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Routman DM, Van Abel KM, Price KA, Moore EJ, Patel SH, Hinni ML, Fruth B, Foster NR, Yin LX, Neben-Wittich M, Garces YI, McGee LA, Lester SC, Gamez ME, Rwigema JCM, Holtzman AL, Price DL, Janus JR, Kasperbauer JL, Chintakuntlawar AV, Garcia JJ, Foote RL, Ma DJ. ctDNA and Recurrence Risk for Adjuvant De-Escalation in HPV-Positive Oropharyngeal Carcinoma: A Secondary Analysis of the DART Phase 3 Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg 2025:2834560. [PMID: 40402484 PMCID: PMC12100506 DOI: 10.1001/jamaoto.2025.0903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 03/30/2025] [Indexed: 05/23/2025]
Abstract
Importance The De-escalated Adjuvant Radiation Therapy (DART) phase 3 randomized clinical trial (RCT) showed that in patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma, postoperative minimal residual disease (MRD), detected through circulating tumor HPV DNA (ctHPVDNA), was associated with a higher risk of disease progression. When considered along with pathologic factors, postoperative ctHPVDNA assessment may improve patient selection for adjuvant treatment de-escalation; however, more data are needed to demonstrate how it may be used in personalizing treatment intensity. Objective To determine the association of postoperative MRD status with progression-free survival (PFS) after surgery for HPV-associated oropharyngeal squamous cell carcinoma. Design, Setting, and Participants This was a secondary analysis of the DART RCT, which was conducted from October 2016 to August 2020 in multiple sites in the US. Participants from the de-escalated adjuvant radiation therapy group and the standard of care group with available blood specimen data were included. Reports from 3-month posttreatment surveillance visits were used to assess associations and outcomes. Data analyses were performed from March 2023 to March of 2025. Interventions The DART group received 30 to 36 Gy of radiation therapy in 1.5 to 1.8 Gy twice daily, plus docetaxel, 15 mg/m2, on days 1 and 8. The standard of care group received 60 Gy with or without weekly cisplatin, 40 mg/m2. Main Outcome and Measure PFS. Results The analysis included 140 patients (mean [SD] age, 59.1 [8.4] years; 12 [8.6%] females and 128 [91.4%] males; 97 [69.3%] with no smoking history); characteristics were similar to the overall DART RCT population. Of these, 17 patients (12.1%) had postoperative MRD (13 of 96 [13.5%] receiving DART and 4 of 44 [9.1%] receiving standard of care). For all patients, postoperative MRD positivity was strongly associated with worsened PFS at 24 months (MRD positivity, 69.5%; MRD negativity, 95.9%; hazard ratio [HR], 0.19; 95% CI, 0.06-0.59). MRD positivity was associated with PFS when evaluating only those patients in the DART group, where 24-month PFS was 68.4% compared to 92.6% for MRD-negative patients (HR, 0.28; 95% CI, 0.08-0.93). Three months after completion of all treatment, 8 of 117 patients (6.8%) had detectable ctHPVDNA, whereas 109 of 117 (93.2%) did not, and detection was highly associated with PFS (HR, 20.48; 95% CI, 6.91-60.67). Conclusions and Relevance This secondary analysis of the DART RCT found that patients with detectable ctHPVDNA after surgery had a higher risk of disease progression. When added to the pathologic factors considered, ctHPVDNA assessment may improve selection of patients for treatment de-escalation. In addition, the 3-month posttreatment time point, early in surveillance, may identify a sizable portion of patients with progression and may guide intervention and surveillance after surgery for HPV-associated oropharyngeal squamous cell carcinoma. Trial Registration ClinicalTrials.gov Identifier: NCT02908477.
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Affiliation(s)
- David M. Routman
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Kathryn M. Van Abel
- Department of Otolaryngology, Head and Neck Surgery, Mayo Clinic, Rochester, Minnesota
| | | | - Eric J. Moore
- Department of Otolaryngology, Head and Neck Surgery, Mayo Clinic, Rochester, Minnesota
| | - Samir H. Patel
- Department of Radiation Oncology, Mayo Clinic, Phoenix, Arizona
| | | | - Briant Fruth
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Nathan R. Foster
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Linda X. Yin
- Department of Otolaryngology, Head and Neck Surgery, Mayo Clinic, Rochester, Minnesota
| | | | | | - Lisa A. McGee
- Department of Radiation Oncology, Mayo Clinic, Phoenix, Arizona
| | - Scott C. Lester
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | | | | | - Adam L. Holtzman
- Department of Radiation Oncology, Mayo Clinic, Jacksonville, Florida
| | - Daniel L. Price
- Department of Otolaryngology, Head and Neck Surgery, Mayo Clinic, Rochester, Minnesota
| | - Jeffrey R. Janus
- Department of Otolaryngology, Head and Neck Surgery, Mayo Clinic, Jacksonville, Florida
| | - Jan L. Kasperbauer
- Department of Otolaryngology, Head and Neck Surgery, Mayo Clinic, Rochester, Minnesota
| | | | - Joaquin J. Garcia
- Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, Minnesota
| | - Robert L. Foote
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Daniel J. Ma
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
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Mannucci A, Goel A. Stool and blood biomarkers for colorectal cancer management: an update on screening and disease monitoring. Mol Cancer 2024; 23:259. [PMID: 39558327 PMCID: PMC11575410 DOI: 10.1186/s12943-024-02174-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: 07/07/2024] [Accepted: 11/07/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND Biomarkers have revolutionized the management of colorectal cancer (CRC), facilitating early detection, prevention, personalized treatment, and minimal residual disease (MRD) monitoring. This review explores current CRC screening strategies and emerging biomarker applications. MAIN BODY We summarize the landscape of non-invasive CRC screening and MRD detection strategies, discuss the limitations of the current approaches, and highlight the promising potential of novel biomarker solutions. The fecal immunochemical test remained the cornerstone of CRC screening, but its sensitivity has been improved by assays that combined its performance with other stool analytes. However, their sensitivity for advanced adenomas and the patient compliance both remain suboptimal. Blood-based tests promise to increase compliance but require further refinement to compete with stool-based biomarker tests. The ideal scenario involves leveraging blood tests to increase screening participation, and simultaneously promote stool- and endoscopy-based screening among those who are compliant. Once solely reliant on upfront surgery followed by stage and pathology-driven adjuvant chemotherapy, the treatment of stage II and III colon cancer has undergone a revolutionary transformation with the advent of MRD testing after surgery. A decade ago, the concept of using a post-surgical test instead of stage and pathology to determine the need for adjuvant chemotherapy was disruptive. Today, a blood test may be more informative of the need for chemotherapy than the stage at diagnosis. CONCLUSION Biomarker research is not just improving, but bringing a transformative change to CRC clinical management. Early detection is not just getting better, but improving thanks to a multi-modality approach, and personalized treatment plans are not just becoming a reality, but a promising future with MRD testing.
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Affiliation(s)
- Alessandro Mannucci
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute at City of Hope, Monrovia, CA, USA
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Hospital, Milan, Italy
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute at City of Hope, Monrovia, CA, USA.
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
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Lemaitre L, Adeniji N, Suresh A, Reguram R, Zhang J, Park J, Reddy A, Trevino AE, Mayer AT, Deutzmann A, Hansen AS, Tong L, Arjunan V, Kambham N, Visser BC, Dua MM, Bonham CA, Kothary N, D'Angio HB, Preska R, Rosen Y, Zou J, Charu V, Felsher DW, Dhanasekaran R. Spatial analysis reveals targetable macrophage-mediated mechanisms of immune evasion in hepatocellular carcinoma minimal residual disease. NATURE CANCER 2024; 5:1534-1556. [PMID: 39304772 DOI: 10.1038/s43018-024-00828-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 08/14/2024] [Indexed: 09/22/2024]
Abstract
Hepatocellular carcinoma (HCC) frequently recurs from minimal residual disease (MRD), which persists after therapy. Here, we identified mechanisms of persistence of residual tumor cells using post-chemoembolization human HCC (n = 108 patients, 1.07 million cells) and a transgenic mouse model of MRD. Through single-cell high-plex cytometric imaging, we identified a spatial neighborhood within which PD-L1 + M2-like macrophages interact with stem-like tumor cells, correlating with CD8+ T cell exhaustion and poor survival. Further, through spatial transcriptomics of residual HCC, we showed that macrophage-derived TGFβ1 mediates the persistence of stem-like tumor cells. Last, we demonstrate that combined blockade of Pdl1 and Tgfβ excluded immunosuppressive macrophages, recruited activated CD8+ T cells and eliminated residual stem-like tumor cells in two mouse models: a transgenic model of MRD and a syngeneic orthotopic model of doxorubicin-resistant HCC. Thus, our spatial analyses reveal that PD-L1+ macrophages sustain MRD by activating the TGFβ pathway in stem-like cancer cells and targeting this interaction may prevent HCC recurrence from MRD.
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Affiliation(s)
- Lea Lemaitre
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Nia Adeniji
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Akanksha Suresh
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Reshma Reguram
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Josephine Zhang
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Jangho Park
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Amit Reddy
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | | | | | - Anja Deutzmann
- Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA, USA
| | - Aida S Hansen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Ling Tong
- Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA, USA
| | - Vinodhini Arjunan
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Neeraja Kambham
- Department of Pathology, Stanford University, Stanford, CA, USA
| | | | - Monica M Dua
- Department of Surgery, Stanford University, Stanford, CA, USA
| | - C Andrew Bonham
- Department of Surgery, Stanford University, Stanford, CA, USA
| | - Nishita Kothary
- Department of Radiology, Stanford University, Stanford, CA, USA
| | | | | | - Yanay Rosen
- Department of Biomedical Data Science and Computer Science, Stanford University, Stanford, CA, USA
| | - James Zou
- Department of Biomedical Data Science and Computer Science, Stanford University, Stanford, CA, USA
| | - Vivek Charu
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Dean W Felsher
- Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA, USA.
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Abstract
The new generation of cancer early detection tests holds remarkable promise for revolutionizing and changing the paradigm of cancer early detection. Dozens of cancer early detection tests are being developed and evaluated. Some are already commercialized and available for use, most as a complement to and not in place of existing recommended cancer screening tests. This review evaluates existing single- and multi-cancer early detection tests (MCEDs), discussing their performance characteristics including sensitivity, specificity, positive and negative predictive values, and accuracy. It also critically looks at the potential harms that could result from these tests, including false positive and negative results, the risk of overdiagnosis and overtreatment, psychological and economic harms, and the risk of widening cancer inequities. We also review the large-scale, population-based studies that are being launched in the United States and United Kingdom to determine the impact of MCEDs on clinically relevant outcomes and implications for current practice.
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Affiliation(s)
- Carmen E Guerra
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA;
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Leonard David Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Prateek V Sharma
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA;
| | - Brenda S Castillo
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA;
- Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA;
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Fan W, Xia Z, Chen R, Lin D, Li F, Zheng Y, Luo J, Xiong Y, Yu P, Gao W, Gong Y, Zhang F, Zhang S, Li L. Circulating tumor DNA analysis predicts recurrence and avoids unnecessary adjuvant chemotherapy in I-IV colorectal cancer. Ther Adv Med Oncol 2024; 16:17588359231220607. [PMID: 38282662 PMCID: PMC10822076 DOI: 10.1177/17588359231220607] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 11/21/2023] [Indexed: 01/30/2024] Open
Abstract
Background Circulating tumor DNA (ctDNA) has emerged as a biomarker that can define the risk of recurrence after curative-intent surgery for patients with colorectal cancer (CRC). However, beyond the predictive power of postoperative ctDNA detection, the efficacy and potential limitations of ctDNA detection urgently need to be fully elucidated in a large cohort of CRC. Objectives To define potentially cured CRC patients through ctDNA monitoring following surgery. Design A prospective, multicenter, observational study. Methods We enrolled 309 patients with stages I-IV CRC who underwent definitive surgery. Tumor tissues were sequenced by a custom-designed next-generation sequencing panel to identify somatic mutations. Plasma was analyzed using a ctDNA-based molecular residual disease (MRD) assay which integrated tumor-genotype-informed and tumor-genotype-naïve ctDNA analysis. The turnaround time of the assay was 10-14 days. Results Postoperative ctDNA was detected in 5.4%, 13.8%, 15%, and 30% of patients with stage I, II, III, and IV disease, respectively, and in 17.5% of all longitudinal samples. Patients with positive postsurgery MRD had a higher recurrence rate than those with negative postsurgery MRD [hazard ratio (HR), 13.17; p < 0.0001], producing a sensitivity of 64.6%, a specificity of 94.8%, a positive predictive value (PPV) of 75.6%, and a negative predictive value (NPV) of 91.5%. Furthermore, patients with positive longitudinal MRD also had a significantly higher recurrence rate (HR, 14.44; p < 0.0001), with increased sensitivity (75.0%), specificity (94.9%), PPV (79.6%), and NPV (93.4%). Subgroup analyses revealed that adjuvant therapy did not confer superior survival for patients with undetectable or detectable MRD. In addition, MRD detection was less effective in identifying lung-only and peritoneal metastases. Conclusion Postoperative ctDNA status is a strong predictor of recurrence independent of stage and microsatellite instability status. Longitudinal undetectable MRD could be used to define the potentially cured population in CRC patients undergoing curative-intent surgery.
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Affiliation(s)
- Wenhua Fan
- Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zhiyuan Xia
- Department of Colorectal & Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | | | - Dagui Lin
- Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Fang Li
- Geneplus-Beijing, Beijing, China
| | - Yang Zheng
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Jiongyong Luo
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | | | | | - Wei Gao
- Geneplus-Beijing, Beijing, China
| | | | - Feiran Zhang
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, No. 57 Changping Road, Jinping District, Shantou, Guangdong 515041, China
| | - Sen Zhang
- Department of Colorectal & Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, China
| | - Liren Li
- Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China
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Büttner T, Zarbl R, Krausewitz P, Strieth S, Kristiansen G, Eckstein M, Ralser DJ, Hölzel M, Ritter M, Ellinger J, Dietrich D, Klümper N. Hypermethylated SHOX2 in circulating cell-free DNA post renal cell carcinoma surgery as TNM-independent biomarker for recurrence risk. Am J Transl Res 2024; 16:304-313. [PMID: 38322559 PMCID: PMC10839385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 12/19/2023] [Indexed: 02/08/2024]
Abstract
INTRODUCTION Adjuvant immune checkpoint inhibitor trials in renal cell carcinoma (RCC) call for improved recurrence risk stratification. Due to limitations of circulating tumor DNA (ctDNA) use in RCC, the use of hypermethylated SHOX2 gene (mSHOX2) in circulating cell-free DNA is explored as a surrogate marker for identifying high-risk patients after RCC surgery. METHODS Liquid biopsies were collected post-surgery from 45 RCC patients (mean duration 4.3 days). Real-time polymerase chain reaction was used to analyze SHOX2 methylation in circulating cell-free DNA. Patients were categorized as mSHOX2 positive or negative by cut-off. Metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) were assessed using Cox regression and Log-rank analyses (median follow-up time: 60 months). RESULTS 17 patients were mSHOX2 positive, showing unfavorable OS/CSS (Log-rank P = 0.004 and 0.02) and nearly 6-fold higher recurrence risk (hazard ratio 5.89, 95% CI 1.46-23.8). Multivariable Cox analysis confirmed mSHOX2 as an independent recurrence risk factor, disregarding TNM-based stratification. CONCLUSIONS mSHOX2 effectively identifies high-risk RCC patients post-surgery, indicating minimal residual disease. This easy to implement biomarker has potential for guiding of adjuvant therapy decisions.
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Affiliation(s)
- Thomas Büttner
- Department of Urology and Pediatric Urology, University Hospital BonnBonn, Germany
| | - Romina Zarbl
- Department of Otorhinolaryngology, University Hospital BonnBonn, Germany
| | - Philipp Krausewitz
- Department of Urology and Pediatric Urology, University Hospital BonnBonn, Germany
| | - Sebastian Strieth
- Department of Otorhinolaryngology, University Hospital BonnBonn, Germany
| | | | - Markus Eckstein
- Comprehensive Cancer Center EMN, University Hospital ErlangenErlangen, Germany
| | - Damian J Ralser
- Department of Gynaecology and Gynaecological Oncology, University Hospital BonnBonn, Germany
- Institute of Experimental Oncology, University Hospital BonnBonn, Germany
| | - Michael Hölzel
- Institute of Experimental Oncology, University Hospital BonnBonn, Germany
| | - Manuel Ritter
- Department of Urology and Pediatric Urology, University Hospital BonnBonn, Germany
| | - Jörg Ellinger
- Department of Urology and Pediatric Urology, University Hospital BonnBonn, Germany
| | - Dimo Dietrich
- Department of Otorhinolaryngology, University Hospital BonnBonn, Germany
| | - Niklas Klümper
- Department of Urology and Pediatric Urology, University Hospital BonnBonn, Germany
- Institute of Experimental Oncology, University Hospital BonnBonn, Germany
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Arfè A, Narang C, DuBois SG, Reaman G, Bourgeois FT. Clinical development of new drugs for adults and children with cancer, 2010-2020. J Natl Cancer Inst 2023; 115:917-925. [PMID: 37171887 PMCID: PMC10407707 DOI: 10.1093/jnci/djad082] [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: 10/26/2022] [Revised: 01/30/2023] [Accepted: 05/09/2023] [Indexed: 05/14/2023] Open
Abstract
BACKGROUND Many new molecular entities enter clinical development to evaluate potential therapeutic benefits for oncology patients. We characterized adult and pediatric development of the set of new molecular entities that started clinical testing in 2010-2015 worldwide. METHODS We extracted data from AdisInsight, an extensive database of global pharmaceutical development, and the FDA.gov website. We followed the cohort of new molecular entities initiating first-in-human phase I clinical trials in 2010-2015 to the end of 2020. For each new molecular entity, we determined whether it was granted US Food and Drug Administration (FDA) approval, studied in a trial open to pediatric enrollment, or stalled during development. We characterized the cumulative incidence of these endpoints using statistical methods for censored data. RESULTS The 572 new molecular entities starting first-in-human studies in 2010-2015 were studied in 6142 trials by the end of 2020. Most new molecular entities were small molecules (n = 316, 55.2%), antibodies (n = 148, 25.9%), or antibody-drug conjugates (n = 44, 7.7%). After a mean follow-up of 8.0 years, 173 new molecular entities did not advance beyond first-in-human trials, and 39 were approved by the FDA. New molecular entities had a 10.4% estimated probability (95% confidence interval = 6.6% to 14.1%) of being approved by the FDA within 10 years of first-in-human trials. After a median of 4.6 years since start of first-in-human trials, 67 (11.7%) new molecular entities were tested in trials open to pediatric patients, and 5 (0.9%) were approved for pediatric indications. CONCLUSIONS More efficient clinical development strategies are needed to evaluate new cancer therapies, especially for children, and incorporate approaches to ensure knowledge gain from investigational products that stall in development.
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Affiliation(s)
- Andrea Arfè
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Claire Narang
- Pediatric Therapeutics and Regulatory Science Initiative, Computational Health Informatics Program (CHIP), Boston Children’s Hospital, Boston, MA, USA
| | - Steven G DuBois
- Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Gregory Reaman
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Florence T Bourgeois
- Pediatric Therapeutics and Regulatory Science Initiative, Computational Health Informatics Program (CHIP), Boston Children’s Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
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Cheng L, Duan W, Guan J, Wang K, Liu Z, Wang X, Wang Z, Wu H, Chen Z, Jian F. Detection of Glioma-Related Hotspot Mutations Through Sequencing of Cerebrospinal Fluid (CSF)-Derived Circulating Tumor DNA: A Pilot Study on CSF-Based Liquid Biopsy for Primary Spinal Cord Astrocytoma. Neurospine 2023; 20:701-708. [PMID: 37401089 PMCID: PMC10323353 DOI: 10.14245/ns.2346210.105] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/05/2023] [Accepted: 05/22/2023] [Indexed: 07/05/2023] Open
Abstract
OBJECTIVE Although cerebrospinal fluid (CSF)-based liquid biopsy was proved to be practical in molecular analysis of intracranial gliomas, liquid biopsy of primary intramedullary astrocytoma was rarely reported. Given the distinct genomic profiles between primary intramedullary glioma and intracranial astrocytoma, whether the feasibility of CSF-based molecular analysis of intracranial gliomas can be replicated in primary spinal cord astrocytoma needs to be investigated. The aim of this pilot study is to evaluate the feasibility of molecular analysis of primary intramedullary astrocytoma through sequencing CSF-derived circulating tumor DNA (ctDNA). METHODS Two grade IV diffuse midline gliomas, 1 grade II, and 1 grade I astrocytoma were included. Intraoperative collection of peripheral blood and CSF samples was conducted, along with postoperative collection of matched tumor tissues. A panel covering the 1,021 most common driver genes of solid tumors was used for targeted DNA sequencing. RESULTS CSF-derived ctDNA was detected in 3 CSF samples (2 grade IV diffuse midline gliomas and 1 grade I astrocytoma), 5 mutations were found in both tumor tissues and CSF samples, while 11 mutations and 20 mutations were detected exclusively in tumor tissues and CSF samples, respectively. Importantly, hotspot genetic alterations, including H3F3A K28M, TP53, and ATRX, were identified in CSF and the average mutant allele frequency was often higher in CSF than in tumor tissues. CONCLUSION CSF-based liquid biopsy showed potential feasibility for molecular analysis of primary intramedullary astrocytoma through sequencing of ctDNA. This approach may assist in diagnosis and prognostic evaluation of this rare spinal cord tumor.
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Affiliation(s)
- Lei Cheng
- Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, Beijing, China
| | - Wanru Duan
- Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, Beijing, China
| | - Jian Guan
- Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, Beijing, China
| | - Kai Wang
- Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, Beijing, China
| | - Zhenlei Liu
- Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, Beijing, China
| | - Xingwen Wang
- Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, Beijing, China
| | - Zuowei Wang
- Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, Beijing, China
| | - Hao Wu
- Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, Beijing, China
| | - Zan Chen
- Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, Beijing, China
| | - Fengzeng Jian
- Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University, Beijing, China
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Villarreal OE, Kopetz S. EMP1 + tumor cells drive metastatic relapse. Cell Res 2023; 33:337-338. [PMID: 36646758 PMCID: PMC10156804 DOI: 10.1038/s41422-022-00769-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Affiliation(s)
- Oscar E Villarreal
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Leshchiner I, Mroz EA, Cha J, Rosebrock D, Spiro O, Bonilla-Velez J, Faquin WC, Lefranc-Torres A, Lin DT, Michaud WA, Getz G, Rocco JW. Inferring early genetic progression in cancers with unobtainable premalignant disease. NATURE CANCER 2023; 4:550-563. [PMID: 37081260 PMCID: PMC10132986 DOI: 10.1038/s43018-023-00533-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 02/24/2023] [Indexed: 04/22/2023]
Abstract
Analysis of premalignant tissue has identified the typical order of somatic events leading to invasive tumors in several cancer types. For other cancers, premalignant tissue is unobtainable, leaving genetic progression unknown. Here, we demonstrate how to infer progression from exome sequencing of primary tumors. Our computational method, PhylogicNDT, recapitulated the previous experimentally determined genetic progression of human papillomavirus-negative (HPV-) head and neck squamous cell carcinoma (HNSCC). We then evaluated HPV+ HNSCC, which lacks premalignant tissue, and uncovered its previously unknown progression, identifying early drivers. We converted relative timing estimates of driver mutations and HPV integration to years before diagnosis based on a clock-like mutational signature. We associated the timing of transitions to aneuploidy with increased intratumor genetic heterogeneity and shorter overall survival. Our approach can establish previously unknown early genetic progression of cancers with unobtainable premalignant tissue, supporting development of experimental models and methods for early detection, interception and prognostication.
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Affiliation(s)
| | - Edmund A Mroz
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, USA
| | - Justin Cha
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | | | - Oliver Spiro
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Juliana Bonilla-Velez
- Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA
| | - William C Faquin
- Department of Pathology, Massachusetts Eye and Ear, Boston, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Armida Lefranc-Torres
- Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA
| | - Derrick T Lin
- Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, USA
| | - William A Michaud
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Gad Getz
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
- Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
| | - James W Rocco
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
- The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, USA.
- The Ohio State University Comprehensive Cancer Center-James, The Ohio State University, Columbus, OH, USA.
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11
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Role of myeloid-derived suppressor cells in tumor recurrence. Cancer Metastasis Rev 2023; 42:113-142. [PMID: 36640224 PMCID: PMC9840433 DOI: 10.1007/s10555-023-10079-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 01/09/2023] [Indexed: 01/15/2023]
Abstract
The establishment of primary tumor cells in distant organs, termed metastasis, is the principal cause of cancer mortality and is a crucial therapeutic target in oncology. Thus, it is critical to establish a better understanding of metastatic progression for the future development of improved therapeutic approaches. Indeed, such development requires insight into the timing of tumor cell dissemination and seeding of distant organs resulting in occult lesions. Following dissemination of tumor cells from the primary tumor, they can reside in niches in distant organs for years or decades, following which they can emerge as an overt metastasis. This timeline of metastatic dormancy is regulated by interactions between the tumor, its microenvironment, angiogenesis, and tumor antigen-specific T-cell responses. An improved understanding of the mechanisms and interactions responsible for immune evasion and tumor cell release from dormancy would help identify and aid in the development of novel targeted therapeutics. One such mediator of dormancy is myeloid derived suppressor cells (MDSC), whose number in the peripheral blood (PB) or infiltrating tumors has been associated with cancer stage, grade, patient survival, and metastasis in a broad range of tumor pathologies. Thus, extensive studies have revealed a role for MDSCs in tumor escape from adoptive and innate immune responses, facilitating tumor progression and metastasis; however, few studies have considered their role in dormancy. We have posited that MDSCs may regulate disseminated tumor cells resulting in resurgence of senescent tumor cells. In this review, we discuss clinical studies that address mechanisms of tumor recurrence including from dormancy, the role of MDSCs in their escape from dormancy during recurrence, the development of occult metastases, and the potential for MDSC inhibition as an approach to prolong the survival of patients with advanced malignancies. We stress that assessing the impact of therapies on MDSCs versus other cellular targets is challenging within the multimodality interventions required clinically.
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12
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Blakely CM, Weder W, Bubendorf L, He J, Majem M, Shyr Y, Chaft JE. Primary endpoints to assess the efficacy of novel therapeutic approaches in epidermal growth factor receptor-mutated, surgically resectable non-small cell lung cancer: A review. Lung Cancer 2023; 177:59-72. [PMID: 36736076 DOI: 10.1016/j.lungcan.2023.01.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/20/2022] [Accepted: 01/01/2023] [Indexed: 01/04/2023]
Abstract
While the discovery of oncogenic driver mutations has personalized the metastatic non-small cell lung cancer (NSCLC) treatment landscape with effective targeted therapies, implementation of new treatments in resectable NSCLC has been limited due to the long follow-up needed for overall survival (OS). Until recently, treatment for patients with early-stage resectable NSCLC has been limited to perioperative chemotherapy, which provides modest benefits. However, the regulatory acceptance of two surrogate endpoints for OS has allowed recent approval of both adjuvant osimertinib and atezolizumab, providing patients with new treatment options to improve outcomes. In phase 3 oncology trials, OS has historically been viewed as the gold-standard efficacy measure, but disease-free survival and event-free survival (EFS) are now validated surrogate endpoints for OS in clinical trials and should be considered when mature OS data is unavailable. Another potential surrogate endpoint in the adjuvant NSCLC setting is circulating tumor DNA (ctDNA)-based minimal residual disease (MRD), although prospective validation is needed. For neoadjuvant targeted therapies, EFS, major pathologic response and ctDNA-based MRD are potential surrogate endpoints. To fully translate the success of the personalized treatment advances in the metastatic setting to earlier-stage disease, prospective validation studies of these potential surrogate endpoints that can accelerate the evaluation of drug efficacy are needed. A collaborative effort is also needed from all clinical and regulatory parties to collate surrogate endpoint data for large-scale validation. In this review we discuss the trends in surrogate endpoints used in oncology trials, with a focus on considerations for selecting appropriate primary endpoints in early-stage resectable EGFR-mutant NSCLC, an area of unmet need for novel treatment options.
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Affiliation(s)
- Collin M Blakely
- Department of Medicine and Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Walter Weder
- Department of Thoracic Surgery, University of Zurich (director Emeritus), Thoraxchirurgie, Klinik Bethanien, Zürich, Switzerland
| | - Lukas Bubendorf
- Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Switzerland
| | - Jianxing He
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Margarita Majem
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Yu Shyr
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jamie E Chaft
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY 10021, USA.
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13
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Faulkner LG, Howells LM, Pepper C, Shaw JA, Thomas AL. The utility of ctDNA in detecting minimal residual disease following curative surgery in colorectal cancer: a systematic review and meta-analysis. Br J Cancer 2023; 128:297-309. [PMID: 36347967 PMCID: PMC9902552 DOI: 10.1038/s41416-022-02017-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 09/30/2022] [Accepted: 10/04/2022] [Indexed: 11/09/2022] Open
Abstract
INTRODUCTION Colorectal cancer is the fourth most common cancer in the UK. There remains a need for improved risk stratification following curative resection. Circulating-tumour DNA (ctDNA) has gained particular interest as a cancer biomarker in recent years. We performed a systematic review to assess the utility of ctDNA in identifying minimal residual disease in colorectal cancer. METHODS Studies were included if ctDNA was measured following curative surgery and long-term outcomes were assessed. Studies were excluded if the manuscript could not be obtained from the British Library or were not available in English. RESULTS Thirty-seven studies met the inclusion criteria, involving 3002 patients. Hazard ratios (HRs) for progression-free survival (PFS) were available in 21 studies. A meta-analysis using a random effects model demonstrated poorer PFS associated with ctDNA detection at the first liquid biopsy post-surgery [HR: 6.92 CI: 4.49-10.64 p < 0.00001]. This effect was also seen in subgroup analysis by disease extent, adjuvant chemotherapy and assay type. DISCUSSION Here we demonstrate that ctDNA detection post-surgery is associated with a greater propensity to disease relapse and is an independent indicator of poor prognosis. Prior to incorporation into clinical practice, consensus around timing of measurements and assay methodology are critical. PROTOCOL REGISTRATION The protocol for this review is registered on PROSPERO (CRD42021261569).
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Affiliation(s)
- Lucy G Faulkner
- Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
| | - Lynne M Howells
- Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK
| | - Coral Pepper
- Department of Library and Information Services, University Hospitals of Leicester NHS Trust, Leicester, LE1 5WW, UK
| | - Jacqueline A Shaw
- Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK
| | - Anne L Thomas
- Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK
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14
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Sullivan BG, Lo A, Yu J, Gonda A, Dehkordi-Vakil F, Dayyani F, Senthil M. Circulating Tumor DNA is Unreliable to Detect Somatic Gene Alterations in Gastrointestinal Peritoneal Carcinomatosis. Ann Surg Oncol 2023; 30:278-284. [PMID: 35980549 PMCID: PMC9726669 DOI: 10.1245/s10434-022-12399-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 08/02/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Tumor agnostic circulating tumor DNA (ctDNA) is routinely used to guide treatment decisions in gastrointestinal (GI) cancers, especially metastatic cancers. The amount of ctDNA detected in plasma is affected by stage, tumor burden, and tumor vascularization. We hypothesized that peritoneal carcinomatosis (PC) is associated with lower ctDNA levels than other metastatic sites in GI cancers due to the plasma-peritoneal barrier. METHODS We conducted a retrospective analysis of patients with stage II-IV GI cancers treated at our institution between 2015 and 2020 with available panel-based ctDNA results (Guardant 360TM). ctDNA analysis was performed on early and pretreatment samples. We compared the reported maximum variant allele frequency (mVAF) of somatic mutations across metastatic sites. RESULTS Of the 279 patients with GI cancers (colorectal, upper GI, pancreaticobiliary), 212 had stage IV disease (PC: n = 61; visceral metastases: n = 138; other metastases: n = 13). Mean mVAF increased with increasing stages of disease (stage II: 3.6 ± 7; stage III: 6.4 ± 10; stage IV: 28.0 ± 51; p < 0.01). Among patients with stage IV disease, PC was associated with lower ctDNA levels independent of primary tumor site (PC only: 12.1%; PC+ visceral metastases: 26.8%; and visceral metastases only: 35.0%; p < 0.01). In a subset of patients (n = 27, matched pair analysis of genomic alterations (GAs) showed fewer GAs were detected in plasma compared with tissue. CONCLUSIONS PC of GI origin is associated with significantly lower ctDNA levels compared with visceral metastasis. Caution is warranted when interpreting ctDNA results from patients with PC due to lower sensitivity for detecting actionable mutations.
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Affiliation(s)
- Brittany G. Sullivan
- Division of Surgical Oncology, Department of Surgery, University of California Irvine, Orange, CA USA
| | - Angelina Lo
- Division of Surgical Oncology, Department of Surgery, University of California Irvine, Orange, CA USA
| | - Jingjing Yu
- Division of Surgical Oncology, Department of Surgery, University of California Irvine, Orange, CA USA
| | - Amber Gonda
- Division of Surgical Oncology, Department of Surgery, University of California Irvine, Orange, CA USA
| | - Farideh Dehkordi-Vakil
- Division of Surgical Oncology, Department of Surgery, University of California Irvine, Orange, CA USA
| | - Farshid Dayyani
- Division of Hematology-Medical Oncology, Department of Medicine, University of California Irvine, Orange, CA USA
| | - Maheswari Senthil
- Division of Surgical Oncology, Department of Surgery, University of California Irvine, Orange, CA USA
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15
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Grancher A, Beaussire L, Manfredi S, Le Malicot K, Dutherage M, Verdier V, Mulot C, Bouché O, Phelip JM, Levaché CB, Deguiral P, Coutant S, Sefrioui D, Emile JF, Laurent-Puig P, Bibeau F, Michel P, Sarafan-Vasseur N, Lepage C, Di Fiore F. Postoperative circulating tumor DNA detection is associated with the risk of recurrence in patients resected for a stage II colorectal cancer. Front Oncol 2022; 12:973167. [PMID: 36439476 PMCID: PMC9685416 DOI: 10.3389/fonc.2022.973167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 10/17/2022] [Indexed: 11/11/2022] Open
Abstract
Circulating tumor DNA (ctDNA) is reported to be promising in localized colorectal cancer (CRC). The present study aimed to retrospectively evaluate the impact of ctDNA in patients with a resected stage II CRC from the PROGIGE 13 trial with available paired tumor and blood samples. A group of recurrent patients were matched one-to-one with nonrecurrent patients according to sex, tumor location, treatment sequence, and blood collection timing. CtDNA was analyzed by digital PCR according to NGS of tumors. Disease-free survival (DFS) and overall survival (OS) were analyzed based on ctDNA, and the risks of recurrence and death were determined. A total of 134 patients were included, with 67 patients in each group. At least one alteration was identified in 115/134 tumors. Postoperative ctDNA was detected in 10/111 (9.0%) informative samples and was detected more frequently in the recurrent group (16.7% versus 1.8%; p = 0.02). The median DFS of ctDNA+ versus ctDNA- patients was 16.8 versus 54 months (p = 0.002), respectively, and the median OS was 51.3 versus 69.5 months (p = 0.03), respectively. CtDNA was associated with recurrence (ORa = 11.13, p = 0.03) and death (HRa = 3.15, p = 0.01). In conclusion, the presence of postoperative ctDNA is associated with both recurrence and survival in stage II CRC.
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Affiliation(s)
- Adrien Grancher
- Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine and Department of Hepatogastroenterology, Rouen, France
- *Correspondence: Adrien Grancher,
| | - Ludivine Beaussire
- Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine and Department of Hepatogastroenterology, Rouen, France
- Department of Medical Oncology, Henri Becquerel Centre, Rouen, Rouen, France
| | - Sylvain Manfredi
- Burgundy Digestive Cancer Registry, INSERM, Lipides, Nutrition, Cancers (LNC)-UMR1231, University Bourgogne Franche-Comté, Dijon, France
| | - Karine Le Malicot
- Burgundy Digestive Cancer Registry, INSERM, Lipides, Nutrition, Cancers (LNC)-UMR1231, University Bourgogne Franche-Comté, Dijon, France
| | - Marie Dutherage
- Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine and Department of Hepatogastroenterology, Rouen, France
| | - Vincent Verdier
- Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine and Department of Hepatogastroenterology, Rouen, France
| | - Claire Mulot
- Paris University, Biology Resources Center EPIGENETEC, Paris, France
| | - Olivier Bouché
- Department of Digestive Oncology, University Hospital of Reims, Reims, France
| | - Jean-Marc Phelip
- Department of Gastroenterology and Digestive Oncology, University Hospital of Saint Etienne, Saint Etienne, France
| | - Charles-Briac Levaché
- Department of Radiotherapy and Medical Oncology, Polyclinique Francheville, Périgueux, France
| | - Philippe Deguiral
- Department of Gastroenterology, St Nazaire Hospital, Saint-Nazaire, France
| | - Sophie Coutant
- Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine and Department of Hepatogastroenterology, Rouen, France
| | - David Sefrioui
- Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine and Department of Hepatogastroenterology, Rouen, France
| | - Jean-François Emile
- Department of Pathology, Hôpital Ambroise-Paré, Boulogne-Billancourt, France
| | - Pierre Laurent-Puig
- Department of Biology, Georges Pompidou Hospital, Assistance Publique des Hôpitaux de Paris (APHP), Paris, France
| | - Frédéric Bibeau
- Department of Pathology, Caen University Hospital, Caen, France
| | - Pierre Michel
- Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine and Department of Hepatogastroenterology, Rouen, France
| | - Nasrin Sarafan-Vasseur
- Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine and Department of Hepatogastroenterology, Rouen, France
| | - Côme Lepage
- Burgundy Digestive Cancer Registry, INSERM, Lipides, Nutrition, Cancers (LNC)-UMR1231, University Bourgogne Franche-Comté, Dijon, France
| | - Frederic Di Fiore
- Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine and Department of Hepatogastroenterology, Rouen, France
- Department of Medical Oncology, Henri Becquerel Centre, Rouen, Rouen, France
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16
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Ueberroth BE, Jones JC, Bekaii-Saab TS. Circulating tumor DNA (ctDNA) to evaluate minimal residual disease (MRD), treatment response, and posttreatment prognosis in pancreatic adenocarcinoma. Pancreatology 2022; 22:741-748. [PMID: 35725696 DOI: 10.1016/j.pan.2022.06.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/03/2022] [Accepted: 06/09/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND Circulating tumor DNA (ctDNA) has emerged as a blood-based test with multiple utilities in oncology. In the past few years, multiple studies of varying designs, methods, and quality have emerged which show promise for ctDNA as a tool to assess response to treatment and detect minimal residual disease (MRD) across various gastrointestinal (GI) malignancies. We aim to review the current literature for ctDNA as it pertains to assessing treatment response, MRD, prognosis, and risk of recurrence for pancreatic adenocarcinoma. METHODS PubMed was queried with a combination of terms regarding pancreatic adenocarcinoma, minimal residual disease, resection, and prognosis. All resultant articles were reviewed by the authors for appropriate fit with scope. RESULTS Fourteen articles were identified that fit with the scope of this review. CONCLUSIONS Detectable ctDNA after definitive resection, specifically mutated KRAS, correlates with shorter recurrence-free survival (RFS), overall survival (OS), and overall prognosis. Limited data also suggests ctDNA may provide a noninvasive means to assess response to chemotherapy. Whether this information is actionable in terms of altering neoadjuvant or postresection treatment regimens remains an open question requiring further study.
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Affiliation(s)
- Benjamin E Ueberroth
- Department of Internal Medicine, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA.
| | - Jeremy C Jones
- Mayo Clinic Comprehensive Cancer Center, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Tanios S Bekaii-Saab
- Mayo Clinic Comprehensive Cancer Center, 5881 E Mayo Blvd, Phoenix, AZ, 85054, USA
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17
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Ueberroth BE, Marks LA, Borad MJ, Agrwal N. Multicancer Early detection Panels (MCEDs) in the Primary Care Setting. Am J Med 2022; 135:e145-e149. [PMID: 35367445 DOI: 10.1016/j.amjmed.2022.03.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 11/01/2022]
Abstract
Multicancer early detection panels have recently become available to patients with a provider's prescription and an out-of-pocket fee. Beyond theoretical modeling, little is known about how these assays will impact primary care practices despite a high likelihood that primary care providers (PCPs) will be ordering these tests with some frequency. In particular, there are concerns about patient counseling, costs, frequency of testing, patient anxiety, and subsequent testing for a positive result. This review aims to appraise the current literature and provide a framework that PCPs can use to discuss these tests with patients and streamline their ordering, interpretation, and overall use into everyday practice.
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Affiliation(s)
- Benjamin E Ueberroth
- Department of Internal Medicine, Mayo Clinic, 13737 North 92nd Street, Scottsdale, Phoenix, AZ 85260, United States
| | | | | | - Neera Agrwal
- Department of Internal Medicine, Mayo Clinic, 13737 North 92nd Street, Scottsdale, Phoenix, AZ 85260, United States.
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18
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Fu Y, Yang Z, Hu Z, Yang Z, Pan Y, Chen J, Wang J, Hu D, Zhou Z, Xu L, Chen M, Zhang Y. Preoperative serum ctDNA predicts early hepatocellular carcinoma recurrence and response to systemic therapies. Hepatol Int 2022; 16:868-878. [PMID: 35674872 DOI: 10.1007/s12072-022-10348-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 04/24/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND Circulating tumor DNA (ctDNA) can be useful in tumor diagnosis and surveillance. However, its value in hepatocellular carcinoma (HCC) patients receiving curative resection remains unknown. Here, we aim to determine the prognostic value of ctDNA in HCC patients. METHODS A prospective cohort enrolled 258 HCC patients who underwent curative liver resection from April 1, 2019, to September 31, 2020. Blood samples were collected before surgery for the detection of ctDNA. RESULTS The number of total mutant genes in ctDNA was associated with early tumor relapse (HR = 2.2, p < 0.001). We defined a gene set consisting of APC, ARID1A, CDKN2A, FAT1, LRP1B, MAP3K1, PREX2, TERT and TP53 as high-risk genes (HRGs) associated with early recurrence. Patients were classified into low-, median- and high-risk levels based on the number of mutant genes in the HRGs. High-risk patients had worse recurrence free survival, especially single-tumor patients (HR = 13.0, p < 0.001). The risk level and TNM stage were independently associated with tumor recurrence. A preoperative recurrence estimation nomogram based on those two factors was constructed and demonstrated good accuracy with a C index of 0.76 (95% CI 0.70-0.82). Patients preserved FAT1 or LRP1B variants but without TP53 variants had worse progression free survival for receiving lenvatinib combined with immune checkpoint inhibitors after recurrence (HR = 17.1, p < 0.001). Furthermore, RNA sequencing data revealed that ctDNA status was associated with tumor immune infiltration. CONCLUSION Preoperative serum ctDNA can be a practical noninvasive approach to predict recurrence after surgery and response to systemic therapies. ctDNA-guided HCC management should be recommended.
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Affiliation(s)
- Yizhen Fu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Zhenyun Yang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Zili Hu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Zhoutian Yang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Yangxun Pan
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Jinbin Chen
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Juncheng Wang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Dandan Hu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Zhongguo Zhou
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Li Xu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Minshan Chen
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China. .,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China.
| | - Yaojun Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China. .,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China.
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19
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Fischer LE, Stintzing S, Heinemann V, Keilholz U, Keune D, Vollbrecht C, Burmeister T, Kind A, Weiss L, Horst D, Kirchner T, Klauschen F, Jung A, Westphalen CB, Jelas I. Liquid Biopsy in Colorectal Cancer: Quo Vadis? Implementation of Liquid Biopsies in Routine Clinical Patient Care in Two German Comprehensive Cancer Centers. Front Oncol 2022; 12:870411. [PMID: 35646657 PMCID: PMC9134071 DOI: 10.3389/fonc.2022.870411] [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: 02/06/2022] [Accepted: 04/11/2022] [Indexed: 12/02/2022] Open
Abstract
Objectives The use of liquid biopsies (LB) in patients with solid malignancies enables comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) and has the potential to guide therapy stratification and support disease monitoring. To examine clinical uptake of LB in a real-world setting, LB implementation was analyzed at two German cancer centers (LMU Munich and Charité - Universitätsmedizin Berlin) between 2017 and 2021, with focus on colorectal cancer (CRC) patients. Methods In this retrospective analysis, all patients who received a LB between January 2017 and December 2021 as part of routine clinical management were included. To provide adequate context, we collected disease characteristics and technical specifications of the LB methods applied. Additionally, we examined the concordance of RAS status in tumor tissue and LB. Finally, we discuss the potential of LB as a diagnostic tool to drive personalized treatment in CRC patients and how to implement LB in clinical routine. Results In total, our cohort included 86 CRC patients and 161 LB conducted in these patients between 2017 and 2021. In 59 patients, comparison between tissue-based and liquid-based molecular diagnostics, revealed a divergence in 23 (39%) of the evaluable samples. Conclusion Our real-world data analysis indicates that the possibilities of LB are not yet exploited in everyday clinical practice. Currently, the variety of methods and lack of standardization, as well as restricted reimbursement for liquid based CGP hinder the use of LB in clinical routine. To overcome these issues, prospective clinical trials are needed to provide evidence driving the implementation of LB into the management of CRC patients and to support their implementation into clinical guidelines.
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Affiliation(s)
- Laura E Fischer
- Department of Medicine III, University Hospital, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sebastian Stintzing
- Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Partner Site Berlin, Heidelberg, Germany
| | - Volker Heinemann
- Department of Medicine III, University Hospital, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center (CCC Munich LMU), LMU University Hospital Munich, Munich, Germany
| | - Ulrich Keilholz
- German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Partner Site Berlin, Heidelberg, Germany.,Charité Comprehensive Cancer Center, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Dietmar Keune
- Charité Comprehensive Cancer Center, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Claudia Vollbrecht
- Institute of Pathology Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Thomas Burmeister
- Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Labor Berlin - Charité Vivantes, GmbH, Molekulardiagnostik - Hämatologie, Berlin, Germany
| | - Andreas Kind
- Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Lena Weiss
- Department of Medicine III, University Hospital, Munich, Germany
| | - David Horst
- German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Partner Site Berlin, Heidelberg, Germany.,Institute of Pathology Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Thomas Kirchner
- German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center (CCC Munich LMU), LMU University Hospital Munich, Munich, Germany.,Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University (LMU) Munich, München, Germany
| | - Frederick Klauschen
- German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center (CCC Munich LMU), LMU University Hospital Munich, Munich, Germany.,Institute of Pathology Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University (LMU) Munich, München, Germany
| | - Andreas Jung
- German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center (CCC Munich LMU), LMU University Hospital Munich, Munich, Germany.,Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University (LMU) Munich, München, Germany
| | - Christoph Benedikt Westphalen
- Department of Medicine III, University Hospital, Munich, Germany.,German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center (CCC Munich LMU), LMU University Hospital Munich, Munich, Germany
| | - Ivan Jelas
- Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Partner Site Berlin, Heidelberg, Germany
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20
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Bent A, Raghavan S, Dasari A, Kopetz S. The Future of ctDNA-Defined Minimal Residual Disease: Personalizing Adjuvant Therapy in Colorectal Cancer. Clin Colorectal Cancer 2022; 21:89-95. [PMID: 35450837 PMCID: PMC9149115 DOI: 10.1016/j.clcc.2022.03.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 03/17/2022] [Indexed: 12/24/2022]
Abstract
Our understanding of the diagnostic and prognostic use of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) has broadly expanded over the past few years. The utilization of ctDNA to detect minimal residual disease is currently being employed across the continuum of cancer care. The lead-time of ctDNA positivity to radiographic recurrence in stage I to III CRC is up to 9 months on average, which provides a therapeutic window for a group of high-risk patients who will ultimately recur. There are several ongoing prospective clinical trials that investigate whether ctDNA can be used as an integral biomarker to risk stratify CRC patients and guide adjuvant treatment decisions. In this review, we summarize the evidence supporting the promise of ctDNA-defined MRD in CRC and highlight the current ctDNA guided adjuvant prospective clinical trials.
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Affiliation(s)
- Alisha Bent
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
| | - Shreya Raghavan
- Department of Biomedical Engineering, Texas A&M University, College Station, TX
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
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21
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Wu M, Shen H, Wang Z, Kanu N, Chen K. Research Progress on Postoperative Minimal/Molecular Residual Disease Detection in Lung Cancer. Chronic Dis Transl Med 2022; 8:83-90. [PMID: 35774426 PMCID: PMC9215711 DOI: 10.1002/cdt3.10] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/22/2021] [Indexed: 12/05/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 10%-50% of patients experience relapse after radical surgery, which may be attributed to the persistence of minimal/molecular residual disease (MRD). Circulating tumor DNA (ctDNA), a common liquid biopsy approach, has been demonstrated to have significant clinical merit. In this study, we review the evidence supporting the use of ctDNA for MRD detection and discuss the potential clinical applications of postoperative MRD detection, including monitoring recurrence, guiding adjuvant treatment, and driving clinical trials in lung cancer. We will also discuss the problems that prevent the routine application of ctDNA MRD detection. Multi-analyte methods and identification of specific genetic and molecular alterations, especially methylation, are effective detection strategies and show considerable prospects for future development. Interventional prospective studies based on ctDNA detection are needed to determine whether the application of postoperative MRD detection can improve the clinical outcomes of lung cancer patients, and the accuracy, sensitivity, specificity, and robustness of different detection methods still require optimization and refinement.
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Affiliation(s)
- Manqi Wu
- Department of Thoracic SurgeryPeking University People's Hospital, Peking UniversityBeijing100044China
| | - Haifeng Shen
- Department of Thoracic SurgeryPeking University People's Hospital, Peking UniversityBeijing100044China
| | - Ziyang Wang
- Department of Thoracic SurgeryPeking University People's Hospital, Peking UniversityBeijing100044China
| | - Nnennaya Kanu
- Cancer Research UK Lung Cancer Centre of ExcellenceUniversity College London Cancer Institute, University College London72 Huntley StLondonWC1E 6DDUK
| | - Kezhong Chen
- Department of Thoracic SurgeryPeking University People's Hospital, Peking UniversityBeijing100044China
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22
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Abstract
Purpose of Review There has been a huge development in the assessment of malignancies through liquid biopsies last years, especially for NSCLC, where its use has become part of clinical practice in some settings. We aim to summarize current evidence about minimal residual disease and its use in lung cancer. Recent Findings Recent studies using ctDNA in NSCLC but also in other types of cancer found strong correlations between the presence of ctDNA and the risk of disease progression or death after curative intent, despite current technical difficulties in performing this analysis (high sensitivity and specificity required). Summary Evaluation of MRD in NSCLC, especially through ctDNA, could be an important point in future trial designs and could permit a more “targeted” adjuvant treatment.
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23
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Makarem M, García-Pardo M, Leighl NB. Plasma-Based Genotyping in Advanced Solid Tumors: A Comprehensive Review. Cancers (Basel) 2021; 13:5299. [PMID: 34771462 PMCID: PMC8582457 DOI: 10.3390/cancers13215299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 12/25/2022] Open
Abstract
Molecular genotyping for advanced solid malignancies has transformed the clinical management of patients with metastatic disease. Treatment decisions in a growing number of tumors require knowledge of molecularly driven alterations in order to select optimal targeted therapy. Although genomic testing of tumor tissue is the gold standard for identifying targetable genomic alterations, biopsy samples are often limited or difficult to access. This has paved the way for the development of plasma-based approaches for genomic profiling. Recent advances in the detection of plasma-circulating tumor DNA (ctDNA) have enabled the integration of plasma-based molecular profiling into clinical practice as an alternative or complementary tool for genomic testing in the setting of advanced cancer, to facilitate the identification of driver mutations to guide initial treatment and diagnose resistance. Several guidelines now recommend the use of plasma where tumor tissue is limited to identify a targetable genomic alteration. Current plasma-based assays can evaluate multiple genes in comprehensive panels, and their application in advanced disease will be increasingly incorporated into standard practice. This review focuses on current and future applications of plasma ctDNA-based assays in advanced solid malignancies, while highlighting some limitations in implementing this technology into clinical practice.
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Affiliation(s)
| | | | - Natasha B. Leighl
- Princess Margaret Cancer Center, Department of Medical Oncology, Toronto, ON M5G 2C1, Canada; (M.M.); (M.G.-P.)
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24
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Postoperative Circulating Tumor DNA Can Predict High Risk Patients with Colorectal Cancer Based on Next-Generation Sequencing. Cancers (Basel) 2021; 13:cancers13164190. [PMID: 34439344 PMCID: PMC8391973 DOI: 10.3390/cancers13164190] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/16/2021] [Accepted: 08/19/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Circulating tumor DNA (ctDNA) is a minimally invasive biomarker useful for monitoring minimum residual disease, recurrence, and treatment response in colorectal cancer (CRC). We analyzed circulating tumor DNA from patients with CRC to evaluate analytical and clinical performances using next-generation sequencing (NGS). It is clear that postoperative circulating tumor DNA detection provides valuable information to determine whether a patient might at high risk of disease recurrence or have a persistent tumor lesion. The NGS assay not only showed excellent analytical performance, but also shows a state-of-art diagnostic option in patient-oriented precision medicine. Abstract The objective of this study was to characterize circulating tumor DNA (ctDNA) mutations in colorectal cancer (CRC) patients and evaluate their prognostic values during treatment. Forty-nine patients with CRC planned for operation were enrolled. A total of 115 plasma samples were collected pre-operation, post-operation, and post-chemotherapy. ctDNA analysis was performed using next-generation sequencing (NGS) including 14 genes. In 22 (44.9%) out of 49 patients, at least one mutation (40 total mutations) was detected in the initial plasma sample. The median sum of variant allele frequency was 0.74% (range: 0.10–29.57%). TP53 mutations were the most frequent (17 of 49 patients, 34.7%), followed by APC (18.4%), KRAS (12.2%), FBXW7 (8.2%), NRAS (2.0%), PIK3CA (2.0%), and SMAD4 (2.0%). After surgery, five (14.3%) out of 35 patients harbored ctDNA mutation. All five patients experienced relapse or metastasis during follow-up. It was noteworthy that all three patients with persistent ctDNA relapsed after R0 resection. After chemotherapy, ctDNA analysis was performed for 31 patients, all of which were ctDNA-negative. Analytical and clinical performances of NGS to utilize ctDNA in CRC were determined. Results revealed that postoperative ctDNA might serve as a marker for identifying risk of recurrence, thus contributing to patient-oriented treatment strategies.
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25
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Prasanna T, Yip D. Adjuvant Therapies in Colon Cancer. COLORECTAL CANCER 2021. [DOI: 10.5772/intechopen.93874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Most of the patients with localized colon cancer undergo curative resection. However, significant number of patients will recur with metastatic disease, especially those with node positive cancer. Adjuvant chemotherapy has shown to improve cure rate and survival by eradicating micrometastases. The benefit of adjuvant therapy is well established in node-positive cancers, while their role in stage II cancer is not well defined. A number of molecular markers have been identified that are prognostic and/or predictive in colon cancer. Such molecular markers, and other clinicopathological features play an important role in selection of appropriate therapy and duration of treatment. Emerging evidence for the utility of genomic profiling or detection of circulating tumor DNA (ctDNA) are promising which may further facilitate decision making in the future. This chapter reviews the evolution of adjuvant therapy for resected colon cancer, the current evidence and the factors influence the choice of therapy.
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26
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Tie J, Cohen JD, Wang Y, Christie M, Simons K, Lee M, Wong R, Kosmider S, Ananda S, McKendrick J, Lee B, Cho JH, Faragher I, Jones IT, Ptak J, Schaeffer MJ, Silliman N, Dobbyn L, Li L, Tomasetti C, Papadopoulos N, Kinzler KW, Vogelstein B, Gibbs P. Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer. JAMA Oncol 2021; 5:1710-1717. [PMID: 31621801 DOI: 10.1001/jamaoncol.2019.3616] [Citation(s) in RCA: 439] [Impact Index Per Article: 109.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Importance Adjuvant chemotherapy in patients with stage III colon cancer prevents recurrence by eradicating minimal residual disease. However, which patients remain at high risk of recurrence after completing standard adjuvant treatment cannot currently be determined. Postsurgical circulating tumor DNA (ctDNA) analysis can detect minimal residual disease and is associated with recurrence in colorectal cancers. Objective To determine whether serial postsurgical and postchemotherapy ctDNA analysis could provide a real-time indication of adjuvant therapy efficacy in stage III colon cancer. Design, Setting, and Participants This multicenter, Australian, population-based cohort biomarker study recruited 100 consecutive patients with newly diagnosed stage III colon cancer planned for 24 weeks of adjuvant chemotherapy from November 1, 2014, through May 31, 2017. Patients with another malignant neoplasm diagnosed within the last 3 years were excluded. Median duration of follow-up was 28.9 months (range, 11.6-46.4 months). Physicians were blinded to ctDNA results. Data were analyzed from December 10, 2018, through June 23, 2019. Exposures Serial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patients' tumors were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. Personalized assays were designed to quantify ctDNA. Main Outcomes and Measures Detection of ctDNA and recurrence-free interval (RFI). Results After 4 exclusions, 96 eligible patients were eligible; median patient age was 64 years (range, 26-82 years); 49 (51%) were men. At least 1 somatic mutation was identified in the tumor tissue of all 96 evaluable patients. Circulating tumor DNA was detectable in 20 of 96 (21%) postsurgical samples and was associated with inferior recurrence-free survival (hazard ratio [HR], 3.8; 95% CI, 2.4-21.0; P < .001). Circulating tumor DNA was detectable in 15 of 88 (17%) postchemotherapy samples. The estimated 3-year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR, 6.8; 95% CI, 11.0-157.0; P < .001). Postsurgical ctDNA status remained independently associated with RFI after adjusting for known clinicopathologic risk factors (HR, 7.5; 95% CI, 3.5-16.1; P < .001). Conclusions and Relevance Results suggest that ctDNA analysis after surgery is a promising prognostic marker in stage III colon cancer. Postchemotherapy ctDNA analysis may define a patient subset that remains at high risk of recurrence despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches.
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Affiliation(s)
- Jeanne Tie
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Oncology, Western Health, Melbourne, Australia.,Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
| | - Joshua D Cohen
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Yuxuan Wang
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michael Christie
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Pathology, Royal Melbourne Hospital, Melbourne, Australia
| | - Koen Simons
- Western Centre for Health, Research and Education, Western Health, Melbourne, Australia.,Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia
| | - Margaret Lee
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Oncology, Western Health, Melbourne, Australia.,Department of Medical Oncology, Eastern Health, Melbourne, Australia
| | - Rachel Wong
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Oncology, Eastern Health, Melbourne, Australia.,Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
| | - Suzanne Kosmider
- Department of Medical Oncology, Western Health, Melbourne, Australia
| | - Sumitra Ananda
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Oncology, Western Health, Melbourne, Australia.,Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
| | - Joseph McKendrick
- Department of Medical Oncology, Eastern Health, Melbourne, Australia
| | - Belinda Lee
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Jin Hee Cho
- Department of Medical Oncology, Western Health, Melbourne, Australia
| | - Ian Faragher
- Department of Medical Oncology, Western Health, Melbourne, Australia
| | - Ian T Jones
- Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia
| | - Janine Ptak
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mary J Schaeffer
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Natalie Silliman
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lisa Dobbyn
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lu Li
- Division of Biostatistics & Bioinformatics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Cristian Tomasetti
- Division of Biostatistics & Bioinformatics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Nicholas Papadopoulos
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kenneth W Kinzler
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Bert Vogelstein
- Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Peter Gibbs
- Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Oncology, Western Health, Melbourne, Australia.,Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
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27
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Parikh AR, Van Seventer EE, Siravegna G, Hartwig AV, Jaimovich A, He Y, Kanter K, Fish MG, Fosbenner KD, Miao B, Phillips S, Carmichael JH, Sharma N, Jarnagin J, Baiev I, Shah YS, Fetter IJ, Shahzade HA, Allen JN, Blaszkowsky LS, Clark JW, Dubois JS, Franses JW, Giantonio BJ, Goyal L, Klempner SJ, Nipp RD, Roeland EJ, Ryan DP, Weekes CD, Wo JY, Hong TS, Bordeianou L, Ferrone CR, Qadan M, Kunitake H, Berger D, Ricciardi R, Cusack JC, Raymond VM, Talasaz A, Boland GM, Corcoran RB. Minimal Residual Disease Detection using a Plasma-only Circulating Tumor DNA Assay in Patients with Colorectal Cancer. Clin Cancer Res 2021; 27:5586-5594. [PMID: 33926918 DOI: 10.1158/1078-0432.ccr-21-0410] [Citation(s) in RCA: 228] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/23/2021] [Accepted: 04/26/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection. EXPERIMENTAL DESIGN A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence. RESULTS Of 103 patients, 84 [stage I (9.5%), II (23.8%), III (47.6%), IV (19%)] had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (n = 39) or completion of adjuvant therapy (n = 45). In "landmark" plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred [positive predictive value (PPV), 100%; HR, 11.28 (P < 0.0001)]. Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%-36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence [HR, 1.84 (P = 0.18); PPV = 53.9%]. CONCLUSIONS Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection.
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Affiliation(s)
- Aparna R Parikh
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Emily E Van Seventer
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Giulia Siravegna
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | | | | | - Yupeng He
- Guardant Health, Inc, Redwood City, California
| | - Katie Kanter
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Madeleine G Fish
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Kathryn D Fosbenner
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Benchun Miao
- Department of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Susannah Phillips
- Department of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - John H Carmichael
- Department of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Nihaarika Sharma
- Department of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Joy Jarnagin
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Islam Baiev
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Yojan S Shah
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Isobel J Fetter
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Heather A Shahzade
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Jill N Allen
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Lawrence S Blaszkowsky
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Jeffrey W Clark
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Jon S Dubois
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Joseph W Franses
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Bruce J Giantonio
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Lipika Goyal
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Samuel J Klempner
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Ryan D Nipp
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Eric J Roeland
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - David P Ryan
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Colin D Weekes
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Jennifer Y Wo
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
| | - Liliana Bordeianou
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Cristina R Ferrone
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Motaz Qadan
- Department of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Hiroko Kunitake
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - David Berger
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Rocco Ricciardi
- Department of General and Gastrointestinal Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - James C Cusack
- Department of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | | | | | - Genevieve M Boland
- Department of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Ryan B Corcoran
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
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White MG, Tzeng CWD. ASO Author Reflections: Potential Role of Circulating Biomarkers in Resected Pancreatic Adenocarcinoma. Ann Surg Oncol 2021; 28:4623-4624. [PMID: 33507452 DOI: 10.1245/s10434-021-09611-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 01/06/2021] [Indexed: 11/18/2022]
Affiliation(s)
- Michael G White
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ching-Wei D Tzeng
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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29
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Xie H, Kim RD. ASO Author Reflections: Clinical Utility of Circulating Tumor DNA Analysis in Colorectal Cancer: Current Status. Ann Surg Oncol 2020; 27:890. [DOI: 10.1245/s10434-020-09034-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 08/09/2020] [Indexed: 11/18/2022]
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Dasari A, Morris VK, Allegra CJ, Atreya C, Benson AB, Boland P, Chung K, Copur MS, Corcoran RB, Deming DA, Dwyer A, Diehn M, Eng C, George TJ, Gollub MJ, Goodwin RA, Hamilton SR, Hechtman JF, Hochster H, Hong TS, Innocenti F, Iqbal A, Jacobs SA, Kennecke HF, Lee JJ, Lieu CH, Lenz HJ, Lindwasser OW, Montagut C, Odisio B, Ou FS, Porter L, Raghav K, Schrag D, Scott AJ, Shi Q, Strickler JH, Venook A, Yaeger R, Yothers G, You YN, Zell JA, Kopetz S. ctDNA applications and integration in colorectal cancer: an NCI Colon and Rectal-Anal Task Forces whitepaper. Nat Rev Clin Oncol 2020; 17:757-770. [PMID: 32632268 PMCID: PMC7790747 DOI: 10.1038/s41571-020-0392-0] [Citation(s) in RCA: 241] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2020] [Indexed: 02/07/2023]
Abstract
An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal-Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.
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Affiliation(s)
- Arvind Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Van K Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Chloe Atreya
- University of California at San Francisco Comprehensive Cancer Center, San Francisco, CA, USA
| | - Al B Benson
- Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA
| | - Patrick Boland
- Department of Medicine, Roswell Park Cancer Center, Buffalo, NY, USA
| | - Ki Chung
- Division of Hematology & Oncology, Medical University of South Carolina, Charleston, SC, USA
| | - Mehmet S Copur
- CHI Health St Francis Cancer Treatment Center, Grand Island, NE, USA
| | - Ryan B Corcoran
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Dustin A Deming
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Andrea Dwyer
- University of Colorado Cancer Center, Aurora, CO, USA
| | - Maximilian Diehn
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Cathy Eng
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Thomas J George
- Department of Medicine, University of Florida Health Cancer Center, Gainesville, FL, USA
| | - Marc J Gollub
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Stanley R Hamilton
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaclyn F Hechtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Howard Hochster
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MD, USA
| | - Federico Innocenti
- Center for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA
| | - Atif Iqbal
- Section of Colorectal Surgery, Division of Surgery, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Samuel A Jacobs
- National Adjuvant Surgical and Bowel Project Foundation/NRG Oncology, Pittsburgh, PA, USA
| | - Hagen F Kennecke
- Department of Oncology, Virginia Mason Cancer Institute, Seattle, WA, USA
| | - James J Lee
- Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA
| | - Christopher H Lieu
- Division of Medical Oncology, University of Colorado Cancer Center, Aurora, CO, USA
| | - Heinz-Josef Lenz
- Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - O Wolf Lindwasser
- Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Clara Montagut
- Hospital del Mar-Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Pompeu Fabra, Barcelona, Spain
| | - Bruno Odisio
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Fang-Shu Ou
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Laura Porter
- Patient Advocate, NCI Colon Task Force, Boston, MA, USA
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Deborah Schrag
- Division of Population Sciences, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Aaron J Scott
- Division of Hematology and Oncology, Banner University of Arizona Cancer Center, Tucson, AZ, USA
| | - Qian Shi
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - John H Strickler
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Alan Venook
- University of California at San Francisco Comprehensive Cancer Center, San Francisco, CA, USA
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Greg Yothers
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Y Nancy You
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jason A Zell
- Department of Epidemiology, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Kunitoh H, Tsuboi M, Wakabayashi M, Okada M, Suzuki K, Watanabe SI, Asamura H, Fukuda H, Shibata T, Kazato T, Mizutani T, Eba J. A phase III study of adjuvant chemotherapy in patients with completely resected, node-negative non–small cell lung cancer (JCOG 0707). JTCVS OPEN 2020; 4:90-102. [PMID: 36004301 PMCID: PMC9390442 DOI: 10.1016/j.xjon.2020.08.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 08/16/2020] [Accepted: 08/18/2020] [Indexed: 01/16/2023]
Abstract
Objective To evaluate efficacy of S-1 (tegafur/gimeracil/oteracil), an active novel fluoropyrimidine, as compared to UFT (tegafur/uracil) as a postoperative adjuvant therapy in patients with node-negative non–small cell lung cancer (NSCLC). Methods Eligible patients had undergone complete resection of p-stage I (T1 with tumor diameter >2 cm or T2-N0M0 by 5th edition Union for International Cancer Control TNM) NSCLC, and were randomized to receive oral UFT 250 mg/m2/day for 2 years (Arm A) or oral S-1 80 mg/m2/day for 2 weeks with a 1-week rest period, for 1 year (Arm B). The primary end point was relapse-free survival (RFS), with 80% power and a one-sided type I error of 0.05. Results From November 2008 to December 2013, 963 patients were enrolled (Arm A: 482, Arm B: 481). Toxicities (hematologic/nonhematologic) of grade 3 or more were observed in 15.9 (1.5/14.7)% in Arm A, and in 14.9 (3.6/12.1)% in Arm B, respectively. At data cut-off in December 2018, the hazard ratio for RFS was 1.06 (95% confidence interval, 0.82-1.36), showing no superiority of S-1 over UFT. The hazard ratio of overall survival (OS) was 1.10 (95% confidence interval, 0.81-1.50). The 5-year RFS/OS were 79.4%/88.8% in Arm A and 79.5%/89.7% in Arm B, respectively. The original NSCLC accounted for 58%/53%, respectively, of the Arm A/Arm B OS events. Secondary malignancies were observed in 85 (17.8%) and 84 (17.8%) individuals in Arm A and Arm B, respectively. Conclusions S-1 was not superior to UFT as postoperative adjuvant therapy in node-negative NSCLC. Future investigation should incorporate identification of high-risk populations for recurrence.
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Chan G, Chee CE. Perioperative Chemotherapy for Liver Metastasis of Colorectal Cancer. Cancers (Basel) 2020; 12:E3535. [PMID: 33256170 PMCID: PMC7760826 DOI: 10.3390/cancers12123535] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 10/28/2020] [Accepted: 11/12/2020] [Indexed: 02/07/2023] Open
Abstract
The liver is the dominant site of metastasis for patients with colorectal cancer. For those with isolated liver metastases, surgical resection with systemic therapy has led to long-term remission in as high as 80% of patients in well-selected cohorts. This review will focus on how systemic therapy should be integrated with resection of liver metastases; in particular, the use of clinical risk scores based on clinicopathological features that help with patient selection, various approaches to the treatment of micro-metastatic disease (peri-operative versus post-operative chemotherapy), as well as conversion chemotherapy for those with initially upfront unresectable disease will be discussed.
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Affiliation(s)
| | - Cheng E. Chee
- Department of Haematology-Oncology, National University Hospital Singapore, National University Cancer Institute, Singapore 119228, Singapore;
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Miyamoto Y, Hiyoshi Y, Sawayama H, Tokunaga R, Baba H. Precision medicine for adjuvant chemotherapy of resected colorectal cancer. Ann Gastroenterol Surg 2020; 4:635-645. [PMID: 33319153 PMCID: PMC7726679 DOI: 10.1002/ags3.12397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/16/2020] [Accepted: 08/05/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is the most common cancer and the second leading cause of cancer death in Japan. Surgical resection is the only curative option for localized disease. However, undetectable micrometastases remaining after curative surgery may cause disease recurrence. Adjuvant chemotherapy aims to eradicate these micrometastases to improve the cure rate. Unfortunately, few reliable prognostic and predictive markers are available that identify patients at high risk for CRC during early-stage disease. However, promising biomarkers may become available in the near future. Such biomarkers provide information for stratifying a patient's risk and for selecting the optimal treatment. Here, we provide an overview of current relevant prognostic and predictive biomarkers applicable to adjuvant treatment of early-stage CRC and focus on the future of this field.
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Affiliation(s)
- Yuji Miyamoto
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Yukiharu Hiyoshi
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Hiroshi Sawayama
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Ryuma Tokunaga
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Hideo Baba
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
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Halama N, Haberkorn U. The Unmet Needs of the Diagnosis, Staging, and Treatment of Gastrointestinal Tumors. Semin Nucl Med 2020; 50:389-398. [PMID: 32768003 DOI: 10.1053/j.semnuclmed.2020.06.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
New scientific insights in cancer biology and immunobiology have changed the clinical practice of medical oncology in recent years. The molecular stratification of solid tumors has led to improved clinical outcomes and is a key part in the diagnostic workup. Beyond mutational spectra (like Rat sarcoma [RAS] mutations or tumor mutational burden), the investigation of the immunological microenvironment has attracted more efforts. Especially as immunotherapies have changed the standard treatment for some solid tumors dramatically and have become an important part of routine oncology, also for gastrointestinal tumors. Still only a subgroup of patients benefits from immunotherapy in gastrointestinal tumors with prominent examples from colorectal, pancreatic or gastric cancer. Not only microsatellite instability as a marker for response to immunotherapy has shown its utility, there plenty of other approaches currently being investigated to better stratify and understand the microenvironment. But these insights have not translated into clinical utility. Reasons for this are limited technical capabilities for stratification and for coping with heterogeneity of tumor cells and the microenvironment as such. So the situation for gastrointestinal tumors has shown mainly progress for a subgroup of immunotherapy-receptive tumors (eg, microsatellite instability), but advances for the remaining majority have been in the area of stratification and combinatorial therapies, including approaches without chemotherapy. Molecular stratification (eg, B-Rapidly Accelerated Fibrosarcoma [BRAF] V600E mutation in colorectal cancer or NRG1 fusions in Kirsten-rat sarcoma (KRAS) Wild-Type Pancreatic Cancer) has clearly improved the possibilities for directed therapies, but there is a plethora of clinical situations where further developments are needed to improve patient care. Finding these areas and identifying the technical approach to unravel the complexities is the next decisive step. Here the recent advances are summarized and an outlook on possible diagnostic and treatment options in areas of unmet need is given with the context of new molecular imaging possibilities and cutting edge advances in nuclear medicine.
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Affiliation(s)
- Niels Halama
- German Cancer Research Center (DKFZ), Department of Translational Immunotherapy, German Cancer Research Center (DKFZ), Germany; Helmholtz-Institute for Translational Oncology Mainz (HI-TRON Mainz), Germany; Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases (NCT), Heidelberg, Germany; Institute for Immunology, University Hospital Heidelberg, University Heidelberg.
| | - Uwe Haberkorn
- Department of Nuclear Medicine, University Hospital Heidelberg, Germany; Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany
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35
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Chakrabarti S, Peterson CY, Sriram D, Mahipal A. Early stage colon cancer: Current treatment standards, evolving paradigms, and future directions. World J Gastrointest Oncol 2020; 12:808-832. [PMID: 32879661 PMCID: PMC7443846 DOI: 10.4251/wjgo.v12.i8.808] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 05/16/2020] [Accepted: 08/01/2020] [Indexed: 02/05/2023] Open
Abstract
Colon cancer continues to be one of the leading causes of mortality and morbidity throughout the world despite the availability of reliable screening tools and effective therapies. The majority of patients with colon cancer are diagnosed at an early stage (stages I to III), which provides an opportunity for cure. The current treatment paradigm of early stage colon cancer consists of surgery followed by adjuvant chemotherapy in a select group of patients, which is directed at the eradication of minimal residual disease to achieve a cure. Surgery alone is curative for the vast majority of colon cancer patients. Currently, surgery and adjuvant chemotherapy can achieve long term survival in about two-thirds of colon cancer patients with nodal involvement. Adjuvant chemotherapy is recommended for all patients with stage III colon cancer, while the benefit in stage II patients is not unequivocally established despite several large clinical trials. Contemporary research in early stage colon cancer is focused on minimally invasive surgical techniques, strategies to limit treatment-related toxicities, precise patient selection for adjuvant therapy, utilization of molecular and clinicopathologic information to personalize therapy and exploration of new therapies exploiting the evolving knowledge of tumor biology. In this review, we will discuss the current standard treatment, evolving treatment paradigms, and the emerging biomarkers, that will likely help improve patient selection and personalization of therapy leading to superior outcomes.
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Affiliation(s)
- Sakti Chakrabarti
- Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Carrie Y Peterson
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Deepika Sriram
- Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Amit Mahipal
- Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, United States
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Xie H, Kim RD. The Application of Circulating Tumor DNA in the Screening, Surveillance, and Treatment Monitoring of Colorectal Cancer. Ann Surg Oncol 2020; 28:1845-1858. [PMID: 32776184 DOI: 10.1245/s10434-020-09002-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 07/20/2020] [Indexed: 02/06/2023]
Abstract
Precision medicine with genetic profiling of tumor tissue has become an essential part of routine clinical practice in colorectal cancer. However, tissue genetic profiling suffers from clonal evolution, tumor heterogeneity, and time needed to deliver critical information for prompt clinical decision making. In contrast, liquid biopsy with plasma circulating tumor DNA provides genetic and epigenetic information from both the primary and metastatic colorectal cancer, which can potentially capture tumor heterogeneity and evolution with time and treatment. In addition, liquid biopsy with circulating tumor DNA is minimally invasive, quicker, and easily repeatable with high patient compliance to provide both qualitative and quantitative molecular information in real-time. We provide an overview on the potential clinical applications of circulating tumor DNA in the screening, surveillance, and treatment monitoring of colorectal cancer.
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Affiliation(s)
- Hao Xie
- Division of Medical Oncology, Mayo Clinic, Rochester, USA
| | - Richard D Kim
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, USA.
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Deep sequencing of circulating tumor DNA detects molecular residual disease and predicts recurrence in gastric cancer. Cell Death Dis 2020; 11:346. [PMID: 32393783 PMCID: PMC7214415 DOI: 10.1038/s41419-020-2531-z] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 12/29/2022]
Abstract
Identifying locoregional gastric cancer patients who are at high risk for relapse after resection could facilitate early intervention. By detecting molecular residual disease (MRD), circulating tumor DNA (ctDNA) has been shown to predict post-operative relapse in several cancers. Here, we aim to evaluate MRD detection by ctDNA and its association with clinical outcome in resected gastric cancer. This prospective cohort study enrolled 46 patients with stage I–III gastric cancer that underwent resection with curative intent. Sixty resected tumor samples and 296 plasma samples were obtained for targeted deep sequencing and longitudinal ctDNA profiling. ctDNA detection was correlated with clinicopathologic features and post-operative disease-free (DFS) and overall survival (OS). ctDNA was detected in 45% of treatment-naïve plasma samples. Primary tumor extent (T stage) was independently associated with pre-operative ctDNA positivity (p = 0.006). All patients with detectable ctDNA in the immediate post-operative period eventually experienced recurrence. ctDNA positivity at any time during longitudinal post-operative follow-up was associated with worse DFS and OS (HR = 14.78, 95%CI, 7.991–61.29, p < 0.0001 and HR = 7.664, 95% CI, 2.916–21.06, p = 0.002, respectively), and preceded radiographic recurrence by a median of 6 months. In locoregional gastric cancer patients treated with curative intent, these results indicate that ctDNA-detected MRD identifies patients at high risk for recurrence and can facilitate novel treatment intensification studies in the adjuvant setting to improve survival.
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Nicolini A, Rossi G, Ferrari P, Carpi A. Minimal residual disease in advanced or metastatic solid cancers: The G0-G1 state and immunotherapy are key to unwinding cancer complexity. Semin Cancer Biol 2020; 79:68-82. [PMID: 32201368 DOI: 10.1016/j.semcancer.2020.03.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 02/20/2020] [Accepted: 03/13/2020] [Indexed: 02/07/2023]
Abstract
In the last decade, a large amount of research has focused on elucidating the mechanisms that account for homing disseminated cancer cells (DCCs) from solid tumours to distant organs, which successively progress to overt metastatic disease; this is currently incurable. A better understanding of DCC behaviour is expected to allow detectable metastasis prevention by more effectively targeting 'metastatic seeds before they sprout'. As DCC biology co-evolved with that of the primary tumour, and due to the many similarities between them, the term 'niche' has been borrowed from normal adult stem cells (ASCs) to define the site of DCC metastatic colonisation. Moreover, heterogeneity, survival, protection, stemness and plasticity as well as the prolonged G0-G1 dormant state in the metastatic niche have been the main aspects of intense investigation. Consistent with these findings, in solid cancers with minimal residual disease (MRD), it has been proposed to prolong adjuvant therapy by targeting specific molecular pathway(s) involving DCC dormancy. However, so far, few disappointing clinical data have been reported. As an alternative strategy, because immune-surveillance contributes to the steady state of the DCC population and likely to the G0-G1 state of cancer cells, we have used prolonged immune-modulatory cytostatic chemotherapy, active immune stimulation with an INF-β/IL-2 sequence or drugs inhibiting myeloid-derived suppressor cell (MDSC)/Treg-mediated immune suppression. This strategy, mainly aimed at boosting the immune response, is based on recent findings suggesting the downregulation of immune escape mechanisms as well as other principal hallmarks during the G0-G1 state and/or in MRD. Preliminary clinical and/or laboratory data suggest the efficacy of this strategy in gastrointestinal and some endocrine-dependent cancers. Following this, we propose therapeutic schedules to prevent DCC activation and proliferation in solid cancers at a high risk of relapse or as maintenance therapy in metastatic patients after complete response (CR) to conventional treatment.
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Affiliation(s)
- Andrea Nicolini
- Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, Italy.
| | - Giuseppe Rossi
- National Research Council (CNR), Epidemiology and Biostatistics Unit, Institute of Clinical Physiology and G. Monasterio Foundation, Pisa, Italy
| | - Paola Ferrari
- Unit of Oncology 1, University Hospital of Pisa, Pisa, Italy
| | - Angelo Carpi
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
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Calandri M, Siravegna G, Yevich SM, Stranieri G, Gazzera C, Kopetz S, Fonio P, Gupta S, Bardelli A, Veltri A, Odisio BC. Liquid biopsy, a paradigm shift in oncology: what interventional radiologists should know. Eur Radiol 2020; 30:4496-4503. [PMID: 32193642 DOI: 10.1007/s00330-020-06700-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 01/21/2020] [Accepted: 01/31/2020] [Indexed: 02/08/2023]
Abstract
The acquisition of adequate tumor sample is required to verify primary tumor type and specific biomarkers and to assess response to therapy. Historically, invasive surgical procedures were the standard methods to acquire tumor samples until advancements in imaging and minimally invasive equipment facilitated the paradigm shift image-guided biopsy. Image-guided biopsy has improved sampling yield and minimized risk to the patient; however, there are still limitations, such as its invasive nature and its consequent limitations to longitudinal tumor monitoring. The next paradigm shift in sampling technique will need to address these issues to provide a more reliable and less invasive technique. Recently, liquid biopsy (LB) has emerged as a non-invasive alternative to tissue sampling. This technique relies on direct sampling of blood or other bodily fluids in contact with the tumor in order to collect circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and circulating RNAs-in particular microRNA (miRNAs). Clinical applications of LB involve different steps of cancer patient management including screening, detection of disease recurrence, and evaluation of acquired resistance. With any paradigm shift, old techniques are often relegated to a secondary option. Although image-guided biopsies may appear as a passive spectator on the rapid advancement of LB, the two techniques may well be codependent. Interventional radiology may be integral to directly sample the liquid surrounding or draining from the tumor. In addition, LB may help to correctly select the patients for image-guided loco-regional treatments, to determine its treatment endpoint, and to early detect recurrence. KEY POINTS: • Liquid biopsy is a novel technology with potential high impact in the management of patients undergoing image-guided procedures. • Interventional radiology procedures may increase liquid biopsy sensitivity through direct fluid sampling. • Liquid biopsy techniques may provide a venue for improving patients' selection and enhance outcomes of interventional loco-regional therapies performed by interventional radiologists.
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Affiliation(s)
- Marco Calandri
- Radiology Unit, A.O.U. San Luigi Gonzaga - Orbassano (To), Orbassano, TO, Italy.,Department of Oncology, University of Torino, Turin, Italy
| | - Giulia Siravegna
- Candiolo Cancer Institute-FPO, IRCCS, Candiolo (To), Candiolo, TO, Italy.,Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, USA
| | - Steven M Yevich
- Department of Interventional Radiology, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA
| | - Giuseppe Stranieri
- Radiology Unit, A.O.U. San Luigi Gonzaga - Orbassano (To), Orbassano, TO, Italy
| | - Carlo Gazzera
- Radiology Institute, Città della Salute e della Scienza - Torino Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA
| | - Paolo Fonio
- Radiology Institute, Città della Salute e della Scienza - Torino Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Sanjay Gupta
- Department of Interventional Radiology, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA
| | - Alberto Bardelli
- Department of Oncology, University of Torino, Turin, Italy.,Candiolo Cancer Institute-FPO, IRCCS, Candiolo (To), Candiolo, TO, Italy
| | - Andrea Veltri
- Radiology Unit, A.O.U. San Luigi Gonzaga - Orbassano (To), Orbassano, TO, Italy.,Department of Oncology, University of Torino, Turin, Italy
| | - Bruno C Odisio
- Department of Interventional Radiology, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.
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Bi F, Wang Q, Dong Q, Wang Y, Zhang L, Zhang J. Circulating tumor DNA in colorectal cancer: opportunities and challenges. Am J Transl Res 2020; 12:1044-1055. [PMID: 32269733 PMCID: PMC7137038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 03/14/2020] [Indexed: 06/11/2023]
Abstract
Tumor biopsy is the standard method for cancer diagnosis and provides an important sample for pathological assessment. With the development of precision medicine, liquid biopsies are now an important tool to detect molecular changes and tumor heterogeneity. In recent years, research related to circulating tumor DNA (ctDNA) has intensified due to its non-invasive, convenient, comprehensive, and safety characteristics. Herein, we provide a review describing the clinical applications and prospects of ctDNA in colorectal cancer (CRC) diagnosis, monitoring and prognosis.
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Affiliation(s)
- Feifei Bi
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China
| | - Qiwei Wang
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China
| | - Qian Dong
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China
| | - Yuanhe Wang
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China
| | - Liqun Zhang
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China
| | - Jingdong Zhang
- Medical Oncology Department of Gastrointestinal Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China
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41
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Álvarez-Alegret R, Rojo Todo F, Garrido P, Bellosillo B, Rodríguez-Lescure Á, Rodríguez-Peralto JL, Vera R, de Álava E, García-Campelo R, Remon J. [Liquid biopsy in oncology: A consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology]. REVISTA ESPAÑOLA DE PATOLOGÍA : PUBLICACIÓN OFICIAL DE LA SOCIEDAD ESPAÑOLA DE ANATOMÍA PATOLÓGICA Y DE LA SOCIEDAD ESPAÑOLA DE CITOLOGÍA 2020; 53:234-245. [PMID: 33012494 DOI: 10.1016/j.patol.2019.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 11/27/2019] [Accepted: 12/09/2019] [Indexed: 11/18/2022]
Abstract
The proportion of cancer patients with tumours that harbour a potentially targetable genomic alteration is increasing considerably. The diagnosis of these genomic alterations can lead to tailoring of treatment, at the onset of disease or during progression, as well as providing additional, predictive information on the efficacy of immunotherapy. However, in up to 25% of cases, the initial tissue biopsy is inadequate for precision oncology and, in many cases, tumour genomic profiling at progression is not possible due to technical limitations of obtaining new tumour tissue specimens. Efficient diagnostic alternatives are therefore required for molecular stratification, such as liquid biopsy. This technique enables the evaluation of the tumour genomic profile dynamically and as well as capturing intra-patient genomic heterogeneity. To date, there are several diagnostic techniques available for use in liquid biopsy, each with different precision and performance levels. The objective of this consensus statement of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) is to evaluate the viability and effectiveness of the different methodological approaches of liquid biopsy in cancer patients, and the potential application of this method to current clinical practice. The experts contributing to this consensus statement agree that, according to current evidence, liquid biopsy is an acceptable alternative to tumour tissue biopsy for the study of biomarkers in various clinical settings. It is therefore important to standardise pre-analytical and analytical procedures to ensure reproducibility and to generate structured and accessible clinical reports. It is essential to appoint multidisciplinary tumour molecular committees to oversee these processes and to enable the most suitable therapeutic decisions for each patient according to the genomic profile.
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Affiliation(s)
| | - Federico Rojo Todo
- Departamento de Patología, Fundación Universitaria Jiménez Díaz, CIBERONC, Madrid, España
| | - Pilar Garrido
- Universidad de Alcalá; Departamento de Oncología Médica, IRYCIS, Hospital Universitario Ramón y Cajal, CIBERONC, Madrid, España
| | - Beatriz Bellosillo
- Departamento de Patología, Hospital del Mar, CIBERONC, Barcelona, España
| | - Álvaro Rodríguez-Lescure
- Departamento de Oncología Médica, Hospital General Universitario de Elche y Vega Baja, GEICAM, Elche, España
| | | | - Ruth Vera
- Departamento de Oncología Médica, Complejo Hospitalario de Navarra, Navarra Institute for health research (IdiSNA), Pamplona, España
| | - Enrique de Álava
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, CIBERONC, Departamento de Citología e Histología Normal y Patológica, Sevilla, España
| | - Rosario García-Campelo
- Departamento de Oncología Médica, Complexo Hospitalario Universitario A Coruña, A Coruña, España
| | - Jordi Remon
- Departamento de Oncología Médica, Centro Integral Oncológico Clara Campal Barcelona (CIOCCB), HM Delfos, Barcelona, España
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42
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Burke HB, Kopetz S. Is the Patient Cured? JAMA Oncol 2019; 5:1695-1697. [PMID: 31621795 DOI: 10.1001/jamaoncol.2019.3612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Affiliation(s)
- Harry B Burke
- Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
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43
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Poole JC, Wu SF, Lu TT, Vibat CRT, Pham A, Samuelsz E, Patel M, Chen J, Daher T, Singh VM, Arnold LJ. Analytical validation of the Target Selector ctDNA platform featuring single copy detection sensitivity for clinically actionable EGFR, BRAF, and KRAS mutations. PLoS One 2019; 14:e0223112. [PMID: 31581267 PMCID: PMC6776432 DOI: 10.1371/journal.pone.0223112] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 09/15/2019] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Personalized medicine requires accurate molecular profiling for targeted therapy decisions. Insufficient tissue yield or tumor heterogeneity frequently limits the correct tissue biomarker determination. As a noninvasive complement to traditional tissue biopsies, liquid biopsies detect and track cancer driver mutations from biofluids (e.g., blood, urine). Here we present the analytical validation of Target Selector™ ctDNA assays capable of single mutant DNA copy detection. METHODS The Target Selector ctDNA assay applies a patented Switch-Blocker technology to suppress amplification of background (wild-type) WT alleles, while allowing specific amplification of very low frequency mutant alleles. In contrast to allele specific enrichment technologies like ddPCR, one Switch-Blocker inhibits amplification of a DNA target up to 15 bp in length (e.g., one Switch-Blocker covers all KRAS exon 2, codon 12 and 13 variants). Target enrichment is achieved through a quantitative PCR reaction; subsequent DNA sequencing confirms mutation identity. Analytical validation with cancer cell line DNA was conducted by three independent operators using five instruments across five days. RESULTS A total of 3086 samples were tested on EGFR, BRAF and KRAS Target Selector ctDNA assays, with EGFR WT as a reference. All assays showed >99% analytical sensitivity and specificity. Single mutant copy detection is confirmed by experimental data and theoretical estimates. In the presence of 14000 WT DNA copies, limits of detection were: EGFR Del19, 0.01%; EGFR L858R, 0.02%; EGFR T790M, 0.01%; BRAF V600E, 0.01%; KRAS G12C, 0.02%. Inter- and intra-assay analyses showed r2>0.94, suggesting consistent performance among operational variables. Healthy donor samples (100 tests) showed clinical specificity at >99%. Finally, Target Selector clinical experience data of >2200 patient samples is consistent with published tissue mutation prevalence. CONCLUSIONS Highly sensitive Target Selector ctDNA assays with single mutant copy detection and limit of detection at 0.02% or better enable accurate molecular profiling vital for disease management.
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Affiliation(s)
- Jason C. Poole
- Biocept, Inc., San Diego, California, United States of America
| | - Shan-Fu Wu
- Biocept, Inc., San Diego, California, United States of America
| | - Timothy T. Lu
- Biocept, Inc., San Diego, California, United States of America
| | | | - Anh Pham
- Biocept, Inc., San Diego, California, United States of America
| | - Errin Samuelsz
- Biocept, Inc., San Diego, California, United States of America
| | - Manisha Patel
- Biocept, Inc., San Diego, California, United States of America
| | - Jeffrey Chen
- Biocept, Inc., San Diego, California, United States of America
| | - Tony Daher
- Biocept, Inc., San Diego, California, United States of America
| | - Veena M. Singh
- Biocept, Inc., San Diego, California, United States of America
| | - Lyle J. Arnold
- Biocept, Inc., San Diego, California, United States of America
- Aegea Biotechnologies, Inc., San Diego, California, United States of America
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44
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Keller L, Pantel K. Unravelling tumour heterogeneity by single-cell profiling of circulating tumour cells. Nat Rev Cancer 2019; 19:553-567. [PMID: 31455893 DOI: 10.1038/s41568-019-0180-2] [Citation(s) in RCA: 384] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/09/2019] [Indexed: 12/17/2022]
Abstract
Single-cell technologies have contributed to unravelling tumour heterogeneity, now considered a hallmark of cancer and one of the main causes of tumour resistance to cancer therapies. Liquid biopsy (LB), defined as the detection and analysis of cells or cell products released by tumours into the blood, offers an appealing minimally invasive approach that allows the characterization and monitoring of tumour heterogeneity in individual patients. Here, we will review and discuss how circulating tumour cell (CTC) analysis at single-cell resolution provides unique insights into tumour heterogeneity that are not revealed by analysis of circulating tumour DNA (ctDNA) derived from LBs. The molecular analysis of CTCs provides complementary information to that of genomic aberrations determined using ctDNA to fully describe many different cellular components (for example, DNA, RNA, proteins and metabolites) that can influence tumour heterogeneity.
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Affiliation(s)
- Laura Keller
- Department of Tumour Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Pantel
- Department of Tumour Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
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45
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Dienstmann R, Villacampa G, Sveen A, Mason MJ, Niedzwiecki D, Nesbakken A, Moreno V, Warren RS, Lothe RA, Guinney J. Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer. Ann Oncol 2019; 30:1622-1629. [PMID: 31504112 PMCID: PMC6857614 DOI: 10.1093/annonc/mdz287] [Citation(s) in RCA: 154] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC). PATIENTS AND METHODS We carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological [ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and microenvironment cells [MicroCells: CytoLym+CAF]). RESULTS In multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata [HR=0.71 (0.6-0.9); P = 0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P = 0.04). CONCLUSIONS Our results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns.
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Affiliation(s)
- R Dienstmann
- Oncology Data Science Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain; Computational Oncology Group, Sage Bionetworks, Seattle, USA.
| | - G Villacampa
- Oncology Data Science Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - A Sveen
- Department of Molecular Oncology, Institute for Cancer Research and K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - M J Mason
- Computational Oncology Group, Sage Bionetworks, Seattle, USA
| | - D Niedzwiecki
- Department of Bioinformatics and Biostatistics, Duke University, Durham, USA
| | - A Nesbakken
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Gastrointestinal Surgery, K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - V Moreno
- Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology, Oncobell Program of IDIBELL, CIBERESP, University of Barcelona, Barcelona, Spain
| | - R S Warren
- Department of Surgery, The Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA
| | - R A Lothe
- Department of Molecular Oncology, Institute for Cancer Research and K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - J Guinney
- Computational Oncology Group, Sage Bionetworks, Seattle, USA
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Liquid biopsy in oncology: a consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology. Clin Transl Oncol 2019; 22:823-834. [PMID: 31559582 PMCID: PMC7854395 DOI: 10.1007/s12094-019-02211-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023]
Abstract
The proportion of cancer patients with tumours that harbour a potentially targetable genomic alteration is growing considerably. The diagnosis of these genomic alterations can lead to tailored treatment at the onset of disease or on progression and to obtaining additional predictive information on immunotherapy efficacy. However, in up to 25% of cases, the initial tissue biopsy is inadequate for precision oncology and, in many cases, tumour genomic profiling at progression is not possible due to technical limitations of obtaining new tumour tissue specimens. Efficient diagnostic alternatives are therefore required for molecular stratification, which includes liquid biopsy. This technique enables the evaluation of the tumour genomic profile dynamically and captures intra-patient genomic heterogeneity as well. To date, there are several diagnostic techniques available for use in liquid biopsy, each one of them with different precision and performance levels. The objective of this consensus statement of the Spanish Society of Pathology and the Spanish Society of Medical Oncology is to evaluate the viability and effectiveness of the different methodological approaches in liquid biopsy in cancer patients and the potential application of this method to current clinical practice. The experts contributing to this consensus statement agree that, according to current evidence, liquid biopsy is an acceptable alternative to tumour tissue biopsy for the study of biomarkers in various clinical settings. It is therefore important to standardise pre-analytical and analytical procedures, to ensure reproducibility and generate structured and accessible clinical reports. It is essential to appoint multidisciplinary tumour molecular boards to oversee these processes and to enable the most suitable therapeutic decisions for each patient according to the genomic profile.
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47
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Nicolini A, Ferrari P, Carpi A. Limiting research on molecular targeted therapies in advanced solid cancers: beyond a cost–effectiveness ratio analysis. Biomark Med 2019; 13:887-890. [DOI: 10.2217/bmm-2019-0216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Andrea Nicolini
- Department of Oncology, Transplantations & New Technologies in Medicine, University of Pisa, Italy
| | - Paola Ferrari
- Department of Oncology, Transplantations & New Technologies in Medicine, University of Pisa, Italy
| | - Angelo Carpi
- Department of Clinical & Experimental Medicine, University of Pisa, Italy
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