatment.

DOI: https://doi.org/10.1038/s41598-025-90013-3
Lab Invest. 2025 Feb 19. pii: S0023-6837(25)00026-1. [Epub ahead of print] 104116

Clinical Utility of Liquid-based Comprehensive Genomic Profiling (CGP) in Gastrointestinal Stromal Tumors (GIST).

Hiba Mechahougui, Lindsey Hildebrand, James Haberberger, Smruthy Sivakumar, Essia Saiji, Hanna Tukachinsky, Russell Madison, Jonathan K Killian, Richard S P Huang, Julia A Elvin, Eric Marks, Michael C Heinrich, Thibaud Koessler, Douglas I Lin.

  Treatment for GIST focuses on tyrosine kinase inhibitors (TKI), whose selection depends on specific mutations. We sought to determine the clinical utility of liquid biopsy in advanced GIST. Liquid (n=181) (FoundationOne®Liquid CDx) and tissue (n=2,198) (FoundationOne® and FoundationOne®CDx) CGP of GIST were evaluated. The presence of circulating tumor DNA in liquid was determined via tumor fraction (TF), with elevated TF defined as TF ≥1%. Liquid CGP revealed 30% (54/181) of samples had an elevated TF, among which the prevalence of KIT and PDGFRA alterations were 89% (48/54) and 2% (1/54), respectively. In patient-matched tissue/liquid samples (n=49), positive percent agreement of driver alterations in liquid with elevated TF relative to tissue was 100%. 55% (42/77) of liquid samples with a KIT-driver mutation had a co-occurring imatinib-resistant alteration; a minority of cases harbored non-KIT mechanisms of resistance such as FGFR2 fusion, BRAF or EGFR alterations. The relative prevalence of imatinib-resistance KIT exon 13 and 17 mutations was enriched in liquid compared to tissue. Finally, in the liquid cohort, 2.2%, 1.7% and 1.1% of patients were predicted to harbor germline KIT, SDHx, or NF1 mutations, respectively. In conclusion, known driver and TKI-resistant mutations were identified in liquid biopsies of GIST patients with high concordance to tissue in the presence of elevated TF. Liquid biopsy may be valuable in the molecular classification and medical management of GIST.

Keywords:  GIST; KIT; ctDNA; liquid biopsy; tumor fraction

DOI:  https://doi.org/10.1016/j.labinv.2025.104116
Nat Commun. 2025 Feb 21. 16(1): 1837

Longitudinal evaluation of circulating tumor DNA in patients undergoing neoadjuvant therapy for early breast cancer using a tumor-informed assay.

Mitchell J Elliott, Philippe Echelard, Christodoulos Pipinikas, Sasha Main, Jesús Fuentes Antrás, Aaron Dou, Zachary Veitch, Eitan Amir, Michelle B Nadler, Nicholas Meti, Eshetu Atenafu, Elizabeth Shah, Celeste Yu, Nathan Campbell, Robert Ventura, Lillian L Siu, Philippe L Bedard, Hal K Berman, David W Cescon.

Circulating tumor DNA (ctDNA) is an emerging biomarker for the treatment of early breast cancer (EBC). We sought to evaluate a highly sensitive tumor-informed ctDNA assay in a real-world cohort of patients receiving neoadjuvant therapy (NAT) to assess clinical validity and explore prognostic outcomes. ctDNA is detected in 77.2% (88/114) of participants at baseline, with 18/88 (20.5%) having a baseline estimated variant allele frequency (eVAF) of <0.01%. Persistent detection of ctDNA, measured midway through NAT (mid-NAT), is associated with disease recurrence in all participants, reaching statistical significance in those with HER2-negative disease. Stratified analyses demonstrate that ctDNA detected mid-NAT enhances the prognostic accuracy of the residual cancer burden (RCB) score for disease recurrence. Postoperative or follow-up detection of ctDNA demonstrates a 100% positive predictive value for disease recurrence, with a median lead time of 374 days (range: 13-1010 days). These data suggest that assays with high analytical sensitivity may improve baseline ctDNA detection in patients with EBC. The ability to replicate the prognostic association of ctDNA dynamics in a real-world cohort supports further investigation. Prospective trials incorporating ctDNA testing are warranted to assess and develop the clinical utility of ctDNA-guided treatment strategies.

DOI: https://doi.org/10.1038/s41467-025-56658-4
Front Pharmacol. 2025 ;16 1472945

A review on intrathecal administration of medications for leptomeningeal metastases in solid tumors.

Xuemei Wang, Chi Yao, Li Quan, Junxiang Zhou.

  Leptomeningeal disease (LMD) is a particular mode of central metastasis in malignant tumors. It occurs when tumor cells infiltrate the subarachnoid space and cerebrospinal fluid (CSF), spreading throughout the central nervous system (CNS). LMD is a rare but devastating complication of malignant tumors. It can occur in various types of cancers, with lung and breast cancer being the most frequently associated. The treatment approach for LMD includes a combination of supportive care, surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, and intrathecal (IT) therapy, among other modalities. Despite the challenges in determining the optimal treatment for LMD, IT therapy remains one of the primary therapeutic strategies. This therapy can directly circumvent the blood-brain barrier. Moreover, a low-dose medication can achieve a higher drug concentration in the CSF, resulting in better cytotoxic effects. Chemotherapy drugs such as methotrexate, cytarabine, and thiotepa have been widely studied as traditional IT therapies. In recent years, the advent of novel anti-tumor drugs has led to a growing number of agents being employed for IT administration in the treatment of malignant tumors with LMD. This article presents a comprehensive review of the current advancements in IT administration of chemotherapy, targeted, and immunotherapy drugs for the treatment of LMD in solid tumors. In addition, we also discuss the safety issues associated with IT therapy, summarize the advantages of IT administration of different types of anti-tumor drugs, and put forward some suggestions for reducing adverse reactions. It is hoped that future research will focus on exploring more potentially effective anti-tumor drugs for IT treatment, conducting in-depth pharmacokinetic studies, and developing long-acting and low-toxic IT administration regimens for the treatment of meningeal metastases.

Keywords:  anti-tumor drugs; chemotherapy drugs; immunotherapy drugs; intrathecal therapy; leptomeningeal disease; solid tumors; targeted drugs

DOI:  https://doi.org/10.3389/fphar.2025.1472945
J Clin Oncol. 2025 Feb 21. JCO2402076

Selpercatinib in RET Fusion-Positive Non-Small Cell Lung Cancer: Final Safety and Efficacy, Including Overall Survival, From the LIBRETTO-001 Phase I/II Trial.

Oliver Gautschi, Keunchil Park, Benjamin J Solomon, Pascale Tomasini, Herbert H Loong, Filippo De Braud, Koichi Goto, Patrick Peterson, Scott Barker, Katherine Liming, Geoffrey R Oxnard, Bente Frimodt-Moller, Alexander Drilon.

LIBRETTO-001 (ClinicalTrials.gov identifier: NCT03157128) is a registrational phase I/II, single-arm, open-label trial of selpercatinib in RET-dependent cancers. With 19 months of additional follow-up, we report the final efficacy and safety results of selpercatinib in patients with RET fusion-positive non-small cell lung cancer (NSCLC) who had previously received platinum-based chemotherapy (N = 247) or were treatment-naïve (N = 69). The objective response rate (ORR) was 62% for pretreated patients and 83% for treatment-naïve patients. Duration of response (DoR) was 31.6 months for pretreated and 20.3 months for treatment-naïve patients (median follow-up approximately 38 months). Median progression-free survival (PFS) was 26.2 months for pretreated and 22.0 months for treatment-naïve patients (median follow-up approximately 40 months). Median overall survival was 47.6 months in pretreated patients and was not reached in the treatment-naïve group (median follow-up approximately 43 months). At the 3-year landmark estimate, 57% of pretreated and 66% of treatment-naïve patients were alive. Among 26 patients with measurable CNS metastases at baseline, the CNS-ORR was 85% with a CNS-DoR of 9.4 months and CNS-PFS of 11.0 months. The safety profile of selpercatinib was consistent with previous reports. With substantial additional follow-up, selpercatinib continued to show durable responses and intracranial activity, with a manageable safety profile in patients with RET fusion-positive NSCLC.

DOI: https://doi.org/10.1200/JCO-24-02076
Nat Cancer. 2025 Feb 20.

Pembrolizumab in microsatellite-instability-high and mismatch-repair-deficient advanced solid tumors: updated results of the KEYNOTE-158 trial.

Aurelien Marabelle, David M O'Malley, Andrew E Hendifar, Paolo A Ascierto, Daniel Motola-Kuba, Nicolas Penel, Philippe A Cassier, Giovanni Bariani, Ana De Jesus-Acosta, Toshihiko Doi, Federico Longo, Wilson H Miller, Do-Youn Oh, Maya Gottfried, Lili Yao, Fan Jin, Alexander Gozman, Michele Maio.

The phase 2 trial KEYNOTE-158 ( NCT02628067 ) evaluated pembrolizumab in microsatellite-instability-high and mismatch-repair-deficient (MSI-H/dMMR) noncolorectal tumors. With 373 participants (95% with baseline MSI/dMMR documentation) and 4.5 years of follow-up, the primary endpoint of overall response rate was 33.8%. Secondary endpoints of duration of response, overall survival and progression-free survival were 63.2, 19.8 and 4.0 months, respectively. Grade ≥3 treatment-related adverse events occurred in 50 (13%) participants. These results further support pembrolizumab use in MSI-H/dMMR tumors.

DOI: https://doi.org/10.1038/s43018-024-00894-y
Eur J Cancer. 2025 Feb 11. pii: S0959-8049(25)00082-6. [Epub ahead of print]219 115301

Real-world effectiveness and tolerability of sotorasib in patients with KRAS G12C-mutated metastatic non-small cell lung cancer: The IFCT-2102 Lung KG12Ci study.

M Wislez, C Mascaux, J Cadranel, Q D Thomas, C Ricordel, A Swalduz, E Pichon, R Veillon, V Gounant, G Rousseau-Bussac, A Madroszyk, C Daniel, M Ravoire, A-C Metivier, P Fournel, P Missy, F Morin, F Guisier, V Westeel.

   INTRODUCTION: Sotorasib has shown efficacy in a phase 3 trial compared to docetaxel among previously treated non-small cell lung cancer (NSCLC) patients with a KRAS G12C mutation. However, its real-world effectiveness and tolerance, especially post-immunotherapy, remain debated.
METHODS: This French retrospective multicentre study analysed NSCLC patients receiving at least one dose of sotorasib as part of early access program The main objective was to assess real-world progression-free survival (rwPFS), and secondary objectives included assessment of overall survival (rwOS) and sotorasib-related hepatotoxicity.
RESULTS: 458 patients from 76 centres were analysed, with a median age 65.8. Among them, 43.4 % were female, 28.3 % had performance status ≥ 2, 95.4 % were active/former smokers, and 38.0 % had brain metastases with 55.2 % in progression at sotorasib initiation. PD-L1 expression was < 1 %, ≥ 1-49 %, ≥ 50 %, and unknown in 35.1 %, 34.1 %, 23.4 %, and 7.4 % of patients, respectively. Most patients had received prior treatments (96.7 %), including immunotherapy (54.9 %). Median (95 % confidence interval [CI]) rwPFS and rwOS were 3.5 (3.1-4.2) and 8.3 (7.5-9.3) months, with a median (95 % CI) follow-up of 15.8 (13.9-17.3) and 16.4 (15.5-17.3) months, respectively. The real-world objective response rate (rwORR) was 33.2 % and disease control rate (rwDCR) was 63.2 %. In patients with brain metastases, cerebral rwORR and rwDCR were 20.1 % and 66.9 %, respectively. Grade 3-4 adverse events related to hepatotoxicity occurred in 5.2 % of patients. Sotorasib was discontinued for toxicity in 16.5 % of patients.
CONCLUSION: This study gave insights into effectiveness and safety of sotorasib in a real-world setting, in advanced or metastatic KRAS G12C-mutated non-squamous NSCLC.

Keywords:  KRAS inhibitor; KRAS mutation; Non-small-cell lung cancer; Real-world evidence; Sotorasib; Targeted therapy

DOI:  https://doi.org/10.1016/j.ejca.2025.115301
Hered Cancer Clin Pract. 2025 Feb 17. 23(1): 5

Assessing germline TP53 mutations in cancer patients: insights into Li-Fraumeni syndrome and genetic testing guidelines.

Anastasiia Danishevich, Daria Fedorova, Natalia Bodunova, Maria Makarova, Maria Byakhova, Anna Semenova, Vsevolod Galkin, Maria Litvinova, Sergey Nikolaev, Irina Efimova, Pavel Osinin, Tatyana Lisitsa, Anastasiya Khakhina, German Shipulin, Tatiana Nasedkina, Syuykum Shumilova, Oleg Gusev, Airat Bilyalov, Elena Shagimardanova, Leyla Shigapova, Marina Nemtsova, Olesya Sagaydak, Mary Woroncow, Saida Gadzhieva, Igor Khatkov.

   BACKGROUND: Germline TP53 gene variants are intricately linked to Li-Fraumeni syndrome, a rare and aggressive hereditary cancer syndrome. This study investigated the frequency and spectrum of TP53 pathogenic variants associated with Li-Fraumeni syndrome in a large cohort of mainly breast cancer patients from Russia.
METHODS: The study analyzed 3,455 genomic DNA samples from cancer patients using next-generation sequencing panels and whole-genome sequencing. Clinically significant TP53 variants were identified and validated using Sanger sequencing. The clinical and family history characteristics of patients with TP53 variants were analyzed.
RESULTS: The analysis identified 13 (0.4%) individuals with clinically significant germline TP53 variants, all of whom were females with either unilateral breast cancer or breast cancer as part of multiple primary malignant neoplasms. The average age of breast cancer manifestation was 39.9 years, with a median of 36 years. Only 38.5% of the TP53 mutation carriers met the modified Chompret criteria for TP53 testing.
CONCLUSIONS: The findings underscore the necessity of thorough phenotype and family history analysis in genetic counseling to effectively diagnose LFS, and emphasize the importance of identifying TP53 variant carriers for developing treatment strategies, prognosis, and monitoring, as well as for identifying high-risk family members. The study also highlights that the current guidelines fail to identify over half of the TP53 mutation carriers, suggesting the need for a more comprehensive approach to genetic testing in suspected hereditary cancer cases.

Keywords:   TP53 ; Germline mutations; Li-Fraumeni syndrome; NGS

DOI:  https://doi.org/10.1186/s13053-025-00307-w