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Riedl JM, Fece de la Cruz F, Lin JJ, Parseghian C, Kim JE, Matsubara H, Barnes H, Caughey B, Norden BL, Morales A, Kushner EW, Ehnstrom S, Nakamura H, Patel PS, Ellis H, Pappas L, Vakaris A, Gainor JF, Kopetz S, Klempner SJ, Parikh AR, Hata AN, Heist RS, Corcoran RB. Genomic landscape of clinically acquired resistance alterations in patients treated with KRAS G12C inhibitors. Ann Oncol 2025:S0923-7534(25)00052-3. [PMID: 39914665 DOI: 10.1016/j.annonc.2025.01.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/24/2025] [Accepted: 01/27/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Mutant-selective inhibitors of KRASG12C (KRASG12Ci) have demonstrated efficacy in KRASG12C cancers. However, resistance invariably develops, resulting in short-lived responses. We aimed to define the genomic landscape of acquired resistance to KRASG12Ci and to elucidate whether novel classes of KRAS inhibitors can overcome these resistance mechanisms. METHODS To assess clinical frequencies of acquired resistance alterations, we evaluated genomic sequencing data from post-progression cell-free DNA samples in patients treated with KRASG12Ci at two US cancer centers, alongside data from six previously published studies. Cell viability assays using engineered cell models were employed to functionally validate candidate resistance drivers and to evaluate novel classes of KRAS inhibitors. RESULTS A total of 143 patients were analyzed. Most patients had non-small cell lung cancer (NSCLC, n=68) or colorectal cancer (CRC, n=58) and were treated with single-agent KRASG12Ci (n=109) or combined with anti-EGFR antibodies (n=30). RAS/MAPK alterations emerged in 46% of patients (n=66), with 39% developing ≥1 new KRAS alteration (n=56) and 23% (n=33) showing multiple concurrent alterations. The genomic landscape of acquired alterations included KRAS activating mutations (25% of patients), KRAS amplifications (22%), RAF/MAPK mutations/fusions (21%), KRAS switch-II pocket mutations (14%) and NRAS/HRAS mutations (8%). Notably, the proportion of patients with ≥1 acquired RAS/MAPK alteration was significantly higher in CRC compared to NSCLC (69% vs. 26%, p<0.001). Functional studies confirmed most alterations as resistance drivers. Sotorasib, adagrasib, and divarasib demonstrated distinct activity against KRAS switch-II pocket mutations, yet all were responsive to the RAS(ON) G12C-selective tri-complex inhibitor RM-018. The KRAS-selective inhibitor Pan-KRAS-In-1 effectively targeted KRAS activating mutations, and the RAS(ON) multi-selective tri-complex inhibitor RMC-7797 demonstrated high potency across all RAS alterations. CONCLUSION Acquired RAS/MAPK alterations are recurrent drivers of resistance to KRASG12Ci detected in CRC and, less frequently, in NSCLC. Preclinical data suggest that novel (K)RAS inhibitors may overcome many of these resistance alterations.
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Affiliation(s)
- J M Riedl
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - F Fece de la Cruz
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - J J Lin
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - C Parseghian
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - J E Kim
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - H Matsubara
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - H Barnes
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - B Caughey
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - B L Norden
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - A Morales
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - E W Kushner
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - S Ehnstrom
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - H Nakamura
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - P S Patel
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - H Ellis
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - L Pappas
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - A Vakaris
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - J F Gainor
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - S Kopetz
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - S J Klempner
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - A R Parikh
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - A N Hata
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - R S Heist
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - R B Corcoran
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
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Qi Z, Tokuhiro S, Odegaard JI, Wienke S, Karnoub M, Feng W, Shiga R, Smit EF, Goto Y, De Langen AJ, Goto K, Pereira K, Khambata-Ford S. Analytical and Clinical Validation of the Plasma-Based Guardant360 CDx Test for Assessing HER2 (ERBB2) Mutation Status in Patients with Non-Small-Cell Lung Cancer for Treatment with Trastuzumab Deruxtecan in DESTINY-Lung01/02. J Mol Diagn 2025; 27:119-129. [PMID: 39880580 DOI: 10.1016/j.jmoldx.2024.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/25/2024] [Accepted: 11/12/2024] [Indexed: 01/31/2025] Open
Abstract
This study demonstrates the analytical and clinical validity of the approved (United States and Japan) plasma-based Guardant360 companion diagnostic (CDx) test for selecting patients with human epidermal growth factor receptor 2 (HER2 [ERBB2])-mutated (HER2m) non-small-cell lung cancer (NSCLC) for trastuzumab deruxtecan (T-DXd) treatment. Concordance between the Guardant360 CDx test and the plasma-based AVENIO ctDNA Expanded Kit Assay (AVENIO), as well as the tissue-based clinical trial assays (CTAs) was investigated. Clinical utility was assessed by comparing T-DXd clinical efficacy results of patients in DESTINY-Lung01/02 who tested positive for HER2 mutations using the Guardant360 CDx test to benchmark efficacy results from DESTINY-Lung01/02. Finally, concordance between the Guardant360 CDx test and the tissue-based Oncomine Dx Target (ODxT) test was explored. High concordance was observed between the Guardant360 CDx test versus AVENIO [positive percent agreement (PPA), 98.8%; negative percent agreement (NPA), 91.5%] and CTAs (DESTINY-Lung01 Cohort 2-PPA, 91.0%; NPA, 100%; DESTINY-Lung02 arm 1-PPA, 86.0%; NPA, 100%). Confirmed objective response rates were similar in patients with HER2m NSCLC identified by the Guardant360 CDx test and by CTAs. There was a high level of agreement between the Guardant360 CDx test and the ODxT test. The Guardant360 CDx test demonstrated analytical and clinical validity for identifying patients with HER2m NSCLC for T-DXd therapy; results support plasma-based testing when tissue-based testing is not feasible.
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Affiliation(s)
- Zhenhao Qi
- Daiichi Sankyo, Inc., Basking Ridge, New Jersey.
| | | | | | | | | | - Wenqin Feng
- Daiichi Sankyo, Inc., Basking Ridge, New Jersey
| | - Ryota Shiga
- Daiichi Sankyo, Inc., Basking Ridge, New Jersey
| | - Egbert F Smit
- Netherlands Cancer Institute, Amsterdam, the Netherlands
| | | | | | - Koichi Goto
- National Cancer Center Hospital East, Kashiwa, Japan
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3
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Szakállas N, Kalmár A, Barták BK, Nagy ZB, Valcz G, Linkner TR, Rada KR, Takács I, Molnár B. Investigation of Exome-Wide Tumor Heterogeneity on Colorectal Tissue-Based Single Cells. Int J Mol Sci 2025; 26:737. [PMID: 39859451 PMCID: PMC11766235 DOI: 10.3390/ijms26020737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/09/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
The progression of colorectal cancer is strongly influenced by environmental and genetic conditions. One of the key factors is tumor heterogeneity which is extensively studied by cfDNA and bulk sequencing methods; however, we lack knowledge regarding its effects at the single-cell level. Motivated by this, we aimed to employ an end-to-end single-cell sequencing workflow from tissue-derived sample isolation to exome sequencing. Our main goal was to investigate the heterogeneity patterns by laser microdissecting samples from different locations of a tissue slide. Moreover, by studying healthy colon control, tumor-associated normal, and colorectal cancer tissues, we explored tissue-specific heterogeneity motifs. For completeness, we also compared the performance of the whole-exome bulk, cfDNA, and single-cell sequencing methods based on variation at the level of a single nucleotide.
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Affiliation(s)
- Nikolett Szakállas
- Department of Biological Physics, Faculty of Science, Eötvös Loránd University, 1053 Budapest, Hungary
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary; (A.K.); (B.K.B.); (Z.B.N.); (T.R.L.); (K.R.R.); (I.T.); (B.M.)
| | - Alexandra Kalmár
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary; (A.K.); (B.K.B.); (Z.B.N.); (T.R.L.); (K.R.R.); (I.T.); (B.M.)
| | - Barbara Kinga Barták
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary; (A.K.); (B.K.B.); (Z.B.N.); (T.R.L.); (K.R.R.); (I.T.); (B.M.)
| | - Zsófia Brigitta Nagy
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary; (A.K.); (B.K.B.); (Z.B.N.); (T.R.L.); (K.R.R.); (I.T.); (B.M.)
| | - Gábor Valcz
- HUN-REN-SU Translational Extracellular Vesicle Research Group, 1117 Budapest, Hungary;
| | - Tamás Richárd Linkner
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary; (A.K.); (B.K.B.); (Z.B.N.); (T.R.L.); (K.R.R.); (I.T.); (B.M.)
| | - Kristóf Róbert Rada
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary; (A.K.); (B.K.B.); (Z.B.N.); (T.R.L.); (K.R.R.); (I.T.); (B.M.)
| | - István Takács
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary; (A.K.); (B.K.B.); (Z.B.N.); (T.R.L.); (K.R.R.); (I.T.); (B.M.)
| | - Béla Molnár
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary; (A.K.); (B.K.B.); (Z.B.N.); (T.R.L.); (K.R.R.); (I.T.); (B.M.)
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Ding H, Yuan M, Yang Y, Xu XS. Longitudinal genomic profiling using liquid biopsies in metastatic nonsquamous NSCLC following first line immunotherapy. NPJ Precis Oncol 2025; 9:5. [PMID: 39779891 PMCID: PMC11711381 DOI: 10.1038/s41698-024-00797-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 12/27/2024] [Indexed: 01/11/2025] Open
Abstract
Tumor genomic profiling is often limited to one or two timepoints due to the invasiveness of tissue biopsies, but longitudinal profiling may provide deeper clinical insights. Using ctDNA data from IMpower150 study, we examined genetic changes in metastatic non-squamous NSCLC post-first-line immunotherapy. Mutations were most frequently detected in TP53, KRAS, SPTA1, FAT3, and LRP1B at baseline and during treatment. Mutation levels rose prior to radiographic progression in most progressing patients, with specific mutations (SPTA1, STK11, KEAP1, SMARCA4, TBX3, CDH2, and MLL3) significantly enriched in those with progression or nondurable response. However, ctDNA's role in detecting hyperprogression and pseudoprogression remains uncertain. STK11, SMARCA4, KRAS, SLT2, and KEAP1 mutations showed the strongest correlation with poorer overall survival, while SMARCA4, STK11, SPTA1, TBX3, and KEAP1 mutations correlated with shorter progression-free survival. Overall, longitudinal liquid biopsy profiling provided valuable insights into lung cancer biology post-immunotherapy, potentially guiding personalized therapies and future drug development.
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Affiliation(s)
- Haolun Ding
- Department of Statistics and Finance, School of Management, University of Science and Technology of China, Hefei, Anhui, China
| | - Min Yuan
- Department of Health Data Science, Anhui Medical University, Hefei, Anhui, China.
| | - Yaning Yang
- Department of Statistics and Finance, School of Management, University of Science and Technology of China, Hefei, Anhui, China
| | - Xu Steven Xu
- Clinical Pharmacology and Quantitative Science, Genmab Inc, Princeton, NJ, USA.
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5
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Iorgulescu JB, Blewett T, Xiong K, Crnjac A, Liu R, Sridhar S, Braun DA, Sellars MC, Cheng J, Rhoades J, Reardon DA, Makrigiorgos GM, Wu CJ, Adalsteinsson VA. Impact of Higher Cell-Free DNA Yields on Liquid Biopsy Testing in Glioblastoma Patients. Clin Chem 2025; 71:215-225. [PMID: 39749509 DOI: 10.1093/clinchem/hvae178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 09/30/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Minimally invasive molecular profiling using cell-free DNA (cfDNA) is increasingly important to the management of cancer patients; however, low sensitivity remains a major limitation, particularly for brain tumor patients. Transiently attenuating cfDNA clearance from the body-thereby, allowing more cfDNA to be sampled-has been proposed to improve the performance of liquid biopsy diagnostics. However, there is a paucity of clinical data on the effect of higher cfDNA recovery. Here, we investigated the impact of collecting greater quantities of cfDNA on circulating tumor DNA (ctDNA) sensitivity in the "low-shedding" cancer type glioblastoma by analyzing up to approximately 15-fold more plasma than routinely obtained clinically. METHODS We tested 70 plasma samples (median 17.0 mL, range 2.5-66.5) from 8 IDH-wild-type glioblastoma patients using an optimized version of the MAESTRO-Pool ctDNA assay. Results were compared with simulated single-blood-tube equivalents of cfDNA. ctDNA results were then compared with magnetic resonance imaging (MRI) and pathology assessments of true progression vs pseudoprogression in glioblastoma patients. RESULTS Larger cfDNA yields exhibited a doubling in ctDNA-positivity while achieving a median specificity of 99% and more precise ctDNA quantification. In 8 glioblastoma patients, ctDNA was detected in 88%, including at multiple timepoints in 6/7. In the setting of indeterminate progression by MRI, our data suggested that MAESTRO-Pool with large plasma volumes can help distinguish true glioblastoma progression from pseudoprogression. CONCLUSIONS Our findings provide a proof-of-principle that most glioblastomas shed ctDNA into plasma and that greater ctDNA yields could help improve liquid biopsies for "low-shedding" cancer types such as glioblastoma.
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Affiliation(s)
- J Bryan Iorgulescu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Timothy Blewett
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Kan Xiong
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Andjela Crnjac
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Ruolin Liu
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Sainetra Sridhar
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - David A Braun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - MacLean C Sellars
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Ju Cheng
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - Justin Rhoades
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - David A Reardon
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - G Mike Makrigiorgos
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Catherine J Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
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6
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Nakamura Y, Ozaki H, Ueno M, Komatsu Y, Yuki S, Esaki T, Taniguchi H, Sunakawa Y, Yamaguchi K, Kato K, Denda T, Nishina T, Takahashi N, Satoh T, Yasui H, Satake H, Oki E, Kato T, Ohta T, Matsuhashi N, Goto M, Okano N, Ohtsubo K, Yamazaki K, Yamashita R, Iida N, Yuasa M, Bando H, Yoshino T. Targeted therapy guided by circulating tumor DNA analysis in advanced gastrointestinal tumors. Nat Med 2025; 31:165-175. [PMID: 39284955 PMCID: PMC11750700 DOI: 10.1038/s41591-024-03244-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 08/09/2024] [Indexed: 01/23/2025]
Abstract
Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors.
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Affiliation(s)
- Yoshiaki Nakamura
- International Research Promotion Office, National Cancer Center Hospital East, Kashiwa, Japan
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroshi Ozaki
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Yoshito Komatsu
- Department of Cancer Center, Hokkaido University Hospital, Sapporo, Japan
| | - Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Taito Esaki
- Department of Gastrointestinal and Medical Oncology, NHO Kyushu Cancer Center, Fukuoka, Japan
| | - Hiroya Taniguchi
- Department of Clinical Oncology, Aichi Cancer Center, Nagoya, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Ken Kato
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Tadamichi Denda
- Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Tomohiro Nishina
- Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan
| | - Naoki Takahashi
- Department of Gastroenterology, Saitama Cancer Center, Ina, Japan
| | - Taroh Satoh
- Center for Cancer Genomics and Precision Medicine, Osaka University Hospital, Suita, Japan
| | - Hisateru Yasui
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Hironaga Satake
- Cancer Treatment Center, Kansai Medical University Hospital, Hirakata, Japan
- Department of Medical Oncology, Kochi Medical School, Nankoku, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Kato
- Department of Surgery, NHO Osaka National Hospital, Osaka, Japan
| | - Takashi Ohta
- Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki, Japan
| | - Nobuhisa Matsuhashi
- Department of Gastroenterological Surgery and Pediatric Surgery, Center for One Medicine Innovative Translational Research (COMIT), Gifu University Graduate School of Medicine, Gifu, Japan
| | - Masahiro Goto
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki, Japan
| | - Naohiro Okano
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Koushiro Ohtsubo
- Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Riu Yamashita
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Naoko Iida
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Mihoko Yuasa
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hideaki Bando
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
- Kindai University Faculty of Medicine, Osakasayama, Japan.
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7
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Gavryushin AV, Papusha LI, Veselkov AA, Zaitseva MA, Khukhlaeva EA, Konovalov AN, Druy AE. [Liquid biopsy for detection of H3K27m and BRAF V600E mutations in patients with diffuse brainstem tumors]. ZHURNAL VOPROSY NEIROKHIRURGII IMENI N. N. BURDENKO 2025; 89:11-19. [PMID: 39907662 DOI: 10.17116/neiro20258901111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
Despite the progress in understanding the pathogenesis of diffuse brainstem tumors, treatment of these neoplasms is usually empirical and conducted without morphological and molecular verification. Liquid biopsy is a minimally invasive technique providing data on tumor biology without standard biopsy. This method is based on analysis of cell-free nucleic acids (predominantly, extracellular DNA) in biological fluids with detection of specific mutations. Despite wide implementation in diagnosis and disease monitoring in extracranial malignancies, it is infrequently applied in neuro-oncology. OBJECTIVE To estimate diagnostic value of liquid biopsy in detecting H3K27 and BRAF V600E mutations in patients with diffuse brainstem tumors. MATERIAL AND METHODS Lumbar puncture with cerebrospinal fluid sampling was performed in 16 patients (5 children and 11 adults) with diffuse brainstem tumors verified by neuroimaging data. Cell-free DNA (cfDNA) was used in digital droplet PCR for determination of H3F3A K28M and BRAF V600E oncogenic missense variants. In 14 patients, investigation of cfDNA was performed in parallel with analysis of correspondent mutations in DNA derived from tumor tissue. RESULTS None patient had BRAF V600E mutation. H3F3A K28M variant was detected in 5 CSF samples and 6 tumor specimens from patients who underwent surgical biopsy. Thus, overall sensitivity of the method in determination of H3F3A K28M variant was 92.9% (13/14). CONCLUSION Liquid biopsy is highly informative for identifying the specific mutation H3F3A K28M and often verifies diffuse brainstem glioma without standard biopsy.
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Affiliation(s)
- A V Gavryushin
- Burdenko Neurosurgical Center, Moscow, Russia
- Dmitry Rogachev National Medical Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | - L I Papusha
- Dmitry Rogachev National Medical Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | | | - M A Zaitseva
- Dmitry Rogachev National Medical Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia
| | | | | | - A E Druy
- Dmitry Rogachev National Medical Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia
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8
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Miceli RT, Chen T, Nose Y, Tichkule S, Brown B, Fullard JF, Saulsbury MD, Heyliger SO, Gnjatic S, Kyprianou N, Cordon‐Cardo C, Sahoo S, Taioli E, Roussos P, Stolovitzky G, Gonzalez‐Kozlova E, Dogra N. Extracellular vesicles, RNA sequencing, and bioinformatic analyses: Challenges, solutions, and recommendations. J Extracell Vesicles 2024; 13:e70005. [PMID: 39625409 PMCID: PMC11613500 DOI: 10.1002/jev2.70005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 09/20/2024] [Accepted: 10/07/2024] [Indexed: 12/06/2024] Open
Abstract
Extracellular vesicles (EVs) are heterogeneous entities secreted by cells into their microenvironment and systemic circulation. Circulating EVs carry functional small RNAs and other molecular footprints from their cell of origin, and thus have evident applications in liquid biopsy, therapeutics, and intercellular communication. Yet, the complete transcriptomic landscape of EVs is poorly characterized due to critical limitations including variable protocols used for EV-RNA extraction, quality control, cDNA library preparation, sequencing technologies, and bioinformatic analyses. Consequently, there is a gap in knowledge and the need for a standardized approach in delineating EV-RNAs. Here, we address these gaps by describing the following points by (1) focusing on the large canopy of the EVs and particles (EVPs), which includes, but not limited to - exosomes and other large and small EVs, lipoproteins, exomeres/supermeres, mitochondrial-derived vesicles, RNA binding proteins, and cell-free DNA/RNA/proteins; (2) examining the potential functional roles and biogenesis of EVPs; (3) discussing various transcriptomic methods and technologies used in uncovering the cargoes of EVPs; (4) presenting a comprehensive list of RNA subtypes reported in EVPs; (5) describing different EV-RNA databases and resources specific to EV-RNA species; (6) reviewing established bioinformatics pipelines and novel strategies for reproducible EV transcriptomics analyses; (7) emphasizing the significant need for a gold standard approach in identifying EV-RNAs across studies; (8) and finally, we highlight current challenges, discuss possible solutions, and present recommendations for robust and reproducible analyses of EVP-associated small RNAs. Overall, we seek to provide clarity on the transcriptomics landscape, sequencing technologies, and bioinformatic analyses of EVP-RNAs. Detailed portrayal of the current state of EVP transcriptomics will lead to a better understanding of how the RNA cargo of EVPs can be used in modern and targeted diagnostics and therapeutics. For the inclusion of different particles discussed in this article, we use the terms large/small EVs, non-vesicular extracellular particles (NVEPs), EPs and EVPs as defined in MISEV guidelines by the International Society of Extracellular Vesicles (ISEV).
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Affiliation(s)
- Rebecca T. Miceli
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Tzu‐Yi Chen
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Yohei Nose
- Department of ImmunologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Swapnil Tichkule
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Briana Brown
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - John F. Fullard
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Genetics and Genomics SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Center for Disease Neurogenetics, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Marilyn D. Saulsbury
- Department of Pharmaceutical Sciences, School of PharmacyHampton UniversityHamptonVirginiaUSA
| | - Simon O. Heyliger
- Department of Pharmaceutical Sciences, School of PharmacyHampton UniversityHamptonVirginiaUSA
| | - Sacha Gnjatic
- Department of ImmunologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Natasha Kyprianou
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of UrologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Carlos Cordon‐Cardo
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Susmita Sahoo
- Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Cardiovascular Research Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Emanuela Taioli
- Department of Population Health and ScienceIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Thoracic SurgeryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Panos Roussos
- Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Genetics and Genomics SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Center for Disease Neurogenetics, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Center for Precision Medicine and Translational TherapeuticsJames J. Peters VA Medicinal CenterBronxNew YorkUSA
- Mental Illness Research Education and Clinical Center (MIRECC)James J. Peters VA Medicinal CenterBronxNew YorkUSA
| | - Gustavo Stolovitzky
- Department of Genetics and Genomics SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Biomedical Data Sciences Hub (Bio‐DaSH), Department of Pathology, NYU Grossman School of MedicineNew YorkNew YorkUSA
| | - Edgar Gonzalez‐Kozlova
- Department of ImmunologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Navneet Dogra
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Genetics and Genomics SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Icahn Genomics Institute, Icahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- AI and Human HealthIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
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9
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Li M. Atomic force microscopy as a nanomechanical tool for cancer liquid biopsy. Biochem Biophys Res Commun 2024; 734:150637. [PMID: 39226737 DOI: 10.1016/j.bbrc.2024.150637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 08/24/2024] [Accepted: 08/30/2024] [Indexed: 09/05/2024]
Abstract
Liquid biopsies have been receiving tremendous attention for their potential to reshape cancer management. Though current studies of cancer liquid biopsy primarily focus on applying biochemical assays to characterize the genetic/molecular profiles of circulating tumor cells (CTCs) and their secondary products shed from tumor sites in bodily fluids, delineating the nanomechanical properties of tumor-associated materials in liquid biopsy specimens yields complementary insights into the biology of tumor dissemination and evolution. Particularly, atomic force microscopy (AFM) has become a standard and versatile toolbox for characterizing the mechanical properties of living biological systems at the micro/nanoscale, and AFM has been increasingly utilized to probe the nanomechanical properties of various tumor-derived analytes in liquid biopsies, including CTCs, tumor-associated cells, circulating tumor DNA (ctDNA) molecules, and extracellular vesicles (EVs), offering additional possibilities for understanding cancer pathogenesis from the perspective of mechanobiology. Herein, the applications of AFM in cancer liquid biopsy are summarized, and the challenges and future directions of AFM as a nanomechanical analysis tool in cancer liquid biopsy towards clinical utility are discussed and envisioned.
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Affiliation(s)
- Mi Li
- State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang, 110016, China.
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10
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Gezer U, Özgür E, Yörüker EE, Polatoglou E, Holdenrieder S, Bronkhorst A. LINE-1 cfDNA Methylation as an Emerging Biomarker in Solid Cancers. Cancers (Basel) 2024; 16:3725. [PMID: 39594682 PMCID: PMC11592170 DOI: 10.3390/cancers16223725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/01/2024] [Accepted: 11/03/2024] [Indexed: 11/28/2024] Open
Abstract
Epigenetic dysregulation is a hallmark of many human malignancies, with DNA methylation being a primary mechanism influencing gene expression and maintaining genomic stability. Genome-wide hypomethylation, characteristic of many cancers, is partly attributed to the demethylation of repetitive elements, including LINE-1, a prevalent non-LTR retrotransposon. The methylation status of LINE-1 is closely associated with overall genomic methylation levels in tumors. cfDNA comprises extracellular DNA fragments found in bodily fluids such as plasma, serum, and urine, offering a dynamic snapshot of the genetic and epigenetic landscape of tumors. This real-time sampling provides a minimally invasive avenue for cancer diagnostics, prognostics, and monitoring. The methylation status of LINE-1 in cfDNA has emerged as a promising biomarker, with several studies highlighting its potential in diagnosing and predicting outcomes in cancer patients. Recent research also suggests that cfDNA-based LINE-1 methylation analysis could serve as a valuable tool in evaluating the efficacy of cancer therapies, including immunotherapy. The growing clinical significance of cfDNA calls for a closer examination of its components, particularly repetitive elements like LINE-1. Despite their importance, the role of LINE-1 elements in cfDNA has not been thoroughly gauged. We aim to address this gap by reviewing the current literature on LINE-1 cfDNA assays, focusing on their potential applications in diagnostics and disease monitoring.
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Affiliation(s)
- Ugur Gezer
- Department of Basic Oncology, Oncology Institute, Istanbul University, 34093 Istanbul, Türkiye; (U.G.); (E.Ö.); (E.E.Y.)
| | - Emre Özgür
- Department of Basic Oncology, Oncology Institute, Istanbul University, 34093 Istanbul, Türkiye; (U.G.); (E.Ö.); (E.E.Y.)
| | - Ebru E. Yörüker
- Department of Basic Oncology, Oncology Institute, Istanbul University, 34093 Istanbul, Türkiye; (U.G.); (E.Ö.); (E.E.Y.)
| | - Eleni Polatoglou
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany (S.H.)
| | - Stefan Holdenrieder
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany (S.H.)
| | - Abel Bronkhorst
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University Munich, 80636 Munich, Germany (S.H.)
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11
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Burr R, Leshchiner I, Costantino CL, Blohmer M, Sundaresan T, Cha J, Seeger K, Guay S, Danysh BP, Gore I, Jacobs RA, Slowik K, Utro F, Rhrissorrakrai K, Levovitz C, Barth JL, Dubash T, Chirn B, Parida L, Sequist LV, Lennerz JK, Mino-Kenudson M, Maheswaran S, Naxerova K, Getz G, Haber DA. Developmental mosaicism underlying EGFR-mutant lung cancer presenting with multiple primary tumors. NATURE CANCER 2024; 5:1681-1696. [PMID: 39406916 PMCID: PMC11584400 DOI: 10.1038/s43018-024-00840-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 09/10/2024] [Indexed: 10/30/2024]
Abstract
Although the development of multiple primary tumors in smokers with lung cancer can be attributed to carcinogen-induced field cancerization, the occurrence of multiple tumors at presentation in individuals with EGFR-mutant lung cancer who lack known environmental exposures remains unexplained. In the present study, we identified ten patients with early stage, resectable, non-small cell lung cancer who presented with multiple, anatomically distinct, EGFR-mutant tumors. We analyzed the phylogenetic relationships among multiple tumors from each patient using whole-exome sequencing (WES) and hypermutable poly(guanine) (poly(G)) repeat genotyping as orthogonal methods for lineage tracing. In four patients, developmental mosaicism, assessed by WES and poly(G) lineage tracing, indicates a common non-germline cell of origin. In two other patients, we identified germline EGFR variants, which confer moderately enhanced signaling when modeled in vitro. Thus, in addition to germline variants, developmental mosaicism defines a distinct mechanism of genetic predisposition to multiple EGFR-mutant primary tumors, with implications for their etiology and clinical management.
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Affiliation(s)
- Risa Burr
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA, USA
| | - Ignaty Leshchiner
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medicine, Boston University, Boston, MA, USA
| | - Christina L Costantino
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA, USA
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Martin Blohmer
- Department of Genetics, Harvard Medical School, Boston, MA, USA
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Tilak Sundaresan
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA, USA
| | - Justin Cha
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Karsen Seeger
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA, USA
| | - Sara Guay
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA, USA
| | - Brian P Danysh
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Ira Gore
- Ascension St. Vincent's Birmingham, Birmingham, AL, USA
| | - Raquel A Jacobs
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Kara Slowik
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | | | | | | | - Jaimie L Barth
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Taronish Dubash
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA, USA
| | - Brian Chirn
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA, USA
| | | | - Lecia V Sequist
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA, USA
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jochen K Lennerz
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Shyamala Maheswaran
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA, USA
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Kamila Naxerova
- Department of Genetics, Harvard Medical School, Boston, MA, USA
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Gad Getz
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA, USA.
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
| | - Daniel A Haber
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA, USA.
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Howard Hughes Medical Institute, Bethesda, MD, USA.
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12
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Yu J, Park R, Miao R, Imanirad I, Shahzad M, Laborde JM, Knepper TC, Walko CM, Kim R. Blood Tumor Mutational Burden Alone Is Not a Good Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Patients With Gastrointestinal Tumors. J Immunother 2024; 47:378-383. [PMID: 39012081 DOI: 10.1097/cji.0000000000000532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 06/05/2024] [Indexed: 07/17/2024]
Abstract
There has been a controversy about the predictive value of tissue-TMB-H for immune checkpoint inhibitors (ICIs) with limited data regarding blood-TMB (bTMB) in GI tumors. We aim to evaluate the predictive value of bTMB compared with MSI-H in GI tumors. Patients with unresectable/metastatic GI cancer, harboring either MSS with bTMB-H (≥10 mut/Mb) or dMMR/MSI-H who received ICI were included. We compared ICIs' efficacy between MSS-bTMB-H (N=45) versus MSI-H (N=50) in GI tumors. Ninety-five patients were identified with the majority having colorectal (49.5%) or esophagogastric (34.7%) cancers. MSS-bTMB-H group had more esophagogastric cancer and later-line ICI recipients, with no significant differences in other known prognostic variables. At a median follow-up of 9.4 months, MSI-H group showed superior ORR (58.0% vs. 26.7%), DCR (84.0% vs. 42.2%), DoR (not-reached vs. 7.6 mo), PFS (22.5 vs. 3.8 mo), and OS (Not-reached vs. 10.1 mo) compared with MSS-bTMB-H. Multivariable analysis showed that MSI-H was an independent favorable factor over MSS-bTMB-H for PFS (HR=0.31, CI 0.15-0.63, P =0.001) and OS (HR=0.33, CI 0.14-0.80, P =0.014). MSI-H group showed favorable outcomes compared with MSS-bTMB-16+ (ORR: 58.0% vs. 26.9%; DCR: 84.0% vs. 42.3%; PFS:22.5 vs. 4.0 mo) and MSS-bTMB-20+ (ORR: 58.0% vs. 31.6%; DCR: 84.0% vs. 42.1%; PFS:22.5 vs. 3.2 mo). There was no difference between MSS-bTMB10-15 compared with MSS-bTMB-16+ in ORR, DCR, and PFS, or between MSS-bTMB10-19 compared with MSS-bTMB20+. Regardless of bTMB cutoff at 10, 16, or 20, bTMB-H did not appear to be a predictive biomarker in MSS GI tumors in this retrospective analysis.
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Affiliation(s)
- James Yu
- Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
| | - Robin Park
- Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
| | - Ruoyu Miao
- Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
| | - Iman Imanirad
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Moazzam Shahzad
- Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
| | - Jose M Laborde
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
| | - Todd C Knepper
- Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
| | - Christine M Walko
- Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
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13
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Battaglin F, Lenz HJ. Clinical Applications of Circulating Tumor DNA Profiling in GI Cancers. JCO Oncol Pract 2024; 20:1481-1490. [PMID: 39531845 PMCID: PMC11567053 DOI: 10.1200/op.24.00167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/11/2024] [Accepted: 05/01/2024] [Indexed: 11/16/2024] Open
Abstract
Over the next few years, the analysis of circulating tumor DNA (ctDNA) through liquid biopsy is expected to enter clinical practice and revolutionize the approach to biomarker testing and treatment selection in GI cancers. In fact, growing evidence support the use of ctDNA testing as a noninvasive, effective, and highly specific tool for molecular profiling in GI cancers. Analysis of blood ctDNA has been investigated in multiple settings including early tumor detection, minimal residual disease evaluation, tumor diagnosis and evaluation of prognostic/predictive biomarkers for targeted treatment selection, longitudinal monitoring of treatment response, and identification of resistance mechanisms. Here, we review the clinical applications, advantages, and limitations of ctDNA profiling for precision oncology in GI cancers.
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Affiliation(s)
- Francesca Battaglin
- Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Heinz-Josef Lenz
- Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
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14
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Hu Q, Chen L, Li K, Liu R, Sun L, Han T. Circulating tumor DNA: current implementation issues and future challenges for clinical utility. Clin Chem Lab Med 2024; 62:2094-2110. [PMID: 38109307 DOI: 10.1515/cclm-2023-1157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/06/2023] [Indexed: 12/20/2023]
Abstract
Over the past decades, liquid biopsy, especially circulating tumor DNA (ctDNA), has received tremendous attention as a noninvasive detection approach for clinical applications, including early diagnosis of cancer and relapse, real-time therapeutic efficacy monitoring, potential target selection and investigation of drug resistance mechanisms. In recent years, the application of next-generation sequencing technology combined with AI technology has significantly improved the accuracy and sensitivity of liquid biopsy, enhancing its potential in solid tumors. However, the increasing integration of such promising tests to improve therapy decision making by oncologists still has complexities and challenges. Here, we propose a conceptual framework of ctDNA technologies and clinical utilities based on bibliometrics and highlight current challenges and future directions, especially in clinical applications such as early detection, minimal residual disease detection, targeted therapy, and immunotherapy. We also discuss the necessities of developing a dynamic field of translational cancer research and rigorous clinical studies that may support therapeutic strategy decision making in the near future.
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Affiliation(s)
- Qilin Hu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, P.R. China
| | - Lujun Chen
- The General Hospital of Northern Theater Command Training Base for Graduate, China Medical University, Shenyang, P.R. China
| | - Kerui Li
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, P.R. China
| | - Ruotong Liu
- Clinical Medicine, Shenyang Medical College, Shenyang, P.R. China
| | - Lei Sun
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang, P.R. China
| | - Tao Han
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, P.R. China
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15
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Schroeder C, Gatidis S, Kelemen O, Schütz L, Bonzheim I, Muyas F, Martus P, Admard J, Armeanu-Ebinger S, Gückel B, Küstner T, Garbe C, Flatz L, Pfannenberg C, Ossowski S, Forschner A. Tumour-informed liquid biopsies to monitor advanced melanoma patients under immune checkpoint inhibition. Nat Commun 2024; 15:8750. [PMID: 39384805 PMCID: PMC11464631 DOI: 10.1038/s41467-024-52923-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 09/20/2024] [Indexed: 10/11/2024] Open
Abstract
Immune checkpoint inhibitors (ICI) have significantly improved overall survival in melanoma patients. However, 60% experience severe adverse events and early response markers are lacking. Circulating tumour DNA (ctDNA) is a promising biomarker for treatment-response and recurrence detection. The prospective PET/LIT study included 104 patients with palliative combined or adjuvant ICI. Tumour-informed sequencing panels to monitor 30 patient-specific variants were designed and 321 liquid biopsies of 87 patients sequenced. Mean sequencing depth after deduplication using UMIs was 6000x and the error rate of UMI-corrected reads was 2.47×10-4. Variant allele fractions correlated with PET/CT MTV (rho=0.69), S100 (rho=0.72), and LDH (rho=0.54). A decrease of allele fractions between T1 and T2 was associated with improved PFS and OS in the palliative cohort (p = 0.008 and p < 0.001). ctDNA was detected in 76.9% of adjuvant patients with relapse (n = 10/13), while all patients without progression (n = 9) remained ctDNA negative. Tumour-informed liquid biopsies are a reliable tool for monitoring treatment response and early relapse in melanoma patients with ICI.
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Affiliation(s)
- Christopher Schroeder
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK), partner site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sergios Gatidis
- Department of Radiology, Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Olga Kelemen
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Leon Schütz
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Irina Bonzheim
- Institute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany
| | - Francesc Muyas
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Peter Martus
- Institute for Clinical Epidemiology and Applied Biostatistics (IKEaB), Tübingen, Germany
| | - Jakob Admard
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- NGS Competence Center Tübingen (NCCT), University of Tübingen, Tübingen, Germany
| | - Sorin Armeanu-Ebinger
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Brigitte Gückel
- Department of Radiology, Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Thomas Küstner
- Department of Radiology, Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Claus Garbe
- Department of Dermatology, University Hospital Tübingen, Tübingen, Germany
| | - Lukas Flatz
- Department of Dermatology, University Hospital Tübingen, Tübingen, Germany
| | - Christina Pfannenberg
- Department of Radiology, Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany
| | - Stephan Ossowski
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- German Cancer Consortium (DKTK), partner site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, Germany
- NGS Competence Center Tübingen (NCCT), University of Tübingen, Tübingen, Germany
- Institute for Bioinformatics and Medical Informatics (IBMI), University of Tübingen, Tübingen, Germany
| | - Andrea Forschner
- Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.
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16
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Song J, Cho MH, Cho H, Song Y, Lee SW, Nam HC, Yoon TH, Shin JC, Hong JS, Kim Y, Ekanayake E, Jeon J, You DG, Im SG, Choi GS, Park JS, Carter BC, Balaj L, Seo AN, Miller MA, Park SY, Kang T, Castro CM, Lee H. Amplifying mutational profiling of extracellular vesicle mRNA with SCOPE. Nat Biotechnol 2024:10.1038/s41587-024-02426-6. [PMID: 39375445 DOI: 10.1038/s41587-024-02426-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 09/09/2024] [Indexed: 10/09/2024]
Abstract
Sequencing of messenger RNA (mRNA) found in extracellular vesicles (EVs) in liquid biopsies can provide clinical information such as somatic mutations, resistance profiles and tumor recurrence. Despite this, EV mRNA remains underused due to its low abundance in liquid biopsies, and large sample volumes or specialized techniques for analysis are required. Here we introduce Self-amplified and CRISPR-aided Operation to Profile EVs (SCOPE), a platform for EV mRNA detection. SCOPE leverages CRISPR-mediated recognition of target RNA using Cas13 to initiate replication and signal amplification, achieving a sub-attomolar detection limit while maintaining single-nucleotide resolution. As a proof of concept, we designed probes for key mutations in KRAS, BRAF, EGFR and IDH1 genes, optimized protocols for single-pot assays and implemented an automated device for multi-sample detection. We validated SCOPE's ability to detect early-stage lung cancer in animal models, monitored tumor mutational burden in patients with colorectal cancer and stratified patients with glioblastoma. SCOPE can expedite readouts, augmenting the clinical use of EVs in precision oncology.
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Affiliation(s)
- Jayeon Song
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Forensic Sciences, Sungkyunkwan University, Suwon, Republic of Korea
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Mi Hyeon Cho
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Hayoung Cho
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA
| | - Younseong Song
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | | | - Ho Chul Nam
- RevoSketch, Inc., Daejeon, Republic of Korea
| | - Tae Ho Yoon
- RevoSketch, Inc., Daejeon, Republic of Korea
| | | | - Jae-Sang Hong
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Yejin Kim
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea
| | - Emil Ekanayake
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA
| | - Jueun Jeon
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Dong Gil You
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA
| | - Sung Gap Im
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Gyu-Seog Choi
- Colorectal Cancer Center, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jun Seok Park
- Colorectal Cancer Center, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Bob C Carter
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA
| | - Leonora Balaj
- Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
| | - Miles A Miller
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Soo Yeun Park
- Colorectal Cancer Center, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Taejoon Kang
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
- Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
| | - Cesar M Castro
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA.
- Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Hakho Lee
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA.
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Center for Nanomedicine, Institute for Basic Science (IBS), Seoul, Republic of Korea.
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17
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Fu SW, Tang C, Tan X, Srivastava S. Liquid biopsy for early cancer detection: technological revolutions and clinical dilemma. Expert Rev Mol Diagn 2024; 24:937-955. [PMID: 39360748 DOI: 10.1080/14737159.2024.2408744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 09/22/2024] [Indexed: 10/05/2024]
Abstract
INTRODUCTION Liquid biopsy is an innovative advancement in oncology, offering a noninvasive method for early cancer detection and monitoring by analyzing circulating tumor cells, DNA, RNA, and other biomarkers in bodily fluids. This technique has the potential to revolutionize precision oncology by providing real-time analysis of tumor dynamics, enabling early detection, monitoring treatment responses, and tailoring personalized therapies based on the molecular profiles of individual patients. AREAS COVERED In this review, the authors discuss current methodologies, technological challenges, and clinical applications of liquid biopsy. This includes advancements in detecting minimal residual disease, tracking tumor evolution, and combining liquid biopsy with other diagnostic modalities for precision oncology. Key areas explored are the sensitivity, specificity, and integration of multi-omics, AI, ML, and LLM technologies. EXPERT OPINION Liquid biopsy holds great potential to revolutionize cancer care through early detection and personalized treatment strategies. However, its success depends on overcoming technological and clinical hurdles, such as ensuring high sensitivity and specificity, interpreting results amidst tumor heterogeneity, and making tests accessible and affordable. Continued innovation and collaboration are crucial to fully realize the potential of liquid biopsy in improving early cancer detection, treatment, and monitoring.
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Affiliation(s)
- Sidney W Fu
- Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Cong Tang
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Xiaohui Tan
- Division of LS Research, LSBioscience, LLC, Frederick, USA
| | - Sudhir Srivastava
- Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
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18
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Nordentoft I, Lindskrog SV, Birkenkamp-Demtröder K, Gonzalez S, Kuzman M, Levatic J, Glavas D, Ptashkin R, Smadbeck J, Afterman D, Lauterman T, Cohen Y, Donenhirsh Z, Tavassoly I, Alon U, Frydendahl A, Rasmussen MH, Andersen CL, Lamy P, Knudsen M, Polak P, Zviran A, Oklander B, Agerbæk M, Jensen JB, Dyrskjøt L. Whole-genome Mutational Analysis for Tumor-informed Detection of Circulating Tumor DNA in Patients with Urothelial Carcinoma. Eur Urol 2024; 86:301-311. [PMID: 38811314 DOI: 10.1016/j.eururo.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/25/2024] [Accepted: 05/16/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND AND OBJECTIVE Circulating tumor DNA (ctDNA) can be used for sensitive detection of minimal residual disease (MRD). However, the probability of detecting ctDNA in settings of low tumor burden is limited by the number of mutations analyzed and the plasma volume available. We used a whole-genome sequencing (WGS) approach for ctDNA detection in patients with urothelial carcinoma. METHODS We used a tumor-informed WGS approach for ctDNA-based detection of MRD and evaluation of treatment responses. We analyzed 916 longitudinally collected plasma samples from 112 patients with localized muscle-invasive bladder cancer who received neoadjuvant chemotherapy (NAC) before radical cystectomy. Recurrence-free survival (primary endpoint), overall survival, and ctDNA dynamics during NAC were assessed. KEY FINDINGS AND LIMITATIONS We found that WGS-based ctDNA detection is prognostic for patient outcomes with a median lead time of 131 d over radiographic imaging. WGS-based ctDNA assessment after radical cystectomy identified recurrence with sensitivity of 91% and specificity of 92%. In addition, genomic characterization of post-treatment plasma samples with a high ctDNA level revealed acquisition of platinum therapy-associated mutational signatures and copy number variations not present in the primary tumors. The sequencing depth is a limitation for studying tumor evolution. CONCLUSIONS AND CLINICAL IMPLICATIONS Our results support the use of WGS for ultrasensitive ctDNA detection and highlight the possibility of plasma-based tracking of tumor evolution. WGS-based ctDNA detection represents a promising option for clinical use owing to the low volume of plasma needed and the ease of performing WGS, eliminating the need for personalized assay design.
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Affiliation(s)
- Iver Nordentoft
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
| | - Sia Viborg Lindskrog
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Karin Birkenkamp-Demtröder
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | | | | | | | | | | | | | | | | | | | | | | | - Amanda Frydendahl
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Mads Heilskov Rasmussen
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Claus Lindbjerg Andersen
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Philippe Lamy
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Michael Knudsen
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
| | | | | | | | - Mads Agerbæk
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
| | - Jørgen Bjerggaard Jensen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Urology, Aarhus University Hospital, Aarhus, Denmark
| | - Lars Dyrskjøt
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
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19
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Tivey A, Lee RJ, Clipson A, Hill SM, Lorigan P, Rothwell DG, Dive C, Mouliere F. Mining nucleic acid "omics" to boost liquid biopsy in cancer. Cell Rep Med 2024; 5:101736. [PMID: 39293399 PMCID: PMC11525024 DOI: 10.1016/j.xcrm.2024.101736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 07/22/2024] [Accepted: 08/21/2024] [Indexed: 09/20/2024]
Abstract
Treatments for cancer patients are becoming increasingly complex, and there is a growing desire from clinicians and patients for biomarkers that can account for this complexity to support informed decisions about clinical care. To achieve precision medicine, the new generation of biomarkers must reflect the spatial and temporal heterogeneity of cancer biology both between patients and within an individual patient. Mining the different layers of 'omics in a multi-modal way from a minimally invasive, easily repeatable, liquid biopsy has increasing potential in a range of clinical applications, and for improving our understanding of treatment response and resistance. Here, we detail the recent developments and methods allowing exploration of genomic, epigenomic, transcriptomic, and fragmentomic layers of 'omics from liquid biopsy, and their integration in a range of applications. We also consider the specific challenges that are posed by the clinical implementation of multi-omic liquid biopsies.
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Affiliation(s)
- Ann Tivey
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK; Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Rebecca J Lee
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK; Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Alexandra Clipson
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK
| | - Steven M Hill
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK
| | - Paul Lorigan
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Dominic G Rothwell
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK
| | - Caroline Dive
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK
| | - Florent Mouliere
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK.
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20
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Hsieh RW, Symonds LK, Siu J, Cohen SA. Identification of circulating tumor DNA as a biomarker for diagnosis and response to therapies in cancer patients. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 391:43-93. [PMID: 39939078 DOI: 10.1016/bs.ircmb.2024.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/14/2025]
Abstract
The sampling of circulating biomarkers provides an opportunity for non-invasive evaluation and monitoring of cancer activity. In modern day practice, this has typically been in the form of circulating tumor DNA (ctDNA) detected in plasma. The field of ctDNA has been a burgeoning technology, with prominent applications for blood-based cancer screening and in disease status assessment, especially after curative-intent surgery to evaluate for minimal residual disease (MRD). Clinical applications for the latter show an incredibly high sensitivity in certain cancer types with a need for additional studies to determine how much clinical decision-making should be adapted based on ctDNA results and which cancer types, stages, and treatments are best informed by ctDNA results. This chapter provides an overview of ctDNA detection as tool for cancer screening, detecting MRD, and/or molecularly characterizing a cancer, highlighting the rapidly amassing research as a prognostic biomarker and emerging data on ctDNA as a predictive biomarker.
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Affiliation(s)
- Ronan W Hsieh
- Division of Hematology/Oncology, University of Washington, Seattle, WA, United States; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Lynn K Symonds
- Division of Hematology/Oncology, University of Washington, Seattle, WA, United States; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Jason Siu
- Department of Laboratory Medicine, University of Washington, Seattle, WA, United States
| | - Stacey A Cohen
- Division of Hematology/Oncology, University of Washington, Seattle, WA, United States; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, United States.
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21
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Choi Y, Dharia NV, Jun T, Chang J, Royer-Joo S, Yau KK, Assaf ZJ, Aimi J, Sivakumar S, Montesion M, Sacher A, LoRusso P, Desai J, Schutzman JL, Shi Z. Circulating Tumor DNA Dynamics Reveal KRAS G12C Mutation Heterogeneity and Response to Treatment with the KRAS G12C Inhibitor Divarasib in Solid Tumors. Clin Cancer Res 2024; 30:3788-3797. [PMID: 38995268 PMCID: PMC11369623 DOI: 10.1158/1078-0432.ccr-24-0255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/26/2024] [Accepted: 07/10/2024] [Indexed: 07/13/2024]
Abstract
PURPOSE To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study. EXPERIMENTAL DESIGN Plasma samples were collected for serial ctDNA profiling at baseline (cycle 1 day 1 prior to treatment) and multiple on-treatment time points (cycle 1 day 15 and cycle 3 day 1). RESULTS KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non-small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as cycle 1 day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction. CONCLUSIONS Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.
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Affiliation(s)
- Yoonha Choi
- Genentech, Inc., South San Francisco, California.
| | | | - Tomi Jun
- Genentech, Inc., South San Francisco, California.
| | - Julie Chang
- Genentech, Inc., South San Francisco, California.
| | | | | | - Zoe J. Assaf
- Genentech, Inc., South San Francisco, California.
| | - Junko Aimi
- Genentech, Inc., South San Francisco, California.
| | | | | | - Adrian Sacher
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
- Department of Medicine, University of Toronto, Toronto, Canada.
- Department of Immunology, University of Toronto, Toronto, Canada.
| | | | - Jayesh Desai
- Peter MacCallum Cancer Centre, Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
| | | | - Zhen Shi
- Genentech, Inc., South San Francisco, California.
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22
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Stritzke F, Held T. [Standard-of-care systemic therapy with or without SBRT in patients with oligoprogressive breast cancer or NSCLC (CURB oligoprogression): an open-label, randomised, controlled, phase 2 study]. Strahlenther Onkol 2024; 200:850-852. [PMID: 39120748 DOI: 10.1007/s00066-024-02261-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2024] [Indexed: 08/10/2024]
Affiliation(s)
| | - Thomas Held
- Universitätsklinikum Heidelberg, Heidelberg, Deutschland.
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23
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Huerta M, Martín-Arana J, Gimeno-Valiente F, Carbonell-Asins JA, García-Micó B, Martínez-Castedo B, Robledo-Yagüe F, Camblor DG, Fleitas T, García Bartolomé M, Alfaro-Cervelló C, Garcés-Albir M, Dorcaratto D, Muñoz-Forner E, Seguí V, Mora-Oliver I, Gambardella V, Roselló S, Sabater L, Roda D, Cervantes A, Tarazona N. ctDNA whole exome sequencing in pancreatic ductal adenocarcinoma unveils organ-dependent metastatic mechanisms and identifies actionable alterations in fast progressing patients. Transl Res 2024; 271:105-115. [PMID: 38782356 DOI: 10.1016/j.trsl.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/28/2024] [Accepted: 05/06/2024] [Indexed: 05/25/2024]
Abstract
Understanding progression mechanisms and developing new targeted therapies is imperative in pancreatic ductal adenocarcinoma (PDAC). In this study, 80 metastatic PDAC patients were prospectively recruited and divided into discovery (n=37) and validation (n=43) cohorts. Tumor and plasma samples taken at diagnosis were pair analyzed using whole exome sequencing (WES) in patients belonging to the discovery cohort alone. The variant allele frequency (VAF) of KRAS mutations was measured by ddPCR in plasma at baseline and response assessment in all patients. Plasma WES identified at least one pathogenic variant across the cohort, uncovering oncogenic mechanisms, DNA repair, microsatellite instability, and alterations in the TGFb pathway. Interestingly, actionable mutations were mostly found in plasma rather than tissue. Patients with shorter survival showed enrichment in cellular organization regulatory pathways. Through WES we could identify a specific molecular profile of patients with liver metastasis, which exhibited exclusive mutations in genes related to the adaptive immune response pathway, highlighting the importance of the immune system in liver metastasis development. Moreover, KRAS mutations in plasma (both at diagnosis and persistent at follow-up) correlated with shorter progression free survival (PFS). Patients presenting a reduction of over 84.75 % in KRAS VAF at response assessment had similar PFS to KRAS-negative patients. Overall, plasma WES reveals molecular profiles indicative of rapid progression, potentially actionable targets, and associations between adaptive immune response pathway alterations and liver tropism.
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Affiliation(s)
- Marisol Huerta
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Jorge Martín-Arana
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Francisco Gimeno-Valiente
- Cancer Evolution and Genome Instability Laboratory, University College London Cancer Institute, London, UK
| | | | - Blanca García-Micó
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Belén Martínez-Castedo
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Fabián Robledo-Yagüe
- Bioinformatics Unit, INCLIVA Biomedical Research Institute, University of Valencia, Spain
| | - Daniel G Camblor
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Tania Fleitas
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Miguel García Bartolomé
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Clara Alfaro-Cervelló
- Department of Pathology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Marina Garcés-Albir
- Liver, Biliary and Pancreatic Unit, Department of General Surgery, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, University of Valencia, Valencia, Spain
| | - Dimitri Dorcaratto
- Liver, Biliary and Pancreatic Unit, Department of General Surgery, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, University of Valencia, Valencia, Spain
| | - Elena Muñoz-Forner
- Liver, Biliary and Pancreatic Unit, Department of General Surgery, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, University of Valencia, Valencia, Spain
| | - Víctor Seguí
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Isabel Mora-Oliver
- Liver, Biliary and Pancreatic Unit, Department of General Surgery, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, University of Valencia, Valencia, Spain
| | - Valentina Gambardella
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Susana Roselló
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Department of General Surgery, INCLIVA Biomedical Research Institute, Hospital Clínico Universitario de Valencia, University of Valencia, Valencia, Spain
| | - Desamparados Roda
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Andrés Cervantes
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
| | - Noelia Tarazona
- Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
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24
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Ou X, Gao G, Habaz IA, Wang Y. Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies. MedComm (Beijing) 2024; 5:e694. [PMID: 39184861 PMCID: PMC11344283 DOI: 10.1002/mco2.694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 07/24/2024] [Accepted: 07/28/2024] [Indexed: 08/27/2024] Open
Abstract
Tyrosine kinase inhibitor (TKI)-targeted therapy has revolutionized cancer treatment by selectively blocking specific signaling pathways crucial for tumor growth, offering improved outcomes with fewer side effects compared with conventional chemotherapy. However, despite their initial effectiveness, resistance to TKIs remains a significant challenge in clinical practice. Understanding the mechanisms underlying TKI resistance is paramount for improving patient outcomes and developing more effective treatment strategies. In this review, we explored various mechanisms contributing to TKI resistance, including on-target mechanisms and off-target mechanisms, as well as changes in the tumor histology and tumor microenvironment (intrinsic mechanisms). Additionally, we summarized current therapeutic approaches aiming at circumventing TKI resistance, including the development of next-generation TKIs and combination therapies. We also discussed emerging strategies such as the use of dual-targeted antibodies and PROteolysis Targeting Chimeras. Furthermore, we explored future directions in TKI-targeted therapy, including the methods for detecting and monitoring drug resistance during treatment, identification of novel targets, exploration of dual-acting kinase inhibitors, application of nanotechnologies in targeted therapy, and so on. Overall, this review provides a comprehensive overview of the challenges and opportunities in TKI-targeted therapy, aiming to advance our understanding of resistance mechanisms and guide the development of more effective therapeutic approaches in cancer treatment.
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Affiliation(s)
- Xuejin Ou
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China HospitalSichuan UniversityChengduChina
| | - Ge Gao
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China HospitalSichuan UniversityChengduChina
- Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China HospitalSichuan UniversityChengduChina
| | - Inbar A. Habaz
- Department of Biochemistry and Biomedical SciencesMcMaster UniversityHamiltonOntarioCanada
| | - Yongsheng Wang
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China HospitalSichuan UniversityChengduChina
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25
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Gharib E, Robichaud GA. From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:9463. [PMID: 39273409 PMCID: PMC11395697 DOI: 10.3390/ijms25179463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/19/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.
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Affiliation(s)
- Ehsan Gharib
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
| | - Gilles A Robichaud
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
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26
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Piana D, Iavarone F, De Paolis E, Daniele G, Parisella F, Minucci A, Greco V, Urbani A. Phenotyping Tumor Heterogeneity through Proteogenomics: Study Models and Challenges. Int J Mol Sci 2024; 25:8830. [PMID: 39201516 PMCID: PMC11354793 DOI: 10.3390/ijms25168830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/31/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Tumor heterogeneity refers to the diversity observed among tumor cells: both between different tumors (inter-tumor heterogeneity) and within a single tumor (intra-tumor heterogeneity). These cells can display distinct morphological and phenotypic characteristics, including variations in cellular morphology, metastatic potential and variability treatment responses among patients. Therefore, a comprehensive understanding of such heterogeneity is necessary for deciphering tumor-specific mechanisms that may be diagnostically and therapeutically valuable. Innovative and multidisciplinary approaches are needed to understand this complex feature. In this context, proteogenomics has been emerging as a significant resource for integrating omics fields such as genomics and proteomics. By combining data obtained from both Next-Generation Sequencing (NGS) technologies and mass spectrometry (MS) analyses, proteogenomics aims to provide a comprehensive view of tumor heterogeneity. This approach reveals molecular alterations and phenotypic features related to tumor subtypes, potentially identifying therapeutic biomarkers. Many achievements have been made; however, despite continuous advances in proteogenomics-based methodologies, several challenges remain: in particular the limitations in sensitivity and specificity and the lack of optimal study models. This review highlights the impact of proteogenomics on characterizing tumor phenotypes, focusing on the critical challenges and current limitations of its use in different clinical and preclinical models for tumor phenotypic characterization.
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Affiliation(s)
- Diletta Piana
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.P.); (F.I.); (F.P.)
- Departmen Unity of Chemistry, Biochemistry and Clinical Molecular Biology, Department of Diagnostic and Laboratory Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (E.D.P.); (A.M.)
| | - Federica Iavarone
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.P.); (F.I.); (F.P.)
- Departmen Unity of Chemistry, Biochemistry and Clinical Molecular Biology, Department of Diagnostic and Laboratory Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (E.D.P.); (A.M.)
| | - Elisa De Paolis
- Departmen Unity of Chemistry, Biochemistry and Clinical Molecular Biology, Department of Diagnostic and Laboratory Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (E.D.P.); (A.M.)
- Departmental Unit of Molecular and Genomic Diagnostics, Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Gennaro Daniele
- Phase 1 Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy;
| | - Federico Parisella
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.P.); (F.I.); (F.P.)
| | - Angelo Minucci
- Departmen Unity of Chemistry, Biochemistry and Clinical Molecular Biology, Department of Diagnostic and Laboratory Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (E.D.P.); (A.M.)
- Departmental Unit of Molecular and Genomic Diagnostics, Genomics Core Facility, Gemelli Science and Technology Park (G-STeP), Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Viviana Greco
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.P.); (F.I.); (F.P.)
- Departmen Unity of Chemistry, Biochemistry and Clinical Molecular Biology, Department of Diagnostic and Laboratory Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (E.D.P.); (A.M.)
| | - Andrea Urbani
- Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.P.); (F.I.); (F.P.)
- Departmen Unity of Chemistry, Biochemistry and Clinical Molecular Biology, Department of Diagnostic and Laboratory Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (E.D.P.); (A.M.)
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Ashouri K, Wong A, Mittal P, Torres-Gonzalez L, Lo JH, Soni S, Algaze S, Khoukaz T, Zhang W, Yang Y, Millstein J, Lenz HJ, Battaglin F. Exploring Predictive and Prognostic Biomarkers in Colorectal Cancer: A Comprehensive Review. Cancers (Basel) 2024; 16:2796. [PMID: 39199569 PMCID: PMC11353018 DOI: 10.3390/cancers16162796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/04/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024] Open
Abstract
Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors have significantly improved patient outcomes, their effectiveness is mostly limited to tumors with microsatellite instability (MSI-H/dMMR) or an increased tumor mutational burden, which comprise 10% of cases. Advancing personalized medicine in CRC hinges on identifying predictive biomarkers to guide treatment decisions. This comprehensive review examines established tissue markers such as KRAS and HER2, highlighting their roles in resistance to anti-EGFR agents and discussing advances in targeted therapies for these markers. Additionally, this review summarizes encouraging data on promising therapeutic targets and highlights the clinical utility of liquid biopsies. By synthesizing current evidence and identifying knowledge gaps, this review provides clinicians and researchers with a contemporary understanding of the biomarker landscape in CRC. Finally, the review examines future directions and challenges in translating promising biomarkers into clinical practice, with the goal of enhancing personalized medicine approaches for colorectal cancer patients.
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Affiliation(s)
- Karam Ashouri
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Alexandra Wong
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Pooja Mittal
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Lesly Torres-Gonzalez
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Jae Ho Lo
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Sandra Algaze
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Taline Khoukaz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Yan Yang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Joshua Millstein
- Department of Population and Public Health Sciences, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
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Beecroft JR, Brar S, Feng X, Hamilton T, Han-Lee C, Henning JW, Josephy PD, Khalili K, Ko YJ, Lemieux C, Liu DM, MacDonald DB, Noujaim J, Pollett A, Salawu A, Saleh R, Smrke A, Warren BE, Zbuk K, Razak AA. Pan-Canadian consensus recommendations for GIST management in high- and low-throughput centres across Canada. Ther Adv Med Oncol 2024; 16:17588359241266179. [PMID: 39386314 PMCID: PMC11461906 DOI: 10.1177/17588359241266179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/18/2024] [Indexed: 10/12/2024] Open
Abstract
Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that originate from the interstitial cells of Cajal. GISTs are mainly driven by gain-of-function mutations in receptor tyrosine kinase or platelet-derived growth factor receptor alpha. Surgical resection is the only curative treatment for localized tumours and all currently approved medical GIST treatments are based on orally available tyrosine kinase inhibitors. Recent discoveries in the molecular and clinical features of GISTs have greatly impacted GIST management. Due to the provincially rather than nationally administered Canadian healthcare system, there have been inconsistencies in the treatment of GISTs across the country. Therefore, guidance on the latest knowledge, clinical management and treatment of GIST is needed to standardize the approach to GIST management nationwide. To establish pan-Canadian guidance, provide up-to-date data and harmonize the clinical practice of GIST management in high- and low-throughput centres across Canada; a panel of 20 physicians with extensive clinical experience in GIST management reviewed relevant literature. This included radiologists, pathologists, interventional radiologists, surgeons and medical oncologists across Canada. The structured literature focused on seven key domains: molecular profiling, radiological techniques/reporting, targeted localized therapy, intricacies of systemic treatments, emerging tests, multidisciplinary care and patient advocacy. This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST.
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Affiliation(s)
- J. Robert Beecroft
- Division of Interventional Radiology, Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital, Toronto, ON, Canada
| | - Savtaj Brar
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Xiaolan Feng
- Division of Medical Oncology, Tom Baker Cancer Center, Calgary, AB, Canada
| | - Trevor Hamilton
- Department of Surgery, BC Cancer, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Cheng Han-Lee
- Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada
| | - Jan-Willem Henning
- Department of Oncology, Tom Baker Cancer Centre, Cuming School of Medicine, University of Calgary, Calgary, AB, Canada
| | | | - Korosh Khalili
- Department of Medical Imaging, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Yoo-Joung Ko
- Department of Medicine, St. Michael’s Hospital, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Christopher Lemieux
- Division of Hematology and Medical Oncology, Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, QC, Canada
| | - David M. Liu
- Department of Radiology, University of British Columbia, School of Biomedical Engineering, Vancouver, BC, Canada
- Department of Interventional Radiology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - D. Blair MacDonald
- Department of Medical Radiology, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada
| | - Jonathan Noujaim
- Division of Medical Oncology, Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, QC, Canada
| | - Aaron Pollett
- Pathology and Laboratory Medicine, Division of Diagnostic Medical Genetics, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Abdulazeez Salawu
- Division of Medical Oncology, Princess Margaret Cancer Centre, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Ramy Saleh
- Division of Medical Oncology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Alannah Smrke
- Division of Medical Oncology, BC Cancer, University of British Columbia, Vancouver, BC, Canada
| | - Blair E. Warren
- Department of Medical Imaging, University of Toronto, Toronto, ON, Canada
| | - Kevin Zbuk
- Department of Oncology, McMaster University, Hamilton, ON, Canada
| | - Albiruni Abdul Razak
- Division of Medical Oncology, Princess Margaret Cancer Centre, Mount Sinai Hospital, University of Toronto, 610 University Ave., Toronto, ON M2G 2M9, Canada
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Penny L, Main SC, De Michino SD, Bratman SV. Chromatin- and nucleosome-associated features in liquid biopsy: implications for cancer biomarker discovery. Biochem Cell Biol 2024; 102:291-298. [PMID: 38478957 DOI: 10.1139/bcb-2024-0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2024] Open
Abstract
Cell-free DNA (cfDNA) from the bloodstream has been studied for cancer biomarker discovery, and chromatin-derived epigenetic features have come into the spotlight for their potential to expand clinical applications. Methylation, fragmentation, and nucleosome positioning patterns of cfDNA have previously been shown to reveal epigenomic and inferred transcriptomic information. More recently, histone modifications have emerged as a tool to further identify tumor-specific chromatin variants in plasma. A number of sequencing methods have been developed to analyze these epigenetic markers, offering new insights into tumor biology. Features within cfDNA allow for cancer detection, subtype and tissue of origin classification, and inference of gene expression. These methods provide a window into the complexity of cancer and the dynamic nature of its progression. In this review, we highlight the array of epigenetic features in cfDNA that can be extracted from chromatin- and nucleosome-associated organization and outline potential use cases in cancer management.
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Affiliation(s)
- Lucas Penny
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Sasha C Main
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Steven D De Michino
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Scott V Bratman
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada
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Megquier K, Husted C, Rhoades J, White ME, Genereux DP, Chen FL, Xiong K, Kwon E, Swofford R, Painter C, Adalsteinsson V, London CA, Gardner HL, Karlsson EK. Impact of preanalytical factors on liquid biopsy in the canine cancer model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.29.605605. [PMID: 39131379 PMCID: PMC11312437 DOI: 10.1101/2024.07.29.605605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
While liquid biopsy has potential to transform cancer diagnostics through minimally-invasive detection and monitoring of tumors, the impact of preanalytical factors such as the timing and anatomical location of blood draw is not well understood. To address this gap, we leveraged pet dogs with spontaneous cancer as a model system, as their compressed disease timeline facilitates rapid diagnostic benchmarking. Key liquid biopsy metrics from dogs were consistent with existing reports from human patients. The tumor content of samples was higher from venipuncture sites closer to the tumor and from a central vein. Metrics also differed between lymphoma and non-hematopoietic cancers, urging cancer-type-specific interpretation. Liquid biopsy was highly sensitive to disease status, with changes identified soon after post chemotherapy administration, and trends of increased tumor fraction and other metrics observed prior to clinical relapse in dogs with lymphoma or osteosarcoma. These data support the utility of pet dogs with cancer as a relevant system for advancing liquid biopsy platforms.
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Affiliation(s)
- Kate Megquier
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Christopher Husted
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA, USA
- Morningside Graduate School of Biomedical Sciences, UMass Chan Medical School, Worcester, MA, USA
| | | | | | | | - Frances L. Chen
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA, USA
| | - Kan Xiong
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Euijin Kwon
- Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA, USA
- Morningside Graduate School of Biomedical Sciences, UMass Chan Medical School, Worcester, MA, USA
| | - Ross Swofford
- Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA, USA
| | | | | | - Cheryl A. London
- Tufts Cummings School of Veterinary Medicine, North Grafton, MA, USA
| | | | - Elinor K. Karlsson
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA, USA
- Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA, USA
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Raei M, Heydari K, Tabarestani M, Razavi A, Mirshafiei F, Esmaeily F, Taheri M, Hoseini A, Nazari H, Shamshirian D, Alizadeh-Navaei R. Diagnostic accuracy of ESR1 mutation detection by cell-free DNA in breast cancer: a systematic review and meta-analysis of diagnostic test accuracy. BMC Cancer 2024; 24:908. [PMID: 39069608 PMCID: PMC11283726 DOI: 10.1186/s12885-024-12674-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND Estrogen receptors express in nearly 70% of breast cancers (ER-positive). Estrogen receptor alpha plays a fundamental role as a significant factor in breast cancer progression for the early selection of therapeutic approaches. Accordingly, there has been a surge of attention to non-invasive techniques, including circulating Cell-free DNA (ccfDNA) or Cell-Free DNA (cfDNA), to detect and track ESR1 genotype. Therefore, this study aimed to examine the diagnosis accuracy of ESR1 mutation detection by cell-free DNA in breast cancer patientsthrough a systematic review and comprehensive meta-analysis. METHODS PubMed, Embase, and Web of Science databases were searched up to 6 April 2022. Diagnostic studies on ESR1 measurement by cfDNA, which was confirmed using the tumour tissue biopsy, have been included in the study. The sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were considered to analyse the data. RESULTS Out of 649 papers, 13 papers with 15 cohorts, including 389 participants, entered the meta-analyses. The comprehensive meta-analysis indicated a high sensitivity (75.52, 95% CI 60.19-90.85), specificity (88.20, 95% CI 80.99-95.40), and high accuracy of 88.96 (95% CI 83.23-94.69) for plasma ESR1. We also found a moderate PPV of 56.94 (95% CI 41.70-72.18) but a high NPV of 88.53 (95% CI 82.61-94.44). We also found an NLR of 0.443 (95% CI 0.09-0.79) and PLR of 1.60 (95% CI 1.20-1.99). CONCLUSION This systematic review and comprehensive meta-analysis reveal that plasma cfDNA testing exhibits high sensitivity and specificity in detecting ESR1 mutations in breast cancer patients. This suggests that the test could be a valuable diagnostic tool. It may serve as a dependable and non-invasive technique for identifying ESR1 mutations in breast cancer patients. However, more extensive research is needed to confirm its prognostic value.
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Affiliation(s)
- Maedeh Raei
- Gastrointestinal Cancer Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Moallem Sq, Sari, Sari, 44817844718, Iran
| | - Keyvan Heydari
- Gastrointestinal Cancer Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Moallem Sq, Sari, Sari, 44817844718, Iran
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Tabarestani
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Alireza Razavi
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Fatemeh Mirshafiei
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Fatemeh Esmaeily
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mahsa Taheri
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Aref Hoseini
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hojjatollah Nazari
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, 2007, Australia
| | - Danial Shamshirian
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Alizadeh-Navaei
- Gastrointestinal Cancer Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Moallem Sq, Sari, Sari, 44817844718, Iran.
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Blanchard CE, Gomeiz AT, Avery K, Gazzah EE, Alsubaie AM, Sikaroodi M, Chiari Y, Ward C, Sanchez J, Espina V, Petricoin E, Baldelli E, Pierobon M. Signaling dynamics in coexisting monoclonal cell subpopulations unveil mechanisms of resistance to anti-cancer compounds. Cell Commun Signal 2024; 22:377. [PMID: 39061010 PMCID: PMC11282632 DOI: 10.1186/s12964-024-01742-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 07/06/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Tumor heterogeneity is a main contributor of resistance to anti-cancer targeted agents though it has proven difficult to study. Unfortunately, model systems to functionally characterize and mechanistically study dynamic responses to treatment across coexisting subpopulations of cancer cells remain a missing need in oncology. METHODS Using single cell cloning and expansion techniques, we established monoclonal cell subpopulations (MCPs) from a commercially available epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer cell line. We then used this model sensitivity to the EGFR inhibitor osimertinib across coexisting cell populations within the same tumor. Pathway-centered signaling dynamics associated with response to treatment and morphological characteristics of the MCPs were assessed using Reverse Phase Protein Microarray. Signaling nodes differentially activated in MCPs less sensitive to treatment were then pharmacologically inhibited to identify target signaling proteins putatively implicated in promoting drug resistance. RESULTS MCPs demonstrated highly heterogeneous sensitivities to osimertinib. Cell viability after treatment increased > 20% compared to the parental line in selected MCPs, whereas viability decreased by 75% in other MCPs. Reduced treatment response was detected in MCPs with higher proliferation rates, EGFR L858R expression, activation of EGFR binding partners and downstream signaling molecules, and expression of epithelial-to-mesenchymal transition markers. Levels of activation of EGFR binding partners and MCPs' proliferation rates were also associated with response to c-MET and IGFR inhibitors. CONCLUSIONS MCPs represent a suitable model system to characterize heterogeneous biomolecular behaviors in preclinical studies and identify and functionally test biological mechanisms associated with resistance to targeted therapeutics.
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Affiliation(s)
- Claire E Blanchard
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Alison T Gomeiz
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Kyle Avery
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Emna El Gazzah
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Abduljalil M Alsubaie
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Masoumeh Sikaroodi
- Microbiome Analysis Center, George Mason University, Manassas, VA, 20110, USA
| | - Ylenia Chiari
- Department of Biology, George Mason University, Fairfax, VA, 22030, USA
- School of Life Sciences, University of Nottingham, Nottingham, NG7 2TQ, UK
| | - Chelsea Ward
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Jonathan Sanchez
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA
| | - Virginia Espina
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA
| | - Emanuel Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA
| | - Elisa Baldelli
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA
| | - Mariaelena Pierobon
- School of Systems Biology, George Mason University, 10920 George Mason Circle, Room 2016, Manassas, VA, 20110, USA.
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA.
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Sementsov M, Ott L, Kött J, Sartori A, Lusque A, Degenhardt S, Segier B, Heidrich I, Volkmer B, Greinert R, Mohr P, Simon R, Stadler JC, Irwin D, Koch C, Andreas A, Deitert B, Thewes V, Trumpp A, Schneeweiss A, Belloum Y, Peine S, Wikman H, Riethdorf S, Schneider SW, Gebhardt C, Pantel K, Keller L. Mutation analysis in individual circulating tumor cells depicts intratumor heterogeneity in melanoma. EMBO Mol Med 2024; 16:1560-1578. [PMID: 38898234 PMCID: PMC11250829 DOI: 10.1038/s44321-024-00082-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 05/03/2024] [Accepted: 05/14/2024] [Indexed: 06/21/2024] Open
Abstract
Circulating tumor DNA (ctDNA) is the cornerstone of liquid biopsy diagnostics, revealing clinically relevant genomic aberrations from blood of cancer patients. Genomic analysis of single circulating tumor cells (CTCs) could provide additional insights into intra-patient heterogeneity, but it requires whole-genome amplification (WGA) of DNA, which might introduce bias. Here, we describe a novel approach based on mass spectrometry for mutation detection from individual CTCs not requiring WGA and complex bioinformatics pipelines. After establishment of our protocol on tumor cell line-derived single cells, it was validated on CTCs of 33 metastatic melanoma patients and the mutations were compared to those obtained from tumor tissue and ctDNA. Although concordance with tumor tissue was superior for ctDNA over CTC analysis, a larger number of mutations were found within CTCs compared to ctDNA (p = 0.039), including mutations in melanoma driver genes, or those associated with resistance to therapy or metastasis. Thus, our results demonstrate proof-of-principle data that CTC analysis can provide clinically relevant genomic information that is not redundant to tumor tissue or ctDNA analysis.
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Affiliation(s)
- Mark Sementsov
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Fleur Hiege Center for Skin Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Leonie Ott
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julian Kött
- Fleur Hiege Center for Skin Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Amelie Lusque
- Biostatistics & Health Data Science Unit, Institut Claudius-Regaud, IUCT-Oncopole, Toulouse, France
| | - Sarah Degenhardt
- Department of Molecular Cell Biology, Skin Cancer Center Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany
| | - Bertille Segier
- Biostatistics & Health Data Science Unit, Institut Claudius-Regaud, IUCT-Oncopole, Toulouse, France
| | - Isabel Heidrich
- Fleur Hiege Center for Skin Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Beate Volkmer
- Department of Molecular Cell Biology, Skin Cancer Center Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany
| | - Rüdiger Greinert
- Department of Molecular Cell Biology, Skin Cancer Center Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany
| | - Peter Mohr
- Department of Dermatology, Elbe Kliniken Buxtehude, 21614, Buxtehude, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julia-Christina Stadler
- Fleur Hiege Center for Skin Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Claudia Koch
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Antje Andreas
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Benjamin Deitert
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Verena Thewes
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Andreas Trumpp
- Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Andreas Schneeweiss
- National Center for Tumor Diseases, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Yassine Belloum
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sven Peine
- Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Harriett Wikman
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sabine Riethdorf
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan W Schneider
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoffer Gebhardt
- Fleur Hiege Center for Skin Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Klaus Pantel
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Laura Keller
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Fleur Hiege Center for Skin Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- CRCT, Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France.
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Jiang R, Cheng X, Li P, Meng E, Wu X, Wu H. Plasma circulating tumor DNA unveils the efficacy of PD-1 inhibitors and chemotherapy in advanced gastric cancer. Sci Rep 2024; 14:14027. [PMID: 38890392 PMCID: PMC11189402 DOI: 10.1038/s41598-024-63486-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 05/29/2024] [Indexed: 06/20/2024] Open
Abstract
Programmed Death Receptor 1 (PD-1) inhibitors, when combined with chemotherapy, have exhibited notable effectiveness in enhancing the survival outcomes of patients afflicted with advanced gastric cancer. However, it is important to acknowledge that not all patients derive substantial benefits from this therapeutic approach, highlighting the crucial necessity of identifying efficacious biomarkers to inform immunotherapy interventions. In this study, we sought to investigate the predictive utility of circulating tumor DNA (ctDNA) as a biomarker in a cohort of 30 patients diagnosed with advanced gastric cancer, all of whom underwent first-line treatment involving PD-1 inhibitor administration alongside chemotherapy. We procured peripheral blood samples both at baseline and following the completion of two treatment cycles. Additionally, baseline tissue specimens were collected for the purpose of genomic alteration assessment, employing both 47-gene and 737-gene next-generation sequencing panels for plasma and tumor tissue, respectively. We delineated a ctDNA response as the eradication of maximum variant allele frequencies relative to baseline levels. Notably, the objective response rate among individuals exhibiting a ctDNA response proved significantly superior in comparison to non-responders (P = 0.0073). Furthermore, patients who manifested a ctDNA response experienced markedly prolonged progression-free survival (PFS) and overall survival (OS) when juxtaposed with those devoid of a ctDNA response (median PFS: 15.6 vs. 6.0 months, P = 0.003; median OS: not reached [NR] vs. 9.0 months, P = 0.011). In summation, patients with advanced gastric cancer receiving first-line treatment with PD-1 inhibitors and chemotherapy, dynamic changes in ctDNA can serve as a potential biomarker for predicting treatment efficacy and long-term outcomes.
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Affiliation(s)
- Rongqi Jiang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
- Institute for Gastric Cancer Research, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, People's Republic of China
| | - Xu Cheng
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Ping Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Enqing Meng
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Xinyi Wu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China
| | - Hao Wu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China.
- Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, People's Republic of China.
- Institute for Gastric Cancer Research, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, People's Republic of China.
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Zeng Z, Zhu Q. Progress and prospects of biomarker-based targeted therapy and immune checkpoint inhibitors in advanced gastric cancer. Front Oncol 2024; 14:1382183. [PMID: 38947886 PMCID: PMC11211377 DOI: 10.3389/fonc.2024.1382183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 05/24/2024] [Indexed: 07/02/2024] Open
Abstract
Gastric cancer and gastroesophageal junction cancer represent the leading cause of tumor-related death worldwide. Although advances in immunotherapy and molecular targeted therapy have expanded treatment options, they have not significantly altered the prognosis for patients with unresectable or metastatic gastric cancer. A minority of patients, particularly those with PD-L1-positive, HER-2-positive, or MSI-high tumors, may benefit more from immune checkpoint inhibitors and/or HER-2-directed therapies in advanced stages. However, for those lacking specific targets and unique molecular features, conventional chemotherapy remains the only recommended effective and durable regimen. In this review, we summarize the roles of various signaling pathways and further investigate the available targets. Then, the current results of phase II/III clinical trials in advanced gastric cancer, along with the superiorities and limitations of the existing biomarkers, are specifically discussed. Finally, we will offer our insights in precision treatment pattern when encountering the substantial challenges.
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Affiliation(s)
| | - Qing Zhu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
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36
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Lu W, Aihaiti A, Abudukeranmu P, Liu Y, Gao H. Unravelling the role of intratumoral bacteria in digestive system cancers: current insights and future perspectives. J Transl Med 2024; 22:545. [PMID: 38849871 PMCID: PMC11157735 DOI: 10.1186/s12967-024-05320-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 05/18/2024] [Indexed: 06/09/2024] Open
Abstract
Recently, research on the human microbiome, especially concerning the bacteria within the digestive system, has substantially advanced. This exploration has unveiled a complex interplay between microbiota and health, particularly in the context of disease. Evidence suggests that the gut microbiome plays vital roles in digestion, immunity and the synthesis of vitamins and neurotransmitters, highlighting its significance in maintaining overall health. Conversely, disruptions in these microbial communities, termed dysbiosis, have been linked to the pathogenesis of various diseases, including digestive system cancers. These bacteria can influence cancer progression through mechanisms such as DNA damage, modulation of the tumour microenvironment, and effects on the host's immune response. Changes in the composition and function within the tumours can also impact inflammation, immune response and cancer therapy effectiveness. These findings offer promising avenues for the clinical application of intratumoral bacteria for digestive system cancer treatment, including the potential use of microbial markers for early cancer detection, prognostication and the development of microbiome-targeted therapies to enhance treatment outcomes. This review aims to provide a comprehensive overview of the pivotal roles played by gut microbiome bacteria in the development of digestive system cancers. Additionally, we delve into the specific contributions of intratumoral bacteria to digestive system cancer development, elucidating potential mechanisms and clinical implications. Ultimately, this review underscores the intricate interplay between intratumoral bacteria and digestive system cancers, underscoring the pivotal role of microbiome research in transforming diagnostic, prognostic and therapeutic paradigms for digestive system cancers.
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Affiliation(s)
- Weiqin Lu
- General Surgery, Cancer Center, Department of Vascular Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | | | | | - Yajun Liu
- Aksu First People's Hospital, Xinjiang, China
| | - Huihui Gao
- Cancer Center, Department of Hospital Infection Management and Preventive Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
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Chen X, Hu X, Liu T. Development of liquid biopsy in detection and screening of pancreatic cancer. Front Oncol 2024; 14:1415260. [PMID: 38887233 PMCID: PMC11180763 DOI: 10.3389/fonc.2024.1415260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 05/14/2024] [Indexed: 06/20/2024] Open
Abstract
Pancreatic cancer is a highly lethal malignant tumor, which has the characteristics of occult onset, low early diagnosis rate, rapid development and poor prognosis. The reason for the high mortality is partly that pancreatic cancer is usually found in the late stage and missed the best opportunity for surgical resection. As a promising detection technology, liquid biopsy has the advantages of non-invasive, real-time and repeatable. In recent years, the continuous development of liquid biopsy has provided a new way for the detection and screening of pancreatic cancer. The update of biomarkers and detection tools has promoted the development of liquid biopsy. Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA) and extracellular vesicles (EVs) provide many biomarkers for liquid biopsy of pancreatic cancer, and screening tools around them have also been developed. This review aims to report the application of liquid biopsy technology in the detection of pancreatic cancer patients, mainly introduces the biomarkers and some newly developed tools and platforms. We have also considered whether liquid biopsy technology can replace traditional tissue biopsy and the challenges it faces.
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Affiliation(s)
- Xiangcheng Chen
- Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Xinyi Hu
- School of The First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Tiancai Liu
- Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
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Takahashi N, Pongor L, Agrawal SP, Shtumpf M, Rajapakse VN, Shafiei A, Schultz CW, Kim S, Roame D, Carter P, Vilimas R, Nichols S, Desai P, Figg WD, Bagheri M, Teif VB, Thomas A. Genomic alterations and transcriptional phenotypes in circulating tumor DNA and matched metastatic tumor. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.02.597054. [PMID: 38895436 PMCID: PMC11185519 DOI: 10.1101/2024.06.02.597054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Background Profiling circulating cell-free DNA (cfDNA) has become a fundamental practice in cancer medicine, but the effectiveness of cfDNA at elucidating tumor-derived molecular features has not been systematically compared to standard single-lesion tumor biopsies in prospective cohorts of patients. The use of plasma instead of tissue to guide therapy is particularly attractive for patients with small cell lung cancer (SCLC), a cancer whose aggressive clinical course making it exceedingly challenging to obtain tumor biopsies. Methods Here, a prospective cohort of 49 plasma samples obtained before, during, and after treatment from 20 patients with recurrent SCLC, we study cfDNA low pass whole genome (0.1X coverage) and exome (130X) sequencing in comparison with time-point matched tumor, characterized using exome and transcriptome sequencing. Results Direct comparison of cfDNA versus tumor biopsy reveals that cfDNA not only mirrors the mutation and copy number landscape of the corresponding tumor but also identifies clinically relevant resistance mechanisms and cancer driver alterations not found in matched tumor biopsies. Longitudinal cfDNA analysis reliably tracks tumor response, progression, and clonal evolution. Genomic sequencing coverage of plasma DNA fragments around transcription start sites shows distinct treatment-related changes and captures the expression of key transcription factors such as NEUROD1 and REST in the corresponding SCLC tumors, allowing prediction of SCLC neuroendocrine phenotypes and treatment responses. Conclusions These findings have important implications for non-invasive stratification and subtype-specific therapies for patients with SCLC, now treated as a single disease.
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Affiliation(s)
- Nobuyuki Takahashi
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
- Medical Oncology Branch, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Medical Oncology, National Cancer Center East Hospital, Kashiwa, Japan
| | - Lorinc Pongor
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | | | - Mariya Shtumpf
- School of Life Sciences, University of Essex, Colchester, UK
| | - Vinodh N Rajapakse
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Ahmad Shafiei
- Department of Radiology and Imaging Sciences, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Christopher W Schultz
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Sehyun Kim
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Diana Roame
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Paula Carter
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Rasa Vilimas
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Samantha Nichols
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Parth Desai
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - William Douglas Figg
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Mohammad Bagheri
- Department of Radiology and Imaging Sciences, Center for Cancer Research, National Cancer Institute, Bethesda, USA
| | - Vladimir B Teif
- School of Life Sciences, University of Essex, Colchester, UK
| | - Anish Thomas
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA
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Li Y, Wu J, Feng Y, Wang D, Tao H, Wen J, Jiang F, Qian P, Liu Y. Kinetics of plasma cell-free DNA as a prospective biomarker to predict the prognosis and radiotherapy effect of esophageal cancer. Cancer Radiother 2024; 28:242-250. [PMID: 38876937 DOI: 10.1016/j.canrad.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 11/03/2023] [Accepted: 11/09/2023] [Indexed: 06/16/2024]
Abstract
PURPOSE The lack of reliable biomarkers for the prognosis and radiotherapy efficacy in esophageal cancer (EC) necessitates further research. The aim of our study was to investigate the predictive utility of plasma cell-free DNA (cfDNA) kinetics in patients with EC. MATERIALS AND METHODS We retrospectively analyzed the clinical data and cfDNA levels (pre-radiotherapy [pre-RT] and post-radiotherapy [post-RT]) and the cfDNA kinetics (cfDNA ratio: post-RT cfDNA/pre-RT cfDNA) of 88 patients. We employed Kaplan-Meier curves to examine the relationship between cfDNA and overall survival (OS) as well as progression-free survival (PFS). Univariate and multivariate Cox regression analyses were executed to ascertain the independent risk factors in EC. RESULTS The pre-RT cfDNA levels were positively correlated with clinical stage (P=0.001). The pre-RT cfDNA levels (cutoff value=16.915ng/mL), but not the post-RT cfDNA levels, were linked to a diminished OS (P<0.001) and PFS (P=0.0137). CfDNA kinetics (cutoff value=0.883) were positively associated with OS (P=0.0326) and PFS (P=0.0020). Notably, we identified independent risk factors for OS in EC treated with RT, including cfDNA ratio (high/low) (HR=0.447 [0.221-0.914] P=0.025), ECOG (0/1/2) (HR=0.501 [0.285-0.880] p=0.016), and histological type (esophagal squamous cell carcinoma [ESCC]/non-ESCC) (HR=3.973 [1.074-14.692] P=0.039). CONCLUSION Plasma cfDNA kinetics is associated with prognosis and radiotherapy effect in EC undergoing RT, suggesting potential clinical application of a cheap and simple blood-based test.
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Affiliation(s)
- Y Li
- Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 21009 Nanjing, China
| | - J Wu
- Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 21009 Nanjing, China
| | - Y Feng
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 21009 Nanjing, China
| | - D Wang
- Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 21009 Nanjing, China
| | - H Tao
- Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 21009 Nanjing, China
| | - J Wen
- Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 21009 Nanjing, China
| | - F Jiang
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 21009 Nanjing, China
| | - P Qian
- Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 21009 Nanjing, China.
| | - Y Liu
- Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 21009 Nanjing, China.
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Pathak PS, Chan G, Deming DA, Chee CE. State-of-the-Art Management of Colorectal Cancer: Treatment Advances and Innovation. Am Soc Clin Oncol Educ Book 2024; 44:e438466. [PMID: 38768405 DOI: 10.1200/edbk_438466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Colorectal cancer (CRC) remains a significant global health challenge, ranking among the leading causes of cancer-related morbidity and mortality worldwide. Recent advancements in molecular characterization have revolutionized our understanding of the heterogeneity within colorectal tumors, particularly in the context of tumor sidedness. Tumor sidedness, referring to the location of the primary tumor in either the right or left colon, has emerged as a critical factor influencing prognosis and treatment responses in metastatic CRC. Molecular underpinnings of CRC, the impact of tumor sidedness, and how this knowledge guides therapeutic decisions in the era of precision medicine have led to improved outcomes and better quality of life in patients. The emergence of circulating tumor DNA as a prognostic and predictive tool in CRC heralds promising advancements in the diagnosis and monitoring of the disease. This innovation facilitates better patient selection for exploration of additional treatment options. As the field progresses, with investigational agents demonstrating potential as future treatments for refractory metastatic CRC, new avenues for enhancing outcomes in this challenging disease are emerging.
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Affiliation(s)
- Priyadarshini S Pathak
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Gloria Chan
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore
| | - Dustin A Deming
- Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
- University of Wisconsin Carbone Cancer Center, Madison, WI
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Cheng Ean Chee
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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McClurg DP, Sanghera C, Mukherjee S, Fitzgerald RC, Jones CM. A systematic review of circulating predictive and prognostic biomarkers to aid the personalised use of radiotherapy in the radical treatment of patients with oesophageal cancer. Radiother Oncol 2024; 195:110224. [PMID: 38479442 DOI: 10.1016/j.radonc.2024.110224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND The availability of circulating biomarkers that are predictive of treatment response or prognostic of overall outcome could enable the personalised and adaptive use of radiotherapy (RT) in patients with oesophageal adenocarcinoma (OAC) and squamous cell carcinoma (OSCC). METHODS A systematic review was carried out following Preferred Reporting Items for Systematic Reviews guidance. Medline, EMBASE, PubMed, Cochrane Library, CINAHL, Scopus and the Web of Science databases were searched for studies published between January 2005-February 2023 relating to circulating biomarkers evaluated in the context of neoadjuvant or definitive RT delivered for OAC/OSCC. Study quality was assessed using predefined criteria. RESULTS A total of 3012 studies were screened and 57 subsequently included, across which 61 biomarkers were reported. A majority (43/57,75.4%) of studies were of Asian origin and retrospective (40/57, 70.2%), with most (52/57, 91.2%) biomarkers reported in the context of patients with OSCC. There was marked inter-study heterogeneity in patient populations, treatment characteristics, biomarker measurement and the cut points used to define biomarker positivity. Nevertheless, there is evidence for the prognostic and predictive value of circulating tumour DNA and numerous miRNAs in OAC and OSCC, as well as for the prognostic and predictive value of circulating levels of CYFRA21.1 in OSCC. CONCLUSIONS There is consistent evidence for the potential predictive and prognostic value of a small number of biomarkers in OSCC and OAC, though these data are insufficient for translation to current clinical practice. Well-designed prospective studies are now required to validate their role in stratified and personalised RT treatment approaches.
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Affiliation(s)
- Dylan P McClurg
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Chandan Sanghera
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Somnath Mukherjee
- Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | | | - Christopher M Jones
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Oncology, University of Cambridge, Cambridge, UK.
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Nasu H, Nishio S, Park J, Tasaki K, Terada A, Tsuda N, Kawano K, Kojiro-Sanada S, Akiba J, Ushijima K. Comprehensive Molecular Profiling and Clinicopathological Characteristics of Gastric-Type Mucinous Carcinoma of the Uterine Cervix in Japanese Women. Kurume Med J 2024; 69:237-249. [PMID: 38369337 DOI: 10.2739/kurumemedj.ms6934018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2024]
Abstract
Gastric-type mucinous carcinoma (GAS) of the uterine cervix is the most common adenocarcinoma that develops independently of human papillomavirus infection; it is typically diagnosed at an advanced stage and has a poorer prognosis than usual-type endocervical adenocarcinoma. Few studies have examined the molecular profile of GAS, but genetic alterations in TP53 and STK11 have been repeatedly reported. We analyzed the clinicopathological characteristics and molecular profile of GAS. Fresh-frozen tissue specimens and formalin-fixed paraffin-embedded (FFPE) tissues from 13 patients with GAS treated between January 2000 and December 2020 were analyzed. We performed next-generation sequencing on eight fresh-frozen GAS specimens using the Cancer Hotspot Panel v2 (cases 1-8) and the FoundationOne companion diagnostic (F1CDx) assay on six FFPE samples (cases 8-13). Seventy-four genomic alterations were identified in 42 genes. In order of frequency, TP53, ATRX, CDKN2A, KRAS, APC, and STK11 were altered in at least three cases. Targetable genomic alterations were identified in all six patients' specimens analyzed using the F1CDx assay. GAS harbors various genomic alterations associated with sustained activation of signaling pathways or cell cycle regulation in addition to abnormalities in TP53, and precision medicine based on molecular profiling will be necessary to overcome GAS.
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Affiliation(s)
- Hiroki Nasu
- Department of Obstetrics and Gynecology, Kurume University School of Medicine
| | - Shin Nishio
- Department of Obstetrics and Gynecology, Kurume University School of Medicine
| | - Jongmyung Park
- Department of Obstetrics and Gynecology, Kurume University School of Medicine
| | - Kazuto Tasaki
- Department of Obstetrics and Gynecology, Kurume University School of Medicine
| | - Atsumu Terada
- Department of Obstetrics and Gynecology, Kurume University School of Medicine
| | - Naotake Tsuda
- Department of Obstetrics and Gynecology, Kurume University School of Medicine
| | | | | | - Jun Akiba
- Department of Diagnostic Pathology, Kurume University Hospital
| | - Kimio Ushijima
- Department of Obstetrics and Gynecology, Kurume University School of Medicine
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Payne KFB, Brotherwood P, Suriyanarayanan H, Brooks JM, Batis N, Beggs AD, Gendoo DMA, Mehanna H, Nankivell P. Circulating tumour DNA detects somatic variants contributing to spatial and temporal intra-tumoural heterogeneity in head and neck squamous cell carcinoma. Front Oncol 2024; 14:1374816. [PMID: 38846976 PMCID: PMC11154907 DOI: 10.3389/fonc.2024.1374816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/09/2024] [Indexed: 06/09/2024] Open
Abstract
Background As circulating tumour DNA (ctDNA) liquid biopsy analysis is increasingly incorporated into modern oncological practice, establishing the impact of genomic intra-tumoural heterogeneity (ITH) upon data output is paramount. Despite advances in other cancer types the evidence base in head and neck squamous cell carcinoma (HNSCC) remains poor. We sought to investigate the utility of ctDNA to detect ITH in HNSCC. Methods In a pilot cohort of 9 treatment-naïve HNSCC patients, DNA from two intra-tumoural sites (core and margin) was whole-exome sequenced. A 9-gene panel was designed to perform targeted sequencing on pre-treatment plasma cell-free DNA and selected post-treatment samples. Results Rates of genomic ITH among the 9 patients was high. COSMIC variants from 19 TCGA HNSCC genes demonstrated an 86.9% heterogeneity rate (present in one tumour sub-site only). Across all patients, cell-free DNA (ctDNA) identified 12.9% (range 7.5-19.8%) of tumour-specific variants, of which 55.6% were specific to a single tumour sub-site only. CtDNA identified 79.0% (range: 55.6-90.9%) of high-frequency variants (tumour VAF>5%). Analysis of ctDNA in serial post-treatment blood samples in patients who suffered recurrence demonstrated dynamic changes in both tumour-specific and acquired variants that predicted recurrence ahead of clinical detection. Conclusion We demonstrate that a ctDNA liquid biopsy identified spatial genomic ITH in HNSCC and reliably detected high-frequency driver mutations. Serial sampling allowed post-treatment surveillance and early identification of treatment failure.
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Affiliation(s)
- Karl F. B. Payne
- Institute of Head and Neck Studies and Education, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Peter Brotherwood
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Harini Suriyanarayanan
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Jill M. Brooks
- Institute of Head and Neck Studies and Education, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Nikolaos Batis
- School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Andrew D. Beggs
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Deena M. A. Gendoo
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
- Institute for Interdisciplinary Data Science and AI, University of Birmingham, Birmingham, United Kingdom
| | - Hisham Mehanna
- Institute of Head and Neck Studies and Education, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Paul Nankivell
- Institute of Head and Neck Studies and Education, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
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Kapriniotis K, Tzelves L, Lazarou L, Mitsogianni M, Mitsogiannis I. Circulating Tumour DNA and Its Prognostic Role in Management of Muscle Invasive Bladder Cancer: A Narrative Review of the Literature. Biomedicines 2024; 12:921. [PMID: 38672275 PMCID: PMC11048625 DOI: 10.3390/biomedicines12040921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 04/18/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024] Open
Abstract
Current management of non-metastatic muscle invasive bladder cancer (MIBC) includes radical cystectomy and cisplatin-based neoadjuvant chemotherapy (NAC), offers a 5-year survival rate of approximately 50% and is associated with significant toxicities. A growing body of evidence supports the role of liquid biopsies including circulating tumour DNA (ctDNA) as a prognostic and predictive marker that could stratify patients according to individualised risk of progression/recurrence. Detectable ctDNA levels prior to radical cystectomy have been shown to be correlated with higher risk of recurrence and worse overall prognosis after cystectomy. In addition, ctDNA status after NAC/neoadjuvant immunotherapy is predictive of the pathological response to these treatments, with persistently detectable ctDNA being associated with residual bladder tumour at cystectomy. Finally, detectable ctDNA levels post-cystectomy have been associated with disease relapse and worse disease-free (DFS) and overall survival (OS) and might identify a population with survival benefit from adjuvant immunotherapy.
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Affiliation(s)
| | - Lazaros Tzelves
- 2nd Department of Urology, Sismanogleio Hospital, National and Kapodistrian University of Athens (NKUA), 115 27 Athens, Greece; (L.L.); (I.M.)
| | - Lazaros Lazarou
- 2nd Department of Urology, Sismanogleio Hospital, National and Kapodistrian University of Athens (NKUA), 115 27 Athens, Greece; (L.L.); (I.M.)
| | - Maria Mitsogianni
- 4th Department of Medical Oncology, “Hygeia” Hospital, 151 23 Athens, Greece;
| | - Iraklis Mitsogiannis
- 2nd Department of Urology, Sismanogleio Hospital, National and Kapodistrian University of Athens (NKUA), 115 27 Athens, Greece; (L.L.); (I.M.)
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Zarkavelis G, Amylidi AL, Torounidou N, Yerolatsite M, Keravasili A, Keramisanou V, Mauri D. Exploring RAS mutation incidence and temporal heterogeneity in metastatic colorectal cancer patients - a single-institution experience utilising circulating tumour DNA. Contemp Oncol (Pozn) 2024; 28:45-50. [PMID: 38800532 PMCID: PMC11117156 DOI: 10.5114/wo.2024.138899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/25/2024] [Indexed: 05/29/2024] Open
Abstract
Introduction Colorectal cancer (CRC) remains a significant global health challenge, ranking among the leading causes of neoplastic mortality. Despite transformative therapeutic advances, a considerable proportion of patients are diagnosed with metastatic disease, and 15-30% of those initially presenting with early-stage CRC eventually experience recurrence. Comprehensive molecular testing, especially the evaluation of microsatellite instability and mutations in KRAS/NRAS or BRAF genes, is essential upon diagnosis of stage IV disease, guiding treatment decisions. Material and methods This manuscript explores the mutational landscape of KRAS and NRAS in patients with CRC, employing digital polymerase chain reaction (PCR) BEAMing for the detection of mutations in liquid biopsy. Our study enrolled patients with histologically confirmed CRC and stage IV disease, focusing on identifying mutations in KRAS and NRAS genes during various stages of therapy. Results Evaluating baseline, midline, and progression samples, we found that 66.6% maintained consistent mutational status post-disease progression, while 33.3% exhibited a shift in mutational status. The application of techniques with high sensitivity, such as BEAMing Digital PCR, is pivotal for accurate circulating tumour DNA (ctDNA) mutation detection. The study underscores the significance of continuous molecular monitoring in guiding therapeutic decisions for patients with metastatic CRC. Conclusions Our findings contribute to our understanding of the evolving mutational landscape and the potential clinical implications of ctDNA ana- lysis in the era of personalised cancer medicine.
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Affiliation(s)
- George Zarkavelis
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece
| | - Anna Lea Amylidi
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece
| | - Nanteznta Torounidou
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Melina Yerolatsite
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Athanasia Keravasili
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Varvara Keramisanou
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Davide Mauri
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece
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Fujiwara Y, Kato S, Kurzrock R. Evolution of Precision Oncology, Personalized Medicine, and Molecular Tumor Boards. Surg Oncol Clin N Am 2024; 33:197-216. [PMID: 38401905 PMCID: PMC10894322 DOI: 10.1016/j.soc.2023.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2024]
Abstract
With multiple molecular targeted therapies available for patients with cancer that correspond to a specific genetic alteration, the selection of the best treatment is essential to ensure therapeutic efficacy. Molecular tumor boards (MTBs) play a key role in this process to deliver personalized medicine to patients with cancer in a multidisciplinary manner. Historically, personalized medicine has been offered to patients with advanced cancer, but the incorporation of molecular targeted therapies and immunotherapy into the perioperative setting requires clinicians to understand the role of the MTB. Evidence is accumulating to support feasibility and survival benefit in patients treated with matched therapy.
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Affiliation(s)
- Yu Fujiwara
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14263, USA.
| | - Shumei Kato
- Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093, USA; Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Razelle Kurzrock
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Froedtert and Medical College of Wisconsin Cancer Center and Linda T. and John A. Mellowes Center for Genomic Sciences and Precision Medicine, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA; WIN Consortium, Paris, France; University of Nebraska, Lincoln, NE, USA
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Efthymiou V, Queenan N, Haas M, Naegele S, Goss D, Faden DL. Circulating Tumor DNA in the Immediate Postoperative Setting. Ann Surg Oncol 2024; 31:2319-2325. [PMID: 38190058 DOI: 10.1245/s10434-023-14860-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 12/17/2023] [Indexed: 01/09/2024]
Abstract
BACKGROUND Circulating tumor DNA (ctDNA) has emerged as an accurate real-time biomarker of disease status across many solid tumor types. Most studies evaluating the utility of ctDNA have focused on time points weeks to months after surgery, which, for many cancer types, is significantly later than decision-making time points for adjuvant treatment. In this systematic review, we summarize the state of the literature on the feasibility of using ctDNA as a biomarker in the immediate postoperative period. METHODS We performed a systematic review evaluating the early kinetics, defined here as 3 days of ctDNA in patients who underwent curative-intent surgery. RESULTS Among the 2057 studies identified, eight cohort studies met the criteria for evaluation. Across six different cancer types, all studies showed an increased risk of cancer recurrence in patients with detectable ctDNA in the immediate postoperative period. CONCLUSION While ctDNA clearance kinetics appear to vary based on tumor type, across all studies detectable ctDNA after surgery was predictive of recurrence, suggesting early postoperative time points could be feasibly used for determining minimal residual disease. However, larger studies need to be performed to better understand the precise kinetics of ctDNA clearance across different cancer types as well as to determine optimal postoperative time points.
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Affiliation(s)
- Vasileios Efthymiou
- Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA
| | - Natalia Queenan
- Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA
| | - Markus Haas
- Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA
| | - Saskia Naegele
- Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA
| | - Deborah Goss
- Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA
| | - Daniel L Faden
- Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Toledo B, Deiana C, Scianò F, Brandi G, Marchal JA, Perán M, Giovannetti E. Treatment resistance in pancreatic and biliary tract cancer: molecular and clinical pharmacology perspectives. Expert Rev Clin Pharmacol 2024; 17:323-347. [PMID: 38413373 DOI: 10.1080/17512433.2024.2319340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 02/12/2024] [Indexed: 02/29/2024]
Abstract
INTRODUCTION Treatment resistance poses a significant obstacle in oncology, especially in biliary tract cancer (BTC) and pancreatic cancer (PC). Current therapeutic options include chemotherapy, targeted therapy, and immunotherapy. Resistance to these treatments may arise due to diverse molecular mechanisms, such as genetic and epigenetic modifications, altered drug metabolism and efflux, and changes in the tumor microenvironment. Identifying and overcoming these mechanisms is a major focus of research: strategies being explored include combination therapies, modulation of the tumor microenvironment, and personalized approaches. AREAS COVERED We provide a current overview and discussion of the most relevant mechanisms of resistance to chemotherapy, target therapy, and immunotherapy in both BTC and PC. Furthermore, we compare the different strategies that are being implemented to overcome these obstacles. EXPERT OPINION So far there is no unified theory on drug resistance and progress is limited. To overcome this issue, individualized patient approaches, possibly through liquid biopsies or single-cell transcriptome studies, are suggested, along with the potential use of artificial intelligence, to guide effective treatment strategies. Furthermore, we provide insights into what we consider the most promising areas of research, and we speculate on the future of managing treatment resistance to improve patient outcomes.
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Affiliation(s)
- Belén Toledo
- Department of Health Sciences, University of Jaén, Jaén, Spain
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, The Netherlands
| | - Chiara Deiana
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Fabio Scianò
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, The Netherlands
- Lumobiotics GmbH, Karlsruhe, Germany
| | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Juan Antonio Marchal
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Sanitaria ibs. GRANADA, Hospitales Universitarios de Granada-Universidad de Granada, Granada, Spain
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, Spain
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, Spain
| | - Macarena Perán
- Department of Health Sciences, University of Jaén, Jaén, Spain
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, Spain
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, Pisa, Italy
- Cancer Pharmacology Lab, Associazione Italiana per la Ricerca sul Cancro (AIRC) Start-Up Unit, Fondazione Pisana per la Scienza, University of Pisa, Pisa, Italy
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Wong J, Muralidhar R, Wang L, Huang CC. Epigenetic modifications of cfDNA in liquid biopsy for the cancer care continuum. Biomed J 2024; 48:100718. [PMID: 38522508 PMCID: PMC11745953 DOI: 10.1016/j.bj.2024.100718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 02/28/2024] [Accepted: 03/14/2024] [Indexed: 03/26/2024] Open
Abstract
This review provides a comprehensive overview of the latest advancements in the clinical utility of liquid biopsy, with a particular focus on epigenetic approaches aimed at overcoming challenges in cancer diagnosis and treatment. It begins by elucidating key epigenetic terms, including methylomics, fragmentomics, and nucleosomics. The review progresses to discuss methods for analyzing circulating cell-free DNA (cfDNA) and highlights recent studies showcasing the clinical relevance of epigenetic modifications in areas such as diagnosis, drug treatment response, minimal residual disease (MRD) detection, and prognosis prediction. While acknowledging hurdles like the complexity of interpreting epigenetic data and the absence of standardization, the review charts a path forward. It advocates for the integration of multi-omic data through machine learning algorithms to refine predictive models and stresses the importance of collaboration among clinicians, researchers, and data scientists. Such cooperative efforts are essential to fully leverage the potential of epigenetic features in clinical practice.
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Affiliation(s)
- Jodie Wong
- Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Rohit Muralidhar
- Nova Southeastern University, Kiran C. Patel College of Osteopathic Medicine, Davie, FL, USA
| | - Liang Wang
- Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
| | - Chiang-Ching Huang
- Zilber College of Public Health, University of Wisconsin, Milwaukee, WI, USA.
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Ohara K, Rendeiro AF, Bhinder B, Eng KW, Ravichandran H, Nguyen D, Pisapia D, Vosoughi A, Fernandez E, Shohdy KS, Manohar J, Beg S, Wilkes D, Robinson BD, Khani F, Bareja R, Tagawa ST, Ouseph MM, Sboner A, Elemento O, Faltas BM, Mosquera JM. The evolution of metastatic upper tract urothelial carcinoma through genomic-transcriptomic and single-cell protein markers analysis. Nat Commun 2024; 15:2009. [PMID: 38499531 PMCID: PMC10948878 DOI: 10.1038/s41467-024-46320-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 02/22/2024] [Indexed: 03/20/2024] Open
Abstract
The molecular characteristics of metastatic upper tract urothelial carcinoma (UTUC) are not well understood, and there is a lack of knowledge regarding the genomic and transcriptomic differences between primary and metastatic UTUC. To address these gaps, we integrate whole-exome sequencing, RNA sequencing, and Imaging Mass Cytometry using lanthanide metal-conjugated antibodies of 44 tumor samples from 28 patients with high-grade primary and metastatic UTUC. We perform a spatially-resolved single-cell analysis of cancer, immune, and stromal cells to understand the evolution of primary to metastatic UTUC. We discover that actionable genomic alterations are frequently discordant between primary and metastatic UTUC tumors in the same patient. In contrast, molecular subtype membership and immune depletion signature are stable across primary and matched metastatic UTUC. Molecular and immune subtypes are consistent between bulk RNA-sequencing and mass cytometry of protein markers from 340,798 single cells. Molecular subtypes at the single-cell level are highly conserved between primary and metastatic UTUC tumors within the same patient.
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Affiliation(s)
- Kentaro Ohara
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - André Figueiredo Rendeiro
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
- Department of Physiology and Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
- Institute for Computational Biomedicine, Weill Cornell Medicine, 1305 York Avenue, New York, NY, 10021, USA
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT 25.3, 1090, Vienna, Austria
| | - Bhavneet Bhinder
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
- Department of Physiology and Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
- Institute for Computational Biomedicine, Weill Cornell Medicine, 1305 York Avenue, New York, NY, 10021, USA
| | - Kenneth Wha Eng
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
- Institute for Computational Biomedicine, Weill Cornell Medicine, 1305 York Avenue, New York, NY, 10021, USA
| | - Hiranmayi Ravichandran
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Duy Nguyen
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - David Pisapia
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Aram Vosoughi
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Evan Fernandez
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
- Institute for Computational Biomedicine, Weill Cornell Medicine, 1305 York Avenue, New York, NY, 10021, USA
| | - Kyrillus S Shohdy
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Jyothi Manohar
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Shaham Beg
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - David Wilkes
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Brian D Robinson
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Francesca Khani
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Rohan Bareja
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
- Department of Physiology and Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
- Institute for Computational Biomedicine, Weill Cornell Medicine, 1305 York Avenue, New York, NY, 10021, USA
| | - Scott T Tagawa
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, 10065, USA
- Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, 10065, USA
| | - Madhu M Ouseph
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Andrea Sboner
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
- Institute for Computational Biomedicine, Weill Cornell Medicine, 1305 York Avenue, New York, NY, 10021, USA
| | - Olivier Elemento
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA
- Department of Physiology and Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA
- Institute for Computational Biomedicine, Weill Cornell Medicine, 1305 York Avenue, New York, NY, 10021, USA
- Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, 10065, USA
| | - Bishoy M Faltas
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA.
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, 10065, USA.
- Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, 10065, USA.
- Departments of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, 10065, USA.
| | - Juan Miguel Mosquera
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA.
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