bims-tumhet Biomed News
on Tumor heterogeneity
Issue of 2026–03–08
seven papers selected by
Sergio Marchini, Humanitas Research
  1. HRD in endometrial cancer: LST loss drives distinct genomic profile and platinum response.
  2. Harnessing genomics for early cancer detection, risk stratification and prevention.
  3. Fragmentomic liquid biopsy enables early breast cancer detection, molecular subtyping and lymph node assessment.
  4. Immune checkpoint inhibitors in clear cell ovarian carcinoma and mixed gynecologic clear cell cohorts: a systematic review and meta-analysis.
  5. Clinical development of molecular residual disease (MRD) and multi-cancer early detection (MCED) using liquid biopsy multiomics with artificial intelligence (AI).
  6. The interplay of clonal hematopoiesis and cancer: Clinical implications in oncology.
  7. De-escalation in stage IC epithelial ovarian cancer: adjuvant treatment.
  1. NPJ Precis Oncol. 2026 Mar 02.
    HRD in endometrial cancer: LST loss drives distinct genomic profile and platinum response.
    Ting Wan, Qiaqia Li, Wen Hao, Ying Xie, Binbin Chen, Mufei Lin, Die Dai, Ziming Du, Jundong Li, Wei Wei.
      While homologous recombination deficiency (HRD) presents therapeutic opportunities in endometrial cancer (EC), its molecular determinants and clinical implications remain poorly characterized. Through genomic analysis of 688 cancer-related genes combined with genomic scar assessment, we investigated HRD molecular features and clinical relevance of HRD across three cohorts: an EC cohort from Sun Yat-sen University Cancer Center (SYSUCC, n = 114), the Cancer Genome Atlas EC cohort (n = 500), and a high-grade serous ovarian cancer (HGSOC) cohort (n = 118). HRD was identified in 23.7% of SYSUCC EC cases, and HRD tumors paradoxically had fewer short-nucleotide variations in HRR genes than proficient (HRP) tumors (18.52% vs. 48.28%, P = 0.007). Mechanistic analysis revealed large-scale transition (LST) losses as the potential predominant HRD driver in EC, occurring significantly more frequently in HRD versus HRP tumors (74.1% vs 5.7%; P < 0.001). Comparative genomics demonstrated enrichment of HRR gene LST losses was EC-specific, contrasting with HGSOC where LST distribution was HRD-independent. Clinically, elevated HRD scores predicted reduced progression-free survival (HR 1.74, 95% CI 1.03-2.94; P = 0.04) yet enhanced platinum sensitivity (HR 0.41, 95% CI 0.18-0.94; P = 0.034). Our findings indicate that the HRD phenotype in EC, driven primarily by LST losses rather than short-nucleotide variations, serves as both a prognostic and predictive biomarker.
    DOI:  https://doi.org/10.1038/s41698-026-01347-8
  2. Nat Genet. 2026 Mar 02.
    Harnessing genomics for early cancer detection, risk stratification and prevention.
    Muxin Gu, Woody Z Zhang, Rebecca C Fitzgerald, Alexander M Frankell, George S Vassiliou.
      Therapeutic advances have improved cancer outcomes, but early-stage detection remains the single most important determinant of favorable prognoses across many cancer types. Cancer genomics has yielded detailed maps of somatic mutation and methylation patterns characteristic of different cancers, enabling the development of assays to detect mutation-bearing tumor-derived DNA in tissue biopsies, blood and other body fluids at the earliest stages of disease. In parallel, it has also become clear that small clones bearing cancer-associated mutations arise commonly in histologically normal tissues, a phenomenon that becomes universal in proliferative tissues with age but leads to cancer in only a small minority of individuals. This review article outlines established strategies for early cancer detection and highlights emerging insights into the genetics of precancerous mutant clones that have led to the recent development of prognostic frameworks for identifying high-risk individuals, making it increasingly possible to intercept evolving cancer at a premalignant or early malignant stage, when interventions are most effective.
    DOI:  https://doi.org/10.1038/s41588-026-02505-1
  3. Nat Commun. 2026 Mar 06. pii: 2276. [Epub ahead of print]17(1):
    Fragmentomic liquid biopsy enables early breast cancer detection, molecular subtyping and lymph node assessment.
    Yuxuan Zhu, Siwei Zheng, Yinkuan Shao, Jun Zhou, Xidong Gu, Lesang Shen, Xue Li, Wenjia Liu, Wei Xue, Haiqi Lu, Jun Zhou, Jinghua Ding, Haiming Deng, Jiayin Chen, Zhuohang Yu, Yao Yao, Wenjie Xia, Wuzhen Chen, Shanshan Sun, Zheng Wang, Tianyi Qian, Xiuyan Yu, Jian Liu, Yiding Chen, Ziao Lin, Jian Huang, Chao Ni.
      Breast cancer remains a leading global health concern in women, while screening is still limited by imaging accessibility and reduced sensitivity in dense breasts. Here we conduct a multicenter case-control study including 503 breast cancer patients and 289 benign controls to develop TuFEst, a machine learning model based on genome-wide cell-free DNA fragmentomic features. TuFEst achieves high sensitivity (95%) and specificity (78.3%) for early cancer detection and reliably identifies malignancies missed by conventional imaging. Extension of this framework enables non-invasive molecular subtyping (TuFEst-MS) and lymph node status prediction (TuFEst-LN), with strong performance in independent validation cohorts and imaging-pathology discordant cases. Transcriptomic profiling of paired bulk tumor samples (n = 79) demonstrates that elevated TuFEst-derived cancer scores reflect tumor aggressiveness and immune-related biological programs. Together, these findings support cfDNA fragmentomics as an integrated liquid biopsy strategy for breast cancer management, enabling concurrent detection, molecular subtyping, and lymph node evaluation with potential clinical utility.
    DOI:  https://doi.org/10.1038/s41467-026-70204-w
  4. Int J Gynecol Cancer. 2026 Feb 28. pii: S1048-891X(25)01987-5. [Epub ahead of print] 102863
    Immune checkpoint inhibitors in clear cell ovarian carcinoma and mixed gynecologic clear cell cohorts: a systematic review and meta-analysis.
    Mariana Macambira Noronha, Luiz Felipe Costa de Almeida, Lara de Holanda Juca Silveira, Valbert Oliveira Costa Filho, Zoe Friedman, Gabriela Aparecida Schiefler Gazzoni, Ana Caroline Fonseca Alves, Ana Carolina Veneziani.
       OBJECTIVE: Clear cell ovarian carcinoma is a rare sub-type characterized by poor prognosis and intrinsic resistance to platinum-based chemotherapy. Unlike high-grade serous ovarian cancer, its distinct molecular profile suggests a potentially greater susceptibility to immunotherapy. However, available evidence remains limited and heterogeneous. This systematic review and meta-analysis evaluated the efficacy and safety of immune checkpoint inhibitors in this setting.
    METHODS: PubMed, Embase, and Cochrane databases were searched through November 2025. Cohort studies and clinical trials enrolling patients with clear cell ovarian carcinoma alone or mixed ovarian and endometrial clear cell carcinoma were eligible. Immune checkpoint inhibitors administered as monotherapy or in combination with other systemic therapies were included. Outcomes were objective response rate, progression-free survival, overall survival, and treatment-related adverse events, including any-grade and grade ≥3 events. A random-effects model was used for pooled analyses with R software version 4.2.0. The study was registered in International Prospective Register of Systematic Reviews (CRD420251130819).
    RESULTS: Fifteen studies (423 patients), including 14 clinical trials and 1 cohort study, met eligibility criteria. The pooled objective response rate across all treatment cohorts was 24.5% (95% confidence interval [CI] 18.3 to 32.7, I2 = 61%, p < .01). Specifically, 14.6% for immune checkpoint inhibitor monotherapy (n = 122, 95% CI 8.8 to 24.2, I2 = 38%, p = .15) and 37.5% for dual blockage (n = 77, 95% CI 24.4 to 57.5, I2 = 42%, p = .16). Four studies (n = 130) provided re-constructable survival data, yielding a pooled median progression-free survival of 3.8 months and overall survival of 18.8 months. Severe treatment-related adverse events grade ≥3 occurred in 29.36% of patients (N = 288, 95% CI 20.30 to 42.47, I2 = 70%).
    CONCLUSIONS: Immune checkpoint inhibitors demonstrate modest clinical activity in clear cell gynecologic carcinomas, with higher response rates observed for dual agent. Treatment-related adverse events were frequent, underscoring the need for careful patient selection and toxicity monitoring. Substantial heterogeneity and limited survival data support the need for biomarker-driven prospective trials to better define which patients benefit the most.
    Keywords:  Clear Cell Gynecologic Cancer; Clear Cell Ovarian Carcinoma; Immune Checkpoint Inhibitors; Meta-Analysis
    DOI:  https://doi.org/10.1016/j.ijgc.2025.102863
  5. Int J Clin Oncol. 2026 Mar 06.
    Clinical development of molecular residual disease (MRD) and multi-cancer early detection (MCED) using liquid biopsy multiomics with artificial intelligence (AI).
    Taro Shibuki, Riu Yamashita, Tadayoshi Hashimoto, Takao Fujisawa, Mitsuho Imai, Junichiro Yuda, Takeshi Kuwata, Toshihiro Misumi, Yoshiaki Nakamura, Hideaki Bando, Kaname Kojima, Sayuri Tokioka, Ippei Chiba, Naoki Nakaya, Atsushi Hozawa, Seizo Koshiba, Nobuo Fuse, Sakae Saito, Ritsuko Shimizu, Woong-Yang Park, Kengo Kinoshita, Takayuki Yoshino.
       BACKGROUND: Early detection of cancer and precise recurrence monitoring remain major unmet needs in oncology. Conventional screening is limited to a few cancer types, leaving nearly half of cancers without established programs. Multi-cancer early detection (MCED) tests based on circulating tumor biomarkers have shown promise, but sensitivity for early-stage remains a challenge. In parallel, detection of molecular residual disease (MRD) using circulating tumor DNA (ctDNA) has emerged as a powerful prognostic and predictive tool, though current assays remain limited in sensitivity and specificity. This study aims to integrate multi-omics data to develop more refined and highly sensitive MCED and MRD assays.
    METHODS: This study leverages clinical information and biospecimens from patients with cancer and cancer-naïve individuals. Samples from patients with cancers will be derived from the MONSTAR-SCREEN-3 study, while those from cancer-naïve individuals will be obtained from the Tohoku Medical Megabank Project. Comprehensive analyses will include whole-genome sequencing (WGS), whole-exome sequencing (WES), whole-transcriptome sequencing (WTS), proteomics, metabolomics, and microbiome profiling using stool and saliva. Artificial intelligence (AI)-based multi-omics integration will be performed to develop novel MCED and MRD assays and to evaluate their clinical performance. The primary endpoints are the sensitivity and specificity of MCED and MRD assays.
    DISCUSSION: This is the first large-scale study to integrate comprehensive multi-omics profiling with AI for MCED and MRD assay development. The findings are expected to advance precision oncology by improving early diagnosis and recurrence monitoring.
    TRIAL REGISTRATION: UMIN000053815, approved by the Institutional Review Board of the National Cancer Center Hospital East.
    Keywords:  Cancer screening; Cell-free DNA; Circulating tumor DNA; MCED; Multi-cancer early detection; Multiomics
    DOI:  https://doi.org/10.1007/s10147-026-03001-6
  6. Cancer Treat Rev. 2026 Feb 15. pii: S0305-7372(26)00023-X. [Epub ahead of print] 103109
    The interplay of clonal hematopoiesis and cancer: Clinical implications in oncology.
    M Tanguay, M Tagliamento, J Samaniego, B Besse, A Renneville, E Bernard, J-B Micol.
      Clonal hematopoiesis (CH) refers to the expansion of hematopoietic stem and progenitor cells carrying somatic mutations and is increasingly identified in oncology through cell-free DNA testing. Once regarded mostly as a precursor to myeloid neoplasms and a contributor to cardiovascular disease, CH is now recognized as a major determinant of clinical outcomes in patients with cancer. Specific anticancer agents selectively promote the expansion of clones with DNA damage response gene mutations, particularly those with TP53 or PPM1D mutations, which are strongly associated with myeloid neoplasms post cytotoxic therapy (MN-pCT). The extent of clonal growth varies with treatment and, in some cases, may regress once therapy is withdrawn. In addition to therapy-driven clonal selection, inflammatory stress accelerates clonal expansion, creating a self-reinforcing cycle that contributes to atherosclerosis and other inflammation-associated complications. In oncology, CH-derived immune cells can infiltrate the tumor microenvironment and remodel local immunity, influencing tumor growth and treatment response. This tissue-infiltrating form of CH, termed tumor-infiltrating CH, has been associated with inferior survival in some cancer cohorts. Together, these findings establish CH as both a clinical challenge and an opportunity in modern oncology. Dedicated CH clinics and molecular tumor boards are emerging to address its implications for risk stratification, treatment selection, and survivorship care. This review examines the biology and clinical impact of CH in oncology, including its mutational spectrum, clonal evolution, role in MN-pCT, effects on inflammation and the tumor microenvironment, and emerging strategies for risk assessment and patient management.
    Keywords:  Cancer; Cell-free DNA; Clonal hematopoiesis; Myeloid neoplasms post cytotoxic therapy; PPM1D; TP53; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ctrv.2026.103109
  7. Int J Gynecol Cancer. 2026 Mar 02. pii: S1048-891X(25)01940-1. [Epub ahead of print] 102818
    De-escalation in stage IC epithelial ovarian cancer: adjuvant treatment.
    Christian Dagher, Minyoung Jang, Dimitrios Nasioudis.
      Epithelial ovarian cancer is a heterogenous group, that includes histologic sub-types with distinct biologic behavior. Stage IC disease confers a higher risk of recurrence and death compared to stage IA. While adjuvant chemotherapy may improve outcomes of patients with high-grade serous ovarian carcinoma, its impact on the oncologic outcomes of other histologic sub-types that are more chemo-resistant, such as clear cell, mucinous, and low-grade serous ovarian carcinoma is not well-established. Retrospective studies have demonstrated that omission of adjuvant chemotherapy can be considered for patients with expansile mucinous, grade 1 endometrioid, and low-grade serous ovarian carcinoma and for those with stage IC1 clear cell ovarian carcinoma. However, in the absence of data from randomized clinical trials, shared decision-making, and careful counseling of patients should be considered. Future multicenter studies are required to further validate the safety of adjuvant chemotherapy omission in certain patient sub-groups with stage IC epithelial ovarian cancer.
    Keywords:  Chemotherapy; Early Stage; Ovarian Cancer
    DOI:  https://doi.org/10.1016/j.ijgc.2025.102818
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