bims-preonc 2024-12-01 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2024–12–01
eight papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Deciphering molecular relapse and intra-tumor heterogeneity in non-metastatic resectable head and neck squamous cell carcinoma using circulating tumor DNA.
Monitoring circulating tumor DNA liquid biopsy in stage III BRAF-mutant melanoma patients undergoing adjuvant treatment.
Minimal residual disease as a target for liquid biopsy in patients with solid tumours.
The prognostic value of tumor-informed minimal residual disease detection using circulating tumor DNA in first-line treatment of ovarian cancer.
Empowering Precision Oncology: Advancing Cancer Research by Augmenting Single-cell RNA and Bulk RNA Sequencing for Confronting the Heterogeneity in Ovarian Cancer.
Homologous recombination deficiency in pancreatic neuroendocrine tumors.
Neoadjuvant immunotherapy in the evolving landscape of sarcoma treatment.
BRCA loss of function including BRCA1 DNA-methylation, but not BRCA-unrelated homologous recombination deficiency, is associated with platinum hypersensitivity in high-grade ovarian cancer.

Oral Oncol. 2024 Nov 28. pii: S1368-8375(24)00429-9. [Epub ahead of print]160 107111

Deciphering molecular relapse and intra-tumor heterogeneity in non-metastatic resectable head and neck squamous cell carcinoma using circulating tumor DNA.

Grégoire Marret, Constance Lamy, Sophie Vacher, Luc Cabel, Mathieu Séné, Ladidi Ahmanache, Laura Courtois, Zakhia El Beaino, Jerzy Klijanienko, Charlotte Martinat, Nicolas Servant, Choumouss Kamoun, Maral Halladjian, Thierry Bronzini, Cédric Balsat, Jean-François Laes, Aubray Prévot, Sébastien Sauvage, Maxime Lienard, Emmanuel Martin, Bérengère Genin, Nathalie Badois, Maria Lesnik, Antoine Dubray-Vautrin, Olivier Choussy, Wahib Ghanem, Rabah Taouachi, Julien Masliah Planchon, Ivan Bièche, Christophe Le Tourneau, Maud Kamal.

   OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is characterized by significant genetic intra-tumor heterogeneity (ITH), which may hinder precision medicine strategies that depend on results from single tumor-biopsy specimens. Treatment response assessment relies on radiologic imaging, which cannot detect minimal residual disease (MRD). We assessed the relevance of circulating tumor DNA (ctDNA) as a biomarker for ITH and MRD in HNSCC.
MATERIALS AND METHODS: We recruited 41 non-metastatic resectable HNSCC patients treated with upfront curative-intent surgery in the prospective biobanking SCANDARE study (NCT03017573). Thirty-one patients (76 %) showed recurrent disease at a median follow-up of 41 months. Targeted next-generation sequencing was performed on resected tumor tissues, as well as on serial blood samples obtained at surgery, within 14 weeks after surgery, at six months and at recurrence.
RESULTS: ctDNA was detected in 21/41 patients at surgery (sensitivity: 51 %; 95 % CI, 35-67 %) and 15/22 patients at recurrence (sensitivity: 68 %; 95 % confidence interval [CI], 45-86 %). Among patients with mutations identified in longitudinal plasma samples, additional mutations missed in tumor tissues were reported in 3/21 patients (14 %), while emerging mutations were reported in 9/21 patients (43 %). In the postoperative surveillance setting, ctDNA-based MRD detection anticipated clinical recurrence with a median lead-time of 9.9 months (interquartile range, 8.0-14.5 months) in 17/27 patients (63 %). When detected within 14 weeks after surgery, MRD correlated with disease recurrence after adjusting for classical prognostic variables (HR = 3.0; 95 % CI, 1.1-7.9; p = 0.03).
CONCLUSIONS: ctDNA detection is a useful biomarker for ITH and MRD in resectable HNSCC patients.

Keywords:  Biomarkers; Head and neck squamous cell carcinoma; Liquid biopsy; Next-generation sequencing; Tumor heterogeneity; circulating tumor DNA

DOI:  https://doi.org/10.1016/j.oraloncology.2024.107111
J Transl Med. 2024 Nov 28. 22(1): 1074

Monitoring circulating tumor DNA liquid biopsy in stage III BRAF-mutant melanoma patients undergoing adjuvant treatment.

Sara Marchisio, Alessia Andrea Ricci, Gabriele Roccuzzo, Eleonora Bongiovanni, Erika Ortolan, Luca Bertero, Enrico Berrino, Valentina Pala, Renata Ponti, Paolo Fava, Simona Osella-Abate, Silvia Deaglio, Caterina Marchiò, Anna Sapino, Rebecca Senetta, Ada Funaro, Simone Ribero, Pietro Quaglino, Paola Cassoni.

   BACKGROUND: The introduction of adjuvant therapies for patients with resected cutaneous melanoma (CM) has increased the need for sensitive biomarkers for risk stratification and disease monitoring. This study aims to investigate the utility of circulating tumor DNA (ctDNA) assessment in predicting and reflecting disease status during adjuvant therapy.
METHODS: We enrolled 32 patients with resected BRAF-mutated stage III CM receiving adjuvant targeted therapy or immunotherapy. Plasma samples of patients were collected at the baseline (treatment initiation) and during the therapy, and BRAF-mutated ctDNA was quantified by droplet digital PCR (ddPCR).
RESULTS: Baseline ctDNA was detected in 11/32 (34.4%) patients and predicted postoperative high risk of relapse [HR 3.79, 95% CI 1.20-12.00, p = 0.023]. The three-year overall survival (OS) rate was 54.6% (95% CI 22.9-77.9) versus 95% (95% CI 69.5-99.3) in ctDNA-positive and negative groups, respectively, with significantly worse OS for ctDNA-positive patients [HR 7.92, 95% CI 1.56-40.36, p = 0.013]. Among the baseline ctDNA-positive group (high-risk patients), longitudinal ctDNA detection during adjuvant therapy reflected the clinical outcomes. Only non-relapsing patients cleared their plasma ctDNA by the end of the treatment, while persistent ctDNA detection provided early evidence of disease recurrence.
CONCLUSIONS: ctDNA detection shows promising results in the post-operative setting for identifying cutaneous melanoma patients at the highest risk of relapse and for real-time monitoring of patients' clinical status and treatment response.

Keywords:  Adjuvant therapy; Cutaneous melanoma; Disease monitoring; Liquid biopsy; ddPCR

DOI:  https://doi.org/10.1186/s12967-024-05783-7
Nat Rev Clin Oncol. 2024 Nov 28.

Minimal residual disease as a target for liquid biopsy in patients with solid tumours.

Klaus Pantel, Catherine Alix-Panabières.

Metastasis is the leading cause of cancer-related death in patients with solid tumours. Current imaging technologies are not sufficiently sensitive to detect minimal residual disease (MRD; also known as measurable or molecular residual disease) after initial surgery or chemotherapy, pointing to the need for more sensitive tests to detect remaining traces of cancer in the body. Liquid biopsy, or the analysis of tumour-derived or tumour-induced cells or cellular products in the blood or other body fluids, has opened a new diagnostic avenue to detect and monitor MRD. Liquid biopsy is already used in clinical decision making for patients with haematological malignancies. Here, we review current knowledge on the use of circulating tumour DNA (ctDNA) to detect and monitor MRD in patients with solid tumours. We also discuss how ctDNA-guided MRD detection and characterization could herald a new era of novel 'post-adjuvant therapies' with the potential to eliminate MRD and cure patients before terminal metastatic disease is evident on imaging.

DOI: https://doi.org/10.1038/s41571-024-00967-y
Gynecol Oncol. 2024 Nov 22. pii: S0090-8258(24)01191-0. [Epub ahead of print]192 94-101

The prognostic value of tumor-informed minimal residual disease detection using circulating tumor DNA in first-line treatment of ovarian cancer.

Tong Shu, Yiming Liang, Siwen Zhang, Tianqi Sun, Yunong Gao, Chang Guo, Zhe Li, Min Gao, Nan Zhang, Nan Song, Naiyi Zhang, Weijiao Gao, Wei Wang, Hongguo Wang, Yan Cai, Feng Zhang, Xuwo Ji, Yu Dong, Hong Zheng.

   OBJECTIVE: This study aims to assess the application and effectiveness of tumor-informed Minimal Residual Disease (MRD) detection using circulating tumor DNA (ctDNA) for predicting disease recurrence and survival outcomes in ovarian cancer patients.
METHODS: Between 2020 and 2022, 31 newly diagnosed stage II-IV ovarian cancer patients were enrolled in this retrospective study. All patients completed standard treatment, including cytoreductive surgery and platinum-based chemotherapy, achieving a complete remission (CR) without receiving first-line PARP inhibitor maintenance therapy. Archived tumor tissue, as well as plasma samples collected pre- and post-treatment, were tested using Whole Exome Sequencing (WES) to identify personalized somatic variants for MRD detection.
RESULTS: All pre-treatment (baseline) blood samples showed a 100 % MRD positive rate, demonstrating the high sensitivity of ctDNA-based MRD detection. This rate decreased to 25.8 % in post-treatment (landmark) samples, indicating a significant reduction of ctDNA levels following effective treatment. The median follow-up time until Sep 2023 was 21.4 months, during which 15 patients experienced recurrence. Landmark MRD-positive patients exhibited a markedly shorter median progression-free survival (PFS) compared to MRD-negative patients (5.8 months vs 24.7 months, HR = 6.678, p = 0.01). Furthermore, a strong correlation was observed between post-treatment MRD status and recurrence, with a higher relapse rate in the MRD-positive group.
CONCLUSION: The study establishes MRD detection via ctDNA analysis as a valuable tool for early and accurate prediction of ovarian cancer recurrence, potentially leading to improved clinical outcomes. As a result, integrating MRD detection into routine clinical practice is advocated to enable more effective and personalized treatment strategies for ovarian cancer patients.

Keywords:  Minimal residual disease; Ovarian cancer; Prognosis; ctDNA

DOI:  https://doi.org/10.1016/j.ygyno.2024.11.002
J Midlife Health. 2024 Jul-Sep;15(3):15(3): 194-196

Empowering Precision Oncology: Advancing Cancer Research by Augmenting Single-cell RNA and Bulk RNA Sequencing for Confronting the Heterogeneity in Ovarian Cancer.

Muhammed Ali Siham, A Ashwin Prabahar.

  Ovarian cancer presents significant challenges in clinical oncology due to its high prevalence, heterogeneity, and late-stage diagnosis. Our study explores the application of single-cell RNA sequencing (scRNA-Seq) and bulk RNA sequencing to enhance our understanding of ovarian cancer at the molecular level. We highlight the diagnostic strategies and emphasize the critical role of scRNA-Seq in unraveling the intricate cellular composition and phenotypic plasticity within ovarian tumors. We also discuss the identification of rare cell subtypes, characterization of distinct cell types, and elucidation of molecular features, signaling pathways, and dysregulated networks using scRNA-Seq. Furthermore, our study showcases how scRNA-Seq aids in the discovery of novel biomarkers for diagnosis, prognosis, and treatment response prediction, as well as identifying therapeutic targets and pathways associated with drug resistance.

Keywords:  Bulk RNA sequencing; cellular composition; ovarian cancer; single-cell RNA sequencing; tumors

DOI:  https://doi.org/10.4103/jmh.jmh_93_23
Future Oncol. 2024 Nov 25. 1-10

Homologous recombination deficiency in pancreatic neuroendocrine tumors.

Camilla Bardasi, Elena Tenedini, Lia Bonamici, Stefania Benatti, Luca Reggiani Bonetti, Gabriele Luppi, Laura Cortesi, Enrico Tagliafico, Massimo Dominici, Fabio Gelsomino.

  Aim: Pancreatic Neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms whose tumor biology is still little known. Thanks to next-generation sequencing, pathogenic mutations in base-excision-repair MUTYH gene and homologous recombination genes CHEK2 and BRCA2 seem to have a role in the development of pNETs.Research design & methods: We assumed that Homologous Recombination Deficiency (HRD) could be a critical pathogenetic mechanism for pNETs. We evaluated the HR status in a case series of 33 patients diagnosed with pNET at the Modena Cancer Center using the AmoyDX HRD Focus assay.Results: The AmoyDx test did not identify any HRD-positive patients (median GSS equal to 1.1, positive score: >50), and no pathogenic BRCA variants were detected. However, thanks to the SNP analysis, a consistent number of partial or complete single-copy deletions or duplications in several chromosomes.Conclusion: The AmoyDX HRD focus assay performed well on pancreatic samples, despite being originally designed for ovarian cancer and used on samples stored for over a year. Larger studies are needed to further assess the role of HRD assays in pNETs research.

Keywords:  BRCA; HRD; International Cancer Genome Consortium; MUTYH; pNET

DOI:  https://doi.org/10.1080/14796694.2024.2421160
J Immunother Cancer. 2024 Nov 24. pii: e010074. [Epub ahead of print]12(11):

Neoadjuvant immunotherapy in the evolving landscape of sarcoma treatment.

Qiyan Cai, Yi Que, Xing Zhang.

  Soft tissue sarcoma is characterized by its rarity and complexity, making it more difficult to conduct large clinical trials compared with other solid tumors. Also known as 'cold tumors,' sarcomas, especially advanced sarcomas, have poor responses to immunotherapy. Based on that, the results of two groundbreaking phase 2 clinical trials about neoadjuvant immunotherapy in patients with liposarcoma or undifferentiated pleomorphic sarcoma are encouraging. In this paper, we discuss the results of these clinical trials and the challenges we are facing to conduct neoadjuvant immunotherapy in sarcomas and call for further research to promote the development of it.

Keywords:  Immune Checkpoint Inhibitor; Immunotherapy; Neoadjuvant; Solid tumor

DOI:  https://doi.org/10.1136/jitc-2024-010074
Clin Epigenetics. 2024 Nov 27. 16(1): 171

BRCA loss of function including BRCA1 DNA-methylation, but not BRCA-unrelated homologous recombination deficiency, is associated with platinum hypersensitivity in high-grade ovarian cancer.

Heidelinde Fiegl, Simon Schnaiter, Daniel U Reimer, Katharina Leitner, Petra Nardelli, Irina Tsibulak, Verena Wieser, Katharina Wimmer, Esther Schamschula, Christian Marth, Alain G Zeimet.

   BACKGROUND: In high-grade ovarian cancer (HGOC), determination of homologous recombination deficiency (HRD) status is commonly used in routine practice to predict response to platinum-based therapy or poly (ADP-ribose) polymerase inhibitors (PARPi). Here we tested the hypothesis that BRCA loss of function (LOF) due to epigenetic or genetic aberrations is a better predictor for the clinical outcome than HRD. One hundred thirty-one HGOC tissues were tested for BRCA DNA-methylation, BRCA mutations, HRD and BRCA1 mRNA expression, followed by a comprehensive survival analysis.
RESULTS: BRCA1-methylation was detected in 11% of the tumors, exclusively in BRCA1-wild-type (wt) HGOCs. BRCA1-methylated tumors (BRCA1-meth) had HRD-scores similar to those of BRCA-mutated (mut) tumors, and higher compared to unmethylated-BRCA-wt tumors (BRCA-wt-unmeth; P < 0.001). Platinum-refractory or -resistant HGOCs at first recurrence were all BRCA-unmeth cancers. Only one of the BRCA-mut cancers had a platinum-resistant recurrence. Thus, 99% of relapses in cancers with epigenetic or genetic BRCA-alterations were platinum-sensitive. Multivariate analysis confirmed BRCA-LOF as an independent predictor of progression-free survival (PFS) and overall survival (OS), whereas HRD-status had no predictive value for PFS and OS. Patients with BRCA-wt-unmeth cancers had the worst outcome compared to patients with cancers harboring epigenetic or genetic BRCA-alterations (PFS: P = 0.007; OS: P = 0.022). Most importantly, the BRCA-wt-unmeth subfraction of HRD-positive HGOCs exhibited the same poor survival as the entire HRD-negative cohort.
CONCLUSION: In HGOC BRCA mutational status together with BRCA1-methylation exhibit the best predictive power for favorable clinical outcome and thus high sensitivity to platinum-based therapy, whereas BRCA-unrelated HRD positivity was not associated with improved platinum sensitivity.

Keywords:   BRCA1 ; BRCA2 ; DNA-methylation; Homologous recombination deficiency (HRD); Ovarian cancer; PARP inhibitor therapy; Platinum sensitivity

DOI:  https://doi.org/10.1186/s13148-024-01781-0