bims-tumhet Biomed News
on Tumor heterogeneity
Issue of 2026–09–27
seven papers selected by
Sergio Marchini, Humanitas Research
  1. Circulating tumor DNA tumor fraction as a biomarker in refractory metastatic colorectal cancer: findings from the CAVE-2 GOIM trial.
  2. Circulating Tumor DNA-Based Molecular Residual Disease in Early-Stage Non-Small-Cell Lung Cancer: Biology, Assays, and the Path Toward MRD-Guided Care.
  3. Performance of a multi-cancer early detection test in the randomized controlled NHS-Galleri trial.
  4. Prognostic and therapeutic implications of BRCA1 and BRCA2 mutations in ovarian cancer.
  5. Microsatellite Instability and Mismatch Repair Subclonality in Human Cancers: Biologic Basis, Diagnostic Pitfalls, and Therapeutic Implications with a Focus on Colorectal Cancer.
  6. Some answers, more questions for multi-cancer early detection tests.
  7. Liquid Biopsy in Head and Neck Squamous Cell Carcinoma: A Molecular Perspective on Circulating Biomarkers and Their Clinical Translation.
  1. J Liq Biopsy. 2026 Dec;14 100504
    Circulating tumor DNA tumor fraction as a biomarker in refractory metastatic colorectal cancer: findings from the CAVE-2 GOIM trial.
    Davide Ciardiello, Giulia Martini, Luca Boscolo Bielo, Gloria Pellizzari, Filippo Pietrantonio, Paola Andena, Silvia Marchesi, Salvatore Pisconti, Claudia Nisi, Giampaolo Tortora, Lisa Salvatore, Andrea Sartore-Bianchi, Salvatore Siena, Federica Papaccio, Marco Messina, Elena Ongaro, Alberto Zaniboni, Carmine Pinto, Lorenzo Antonuzzo, Antonio Avallone, Nicola Normanno, Giuseppe Santabarbara, Maria Giulia Zampino, Alessandra Pia D'Agata, Rossana Berardi, Alessio Cogoni, Claudio Lotesoriere, Tiziana Pia Latiano, Carminia Maria Della Corte, Nicola Fazio, Giuseppe Curigliano, Roberto Bordonaro, Teresa Troiani, Ferdinando De Vita, Erika Martinelli, Fortunato Ciardiello, Stefania Napolitano.
      Liquid biopsy guided anti-EGFR rechallenge therapy is gaining ground as a potential option for patient with refractory metastatic colorectal cancer. However, the identification of potential biomarkers to implement patient's stratification is required. The CAVE-2 GOIM trial investigated the role of rechallenge with cetuximab ± avelumab in patients with circulating tumor DNA (ctDNA) (assessed with the FoundationOne Liquid assay) RAS/BRAF wild type (WT) mCRC. Correlation with molecular profile, ctDNA tumor fraction (TF), and clinicopathological characteristics was performed. In patients with "negative" compared with "positive hyperselected" tumors the overall response rate was 12% vs 3%, median progression free survival (mPFS) mPFS 5.6 months (4.4-6.9) vs 3.65 months (2.8-4.8) (HR 0.61, 95%CI 0.41-0.91; P = 0.0155), median overall survival (mOS) 14.5 months (12.4-19.0) vs 11.6 months (8.5-15.6) (HR0.61, 95% CI 0.40-0.93; P = 0.023). Therefore, we explored potential biomarkers in patients with "negative hyperselected" tumors. Remarkably, among the investigated factors at multivariable analysis for PFS and OS only ctDNA TF retained significance. For patients with negative hyperselected tumors with ctDNA TF ≥ 10 compared with patients with ctDNA TF <10% mPFS was 4.8 months (3.4-3.9) vs 5.7 (4.4-6.9) (HR 1.74, 95% CI 1.20-2.53; P = 0.00382) and mOS 11.0 months (8.3-13.0) vs 21.3 months (HR 2.75, 95% CI 1.79-4.23; P = 0.00000418). This data suggests that a higher ctDNA shedding might better refine cancer aggressiveness and metastatic load than tumor burden. Taken together these results highlights the strong prognostic value of ctDNA TF and the potential role for treatment personalization.
    Keywords:  Anti-EGFR rechallenge; Cetuximab; Liquid biopsy; Molecular hyperselection; ctDNA tumor fraction
    DOI:  https://doi.org/10.1016/j.jlb.2026.100504
  2. Cancers (Basel). 2026 Sep 19. pii: 3043. [Epub ahead of print]18(18):
    Circulating Tumor DNA-Based Molecular Residual Disease in Early-Stage Non-Small-Cell Lung Cancer: Biology, Assays, and the Path Toward MRD-Guided Care.
    Rajan Yadav, Masaoki Ito, Hideki Ujiie, Shuta Ohara, Yasuhiro Tsutani, Goutham Sunny.
      Complete surgical resection remains the cornerstone of curative therapy for early-stage non-small-cell lung cancer (NSCLC), yet a substantial proportion of patients relapse despite a macroscopically complete operation and negative conventional staging. This residual risk reflects micrometastatic disease that is below the resolution of computed tomography and that current clinicopathologic risk factors only coarsely predict. Circulating tumor DNA (ctDNA) provides a direct, blood-based readout of this molecular residual disease (MRD), its detection after definitive treatment is among the strongest known predictors of recurrence, and ctDNA frequently rises months before radiographic progression. In this narrative review, based on a literature search closed on 12 September 2026, we synthesize the foundational and translational literature underpinning ctDNA-MRD in resected NSCLC. We outline the biology of ctDNA shedding and metastatic dissemination established by serial-sampling and phylogenetic studies; the prognostic performance of landmark and longitudinal MRD, tabulated quantitatively across the major cohorts, meta-analyses and trial-nested analyses; the perioperative kinetics that dictate when sampling is informative; the analytical design of tumor-informed versus tumor-agnostic assays and the determinants of their sensitivity; and the biological and technical sources of false-negative and false-positive results, of which clonal hematopoiesis and low-shedding histologies are the most consequential. We then position MRD within the contemporary perioperative treatment landscape-adjuvant targeted therapy and immunotherapy, and neoadjuvant and perioperative chemoimmunotherapy-and review the emerging, still-investigational paradigm of MRD-guided escalation and de-escalation, including the early termination of the MRD-selected MERMAID trials. We conclude with the analytical, evidentiary and implementation barriers-and the current positions of guideline bodies and regulators-that separate a powerful prognostic biomarker from a validated predictive tool, and we set out the trial-design requirements needed to close that gap.
    Keywords:  adjuvant therapy; circulating tumor DNA; clonal hematopoiesis; liquid biopsy; molecular residual disease; non-small-cell lung cancer; perioperative immunotherapy
    DOI:  https://doi.org/10.3390/cancers18183043
  3. Nat Med. 2026 Sep 22.
    Performance of a multi-cancer early detection test in the randomized controlled NHS-Galleri trial.
    Richard D Neal, Saoirse Dolly, Peter Johnson, Helen Jones, Sir Harpal Kumar, Lennard Y W Lee, Yujin Lee, Wei Liang, Thomas Round, Rebecca Smittenaar, Jane Warwick, Peter Sasieni, Charles Swanton.
      The NHS-Galleri trial was a randomized controlled trial evaluating a multi-cancer early detection (MCED) test added to usual care. We reported elsewhere that the primary endpoint of a reduction in the incidence of stage III/IV cancer diagnoses in the intervention arm versus control arm was not met. Here we report prespecified secondary test performance endpoints among evaluable intervention arm participants across three annual screening rounds. These analyses were descriptive; there was no hypothesis testing. Participants aged 50-77 years (N = 142,250) were randomized 1:1 into intervention (MCED) or control arms. Intervention arm participants with positive MCED results were referred to National Health Service (NHS) standard-of-care pathways for diagnostic workup, with referrals informed by the predicted cancer signal origin (CSO). Positive test results were returned for 722 of 70,325 (1.03%), 518 of 64,498 (0.80%) and 561 of 62,323 (0.90%) participants in rounds 1-3, respectively. In aggregate, 937 participants had MCED-detected primary cancers. Respective by-round cancer detection rates were 0.60%, 0.40% and 0.41%; positive predictive values were 58.0% (419/722), 50.4% (261/518) and 45.8% (257/561); and negative predictive values were 98.98% (68,895/69,603), 98.90% (63,278/63,980) and 98.86% (61,058/61,762). Across rounds, specificity ranged from 99.50% to 99.60%; episode sensitivity ranged from 26.7% to 37.2% for all cancers and from 47.6% to 63.4% for 12 prespecified types; and CSO accuracy ranged from 91.1% to 93.6%. These data provide insights on the performance of the MCED test in population screening within the NHS setting. ClinicalTrials.gov: NCT05611632 ; ISRCTN: ISRCTN91431511 .
    DOI:  https://doi.org/10.1038/s41591-026-04652-8
  4. Front Oncol. 2026 ;16 1899836
    Prognostic and therapeutic implications of BRCA1 and BRCA2 mutations in ovarian cancer.
    Weronika Pawul, Paulina Opoka, Agata Dusza, Bernard Blajerski, Julia Orzelska, Natalia Gierulska, Krzysztof Kułak, Rafał Tarkowski.
       Introduction: Ovarian cancer remains one of the leading causes of cancer-related mortality among women because of its asymptomatic early course, delayed diagnosis, and frequent presentation at advanced stages. Germline and somatic mutations in the BRCA1 and BRCA2 genes significantly increase the risk of ovarian cancer by impairing homologous recombination DNA repair, resulting in genomic instability. Beyond their role in carcinogenesis, BRCA mutations have become important prognostic and predictive biomarkers, influencing treatment response and clinical outcomes. This review summarizes current evidence regarding the impact of BRCA1/2 status on prognosis and therapeutic strategies in ovarian cancer.
    Methods: A literature review was conducted using the PubMed and Scopus databases. English-language articles published between 2016 and 2026 were identified using combinations of the keywords ovarian cancer, BRCA1, BRCA2, PARP inhibitors, homologous recombination deficiency, and treatment. Original studies, systematic reviews, meta-analyses, and relevant clinical trials were included.
    Results: The available evidence demonstrates that patients carrying BRCA1 or BRCA2 mutations generally experience improved progression-free survival and, in many studies, prolonged overall survival compared with non-carriers. This survival advantage is largely attributed to increased sensitivity to platinum-based chemotherapy and the efficacy of PARP inhibitors, which exploit synthetic lethality in homologous recombination-deficient tumors. The literature also emphasizes the importance of universal BRCA testing to optimize treatment selection, identify candidates for maintenance PARP inhibitor therapy, and facilitate genetic counseling. In addition, emerging mechanisms of resistance to PARP inhibitors remain a significant therapeutic challenge.
    Conclusion: BRCA1/2 mutation status is a key biomarker in the management of ovarian cancer, supporting personalized treatment strategies and improving patient outcomes. Further research is needed to identify novel predictive biomarkers, overcome therapeutic resistance, and develop more effective targeted therapies.
    Keywords:  BRCA 1/2 mutation; BRCA1/2; HRD (homologous recombination deficiency); PARPi; PARPi resistance; genetic testing; ovarian cancer; treatment
    DOI:  https://doi.org/10.3389/fonc.2026.1899836
  5. Cancers (Basel). 2026 Sep 13. pii: 2955. [Epub ahead of print]18(18):
    Microsatellite Instability and Mismatch Repair Subclonality in Human Cancers: Biologic Basis, Diagnostic Pitfalls, and Therapeutic Implications with a Focus on Colorectal Cancer.
    Alena A Hasenburg, Bradley G Somer, Sebastian Stintzing, Axel Grothey.
      Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) define a molecular subtype of colorectal cancer (CRC) and predict benefit from immune checkpoint inhibition. Clinically, MSI/MMR assessment may yield discordant results across assays, anatomic sites, or time points. A challenging scenario occurs when tissue analysis identifies microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) CRC, whereas circulating tumor DNA (ctDNA) analysis indicates MSI-H. This review evaluates evidence for MSI/MMR heterogeneity and subclonality in CRC. We reviewed literature on spatial, temporal and subclonal MSI/MMR heterogeneity across human cancers, focusing on CRC. Explanations for tissue-plasma and tissue-tissue discordance, including assay limitations, sampling bias, lesions misattribution, biological evolution, and treatment-related selection, were assessed. Although discordance more commonly reflects assay limitations, sampling bias, or profiling of different lesions, increasing evidence supports genuine biological heterogeneity. Distinct tumor regions may show retained MMR protein expression in one area and regional loss with MSI in another. Noncanonical MMR defects, epigenetic heterogeneity, post-treatment evolution, adaptive mutator-state, and immune selection may also generate dynamic or subclonal instability. Therapeutic relevance may depend not simply on MSI detection, but on whether the unstable clone is sufficiently dominant to generate broadly shared neoantigens across the disease burden. MSI/MMR discordance requires careful interpretation and should not automatically be considered as true biological heterogeneity. Nevertheless, genuine subclonality occurs in CRC and other cancers and may affect responsiveness to immune checkpoint inhibition. Integrated tissue, plasma, spatial and longitudinal analyses may improve treatment decisions and biomarker development.
    Keywords:  circulating tumor DNA; colorectal cancer; microsatellite instability
    DOI:  https://doi.org/10.3390/cancers18182955
  6. Nat Med. 2026 Sep 22.
    Some answers, more questions for multi-cancer early detection tests.
    Catherine R Marinac, Timothy R Rebbeck, Elizabeth K O'Donnell.
      
    DOI:  https://doi.org/10.1038/s41591-026-04688-w
  7. Curr Issues Mol Biol. 2026 Aug 22. pii: 853. [Epub ahead of print]48(9):
    Liquid Biopsy in Head and Neck Squamous Cell Carcinoma: A Molecular Perspective on Circulating Biomarkers and Their Clinical Translation.
    Francesca Cascone, Gabriele Riccardi, Dario Benelli, Riccardo Maurizi, Camilla Laureti, Carla Petrella, Carlo Cogoni, Antonio Minni, Christian Barbato.
      Liquid biopsy, the analysis of tumor-derived material in blood, saliva, and other body fluids, is increasingly explored for the diagnosis, surveillance, and molecular characterization of head and neck squamous cell carcinoma (HNSCC). Its performance, however, is not uniform across the disease, and the reason is fundamentally molecular. human papillomavirus (HPV)-positive oropharyngeal cancers carry viral oncogenes that are absent from the host genome and therefore provide a near ideal, tumor specific circulating marker, whereas HPV-negative tumors are driven by a heterogeneous somatic landscape that offers no single universal target. In this narrative review, we adopt a molecular perspective. We first examine the biological origin of circulating tumor DNA and of the other analytes that liquid biopsy can interrogate including circulating tumor HPV DNA, viral transcripts, microRNAs, extracellular vesicles, and methylation signatures. We then consider how analytical platforms, from droplet digital PCR to next generation and ultrasensitive whole-genome sequencing, translate these molecules into measurements. Only afterward do we discuss the clinical questions, organized by clinical objective rather than by individual study: diagnosis and early detection, prognosis and risk stratification, treatment response monitoring, minimal residual disease and surveillance, and biomarker guided de-escalation in HPV-positive disease. Twelve registered clinical trials, involving approximately 1183 patients, are presented as illustrations of these questions. We close on the biological and technical gaps that still separate promising signals from clinical practice, and on the multi analyte and dynamic strategies most likely to bridge them. At present, liquid biopsy should be regarded as a complementary tool rather than as a replacement for established clinicopathological assessment.
    Keywords:  HPV; circulating tumor DNA; ctHPV DNA; head and neck squamous cell carcinoma; liquid biopsy; microRNA; minimal residual disease
    DOI:  https://doi.org/10.3390/cimb48090853
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