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Garcia-Recio S, Zagami P, Felsheim BM, Wheless A, Thomas K, Trimarchi R, Carey LA, Perou CM. Understanding metastasis mixed-treatment responses through genomic analyses. NPJ Breast Cancer 2025; 11:9. [PMID: 39885167 PMCID: PMC11782668 DOI: 10.1038/s41523-025-00724-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 01/19/2025] [Indexed: 02/01/2025] Open
Abstract
Early-stage and metastatic breast cancers (MBC) can exhibit genomic heterogeneity, even within the same individual. Response to therapy in metastatic breast cancer patients with multiple metastases can also be heterogeneous, with different degrees of responsiveness to the same drug(s) across metastatic sites, termed "mixed response," within the same patient. Whether this treatment response variability is influenced by factors such as intrinsic tumor characteristics of metastatic lesions and/or the microenvironment is unknown. Through genomic analysis of multiple metastases from the same patient, assayed in 6 different patients who had exhibited mixed response on imaging, we identified that higher regulatory T cells (T reg) and CDKN2A gene expression values correlate with non-response, while the KRAS gene, KRAS amplicon, and CD8T cells were associated with response in individual metastases. These genomic features may explain mixed clinical responses and provide valuable insights into intrapatient variations in treatment sensitivity.
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Affiliation(s)
- Susana Garcia-Recio
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Paola Zagami
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- University of Milan, Milan, Italy
| | - Brooke M Felsheim
- Bioinformatics and Computational Biology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Amy Wheless
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kerry Thomas
- Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Renato Trimarchi
- Diagnostic and Interventional Radiology Unit, BIOMORF Department, University of Messina, Messina, Italy
| | - Lisa A Carey
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Charles M Perou
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Xing Q, Cui Y, Liu M, Gu XL, Li XT, Xing BC, Sun YS. Preoperative CT-based morphological heterogeneity for predicting survival in patients with colorectal cancer liver metastases after surgical resection: a retrospective study. BMC Med Imaging 2024; 24:343. [PMID: 39696033 DOI: 10.1186/s12880-024-01524-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 12/09/2024] [Indexed: 12/20/2024] Open
Abstract
OBJECTIVE To explore the value of preoperative CT-based morphological heterogeneity (MH) for predicting local tumor disease-free survival (LTDFS) and progression-free survival (PFS) in patients with colorectal cancer liver metastases (CRLM). METHODS The latest CT data of 102 CRLM patients were retrospectively analyzed. The morphological score of each liver metastasis was obtained, and the morphological heterogeneity difference (MHD) was calculated. The receiver operating characteristic (ROC) curve was drawn, and the cutoff value was found. The Kaplan-Meier method was used to draw survival curves of patients with or without MH. The Cox regression analysis was used to build the model with MH and clinical characteristics for predicting PFS. RESULTS In 78 patients without MH, median PFS was 9.0 months (95% CI:6.5-11.5), while in 24 patients with MH, median PFS was 6.0 months (95% CI:4.0-8.1), indicating that MH significantly affected PFS (p = 0.001). MH affected PFS in both the chemotherapy group and the chemotherapy combined with targeted therapy group (p = 0.005, p = 0.043). MH, preoperative carcinoembryonic antigen (CEA) and chemotherapy after surgery were independent predictors for postoperative PFS in patients with CRLM. CONCLUSION Preoperative CT-based MH had good efficacy for predicting LTDFS and PFS of CRLM patients after surgical resection, regardless of preoperative treatment. MH is one of the independent predictors of PFS.
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Affiliation(s)
- Qian Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China
| | - Yong Cui
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China
| | - Ming Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China
| | - Xiao-Lei Gu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China
| | - Xiao-Ting Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China
| | - Bao-Cai Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China.
| | - Ying-Shi Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, No. 52 Fu Cheng Road, Hai Dian District, Beijing, 100142, China.
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3
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Geady C, Abbas-Aghababazadeh F, Kohan A, Schuetze S, Shultz D, Haibe-Kains B. Radiomic-based prediction of lesion-specific systemic treatment response in metastatic disease. Comput Med Imaging Graph 2024; 116:102413. [PMID: 38945043 PMCID: PMC12083477 DOI: 10.1016/j.compmedimag.2024.102413] [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: 08/11/2023] [Revised: 04/08/2024] [Accepted: 06/15/2024] [Indexed: 07/02/2024]
Abstract
Despite sharing the same histologic classification, individual tumors in multi metastatic patients may present with different characteristics and varying sensitivities to anticancer therapies. In this study, we investigate the utility of radiomic biomarkers for prediction of lesion-specific treatment resistance in multi metastatic leiomyosarcoma patients. Using a dataset of n=202 lung metastases (LM) from n=80 patients with 1648 pre-treatment computed tomography (CT) radiomics features and LM progression determined from follow-up CT, we developed a radiomic model to predict the progression of each lesion. Repeat experiments assessed the relative predictive performance across LM volume groups. Lesion-specific radiomic models indicate up to a 4.5-fold increase in predictive capacity compared with a no-skill classifier, with an area under the precision-recall curve of 0.70 for the most precise model (FDR = 0.05). Precision varied by administered drug and LM volume. The effect of LM volume was controlled by removing radiomic features at a volume-correlation coefficient threshold of 0.20. Predicting lesion-specific responses using radiomic features represents a novel strategy by which to assess treatment response that acknowledges biological diversity within metastatic subclones, which could facilitate management strategies involving selective ablation of resistant clones in the setting of systemic therapy.
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Affiliation(s)
- Caryn Geady
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Medical Biophysics, University of Toronto, Toronto, Canada
| | | | - Andres Kohan
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Scott Schuetze
- Department of Medicine, University of Michigan, Ann Arbor, MI, USA
| | - David Shultz
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Medical Biophysics, University of Toronto, Toronto, Canada; Department of Medicine, University of Michigan, Ann Arbor, MI, USA; Vector Institute for Artificial Intelligence, Toronto, Canada; Ontario Institute for Cancer Research, Toronto, Canada; Department of Computer Science, University of Toronto, Toronto, Canada; Department of Biostatistics, Dalla Lana School of Public Health, Toronto, Canada
| | - Benjamin Haibe-Kains
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Medical Biophysics, University of Toronto, Toronto, Canada; Vector Institute for Artificial Intelligence, Toronto, Canada; Ontario Institute for Cancer Research, Toronto, Canada; Department of Computer Science, University of Toronto, Toronto, Canada; Department of Biostatistics, Dalla Lana School of Public Health, Toronto, Canada.
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4
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Geady C, Abbas-Aghababazadeh F, Kohan A, Schuetze S, Shultz D, Haibe-Kains B. Radiomic-Based Prediction of Lesion-Specific Systemic Treatment Response in Metastatic Disease. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2023.09.22.23294942. [PMID: 37873411 PMCID: PMC10593058 DOI: 10.1101/2023.09.22.23294942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Despite sharing the same histologic classification, individual tumors in multi metastatic patients may present with different characteristics and varying sensitivities to anticancer therapies. In this study, we investigate the utility of radiomic biomarkers for prediction of lesion-specific treatment resistance in multi metastatic leiomyosarcoma patients. Using a dataset of n=202 lung metastases (LM) from n=80 patients with 1648 pre-treatment computed tomography (CT) radiomics features and LM progression determined from follow-up CT, we developed a radiomic model to predict the progression of each lesion. Repeat experiments assessed the relative predictive performance across LM volume groups. Lesion-specific radiomic models indicate up to a 4.5-fold increase in predictive capacity compared with a no-skill classifier, with an area under the precision-recall curve of 0.70 for the most precise model (FDR = 0.05). Precision varied by administered drug and LM volume. The effect of LM volume was controlled by removing radiomic features at a volume-correlation coefficient threshold of 0.20. Predicting lesion-specific responses using radiomic features represents a novel strategy by which to assess treatment response that acknowledges biological diversity within metastatic subclones, which could facilitate management strategies involving selective ablation of resistant clones in the setting of systemic therapy.
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Affiliation(s)
- Caryn Geady
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Medical Biophysics, University of Toronto, Toronto, Canada
| | | | - Andres Kohan
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - Scott Schuetze
- Department of Medicine, University of Michigan, Ann Arbor, MI, USA
| | - David Shultz
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Medical Biophysics, University of Toronto, Toronto, Canada
- Department of Medicine, University of Michigan, Ann Arbor, MI, USA
- Vector Institute for Artificial Intelligence, Toronto, Canada
- Ontario Institute for Cancer Research, Toronto, Canada
- Department of Computer Science, University of Toronto, Toronto, Canada
- Department of Biostatistics, Dalla Lana School of Public Health, Toronto, Canada
| | - Benjamin Haibe-Kains
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Medical Biophysics, University of Toronto, Toronto, Canada
- Vector Institute for Artificial Intelligence, Toronto, Canada
- Ontario Institute for Cancer Research, Toronto, Canada
- Department of Computer Science, University of Toronto, Toronto, Canada
- Department of Biostatistics, Dalla Lana School of Public Health, Toronto, Canada
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5
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Hobor S, Al Bakir M, Hiley CT, Skrzypski M, Frankell AM, Bakker B, Watkins TBK, Markovets A, Dry JR, Brown AP, van der Aart J, van den Bos H, Spierings D, Oukrif D, Novelli M, Chakrabarti T, Rabinowitz AH, Ait Hassou L, Litière S, Kerr DL, Tan L, Kelly G, Moore DA, Renshaw MJ, Venkatesan S, Hill W, Huebner A, Martínez-Ruiz C, Black JRM, Wu W, Angelova M, McGranahan N, Downward J, Chmielecki J, Barrett C, Litchfield K, Chew SK, Blakely CM, de Bruin EC, Foijer F, Vousden KH, Bivona TG, Hynds RE, Kanu N, Zaccaria S, Grönroos E, Swanton C. Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling. Nat Commun 2024; 15:4871. [PMID: 38871738 PMCID: PMC11176322 DOI: 10.1038/s41467-024-47606-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 03/28/2024] [Indexed: 06/15/2024] Open
Abstract
The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.
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Affiliation(s)
- Sebastijan Hobor
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - Maise Al Bakir
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - Crispin T Hiley
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK
- Department of Medical Oncology, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, NW1 2BU, UK
| | - Marcin Skrzypski
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK
- Department of Medical Oncology, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, NW1 2BU, UK
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, ul. Mariana Smoluchowskiego 17, 80-214, Gdańsk, Poland
| | - Alexander M Frankell
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK
| | - Bjorn Bakker
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713, the Netherlands
| | - Thomas B K Watkins
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | | | - Jonathan R Dry
- Late Development, Oncology R&D, AstraZeneca, Boston, MA, USA
| | - Andrew P Brown
- Late Development, Oncology R&D, AstraZeneca, Boston, MA, USA
| | | | - Hilda van den Bos
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713, the Netherlands
| | - Diana Spierings
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713, the Netherlands
| | - Dahmane Oukrif
- Research Department of Pathology, University College London Medical School, University Street, London, WC1E 6JJ, UK
| | - Marco Novelli
- Research Department of Pathology, University College London Medical School, University Street, London, WC1E 6JJ, UK
| | - Turja Chakrabarti
- Department of Medicine, University of California, San Francisco, CA, 94158, USA
| | - Adam H Rabinowitz
- Furlong Laboratory, EMBL Meyerhofstraße 1, 69117, Heidelberg, Germany
| | - Laila Ait Hassou
- European Organization for Research and Treatment of Cancer, Brussels, Belgium
| | - Saskia Litière
- Bioinformatics & Biostatistics; Francis Crick Institute, London, UK
| | - D Lucas Kerr
- Department of Medicine, University of California, San Francisco, CA, 94158, USA
| | - Lisa Tan
- Department of Medicine, University of California, San Francisco, CA, 94158, USA
| | - Gavin Kelly
- Bioinformatics & Biostatistics; Francis Crick Institute, London, UK
| | - David A Moore
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK
- Department of Cellular Pathology, University College London Hospitals, London, UK
| | - Matthew J Renshaw
- Advanced Light Microscopy, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - Subramanian Venkatesan
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - William Hill
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - Ariana Huebner
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK
- Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Carlos Martínez-Ruiz
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK
- Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - James R M Black
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK
- Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Wei Wu
- Department of Medicine, University of California, San Francisco, CA, 94158, USA
| | - Mihaela Angelova
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - Nicholas McGranahan
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK
- Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Julian Downward
- Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | | | - Carl Barrett
- Late Development, Oncology R&D, AstraZeneca, Boston, MA, USA
| | - Kevin Litchfield
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - Su Kit Chew
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK
| | - Collin M Blakely
- Department of Medicine, University of California, San Francisco, CA, 94158, USA
| | - Elza C de Bruin
- Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Floris Foijer
- European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713, the Netherlands
| | - Karen H Vousden
- p53 and Metabolism Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
| | - Trever G Bivona
- Department of Medicine, University of California, San Francisco, CA, 94158, USA
- Chan-Zuckerberg Biohub, San Francisco, USA
| | - Robert E Hynds
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK
| | - Nnennaya Kanu
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK.
| | - Simone Zaccaria
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK.
- Computational Cancer Genomics Research Group, University College London Cancer Institute, London, UK.
| | - Eva Grönroos
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
| | - Charles Swanton
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK.
- Department of Medical Oncology, University College London Hospitals, 235 Euston Rd, Fitzrovia, London, NW1 2BU, UK.
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Radomski SN, Dunworth M, West JJ, Greer JB, Johnston FM, Ewald AJ. Intra- and Interpatient Drug Response Heterogeneity Exist in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Nongynecologic Cancers. Ann Surg Oncol 2024; 31:1996-2007. [PMID: 38175427 DOI: 10.1245/s10434-023-14696-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/16/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Select patients with peritoneal metastases are treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We assayed for intra- and interpatient drug response heterogeneity through testing of patient-derived tumor organoids (PDTOs). METHODS PDTOs were generated from CRS/HIPEC patients from December 2021 to September 2022 and subjected to an in vitro HIPEC drug screen. Drug response was assessed with a cell viability assay and cleaved caspase-3 staining. RESULTS A total of 31 patients were consented for tissue collection. Viable tissue was harvested from 23, and PDTO generation was successful in 13 (56%). PDTOs were analyzed from six appendiceal, three colorectal, two small bowel, one gastric, and one adrenal tumor. Drug screen results were generated in as few as 7 days (62%), with an average time of 12 days. Most patients received mitomycin-C (MMC) intraoperatively (n = 9); however, in only three cases was this agent considered the optimal choice in vitro. Three sets of PDTOs were resistant (defined as > 50% PDTO viability) to all agents tested and two were pan-sensitive (defined as 3 or more agents with < 50% PDTO viability). In three patients, organoids were generated from multiple metastatic sites and intrapatient drug response heterogeneity was observed. CONCLUSIONS Both intra- and interpatient drug response heterogeneity exist in patients undergoing CRS/HIPEC for nongynecologic abdominal cancers. Caution must be used when interpreting patient response to chemotherapeutic agents based on a single site of testing in those with metastatic disease.
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Affiliation(s)
- Shannon N Radomski
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Matthew Dunworth
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Junior J West
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jonathan B Greer
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Fabian M Johnston
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Andrew J Ewald
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
- Giovanis Institute for Translational Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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7
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Ou FS, Ahn DH, Dixon JG, Grothey A, Lou Y, Kasi PM, Hubbard JM, Van Cutsem E, Saltz LB, Schmoll HJ, Goldberg RM, Venook AP, Hoff P, Douillard JY, Hecht JR, Hurwitz H, Punt CJA, Koopman M, Bokemeyer C, Fuchs CS, Diaz-Rubio E, Tebbutt NC, Cremolini C, Kabbinavar FF, Bekaii-Saab T, Chibaudel B, Yoshino T, Zalcberg J, Adams RA, de Gramont A, Shi Q. Evaluation of Intratumoral Response Heterogeneity in Metastatic Colorectal Cancer and Its Impact on Patient Overall Survival: Findings from 10,551 Patients in the ARCAD Database. Cancers (Basel) 2023; 15:4117. [PMID: 37627145 PMCID: PMC10452983 DOI: 10.3390/cancers15164117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/30/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). PATIENTS AND METHODS Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. RESULTS Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. CONCLUSION Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes.
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Affiliation(s)
- Fang-Shu Ou
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA
| | - Daniel H Ahn
- Division of Medical Oncology, Mayo Clinic, Phoenix, AZ 85259, USA
| | - Jesse G Dixon
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA
| | - Axel Grothey
- West Cancer Center, University of Tennessee, Memphis, TN 38104, USA
| | - Yiyue Lou
- Vertex Pharmaceuticals, Boston, MA 02210, USA
| | - Pashtoon M Kasi
- Division of Hematology and Oncology, University of Iowa, Iowa City, IA 52242, USA
| | | | - Eric Van Cutsem
- Department of Gastroenterology/Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, 3000 Leuven, Belgium
| | - Leonard B Saltz
- Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Hans-Joachim Schmoll
- Department of Internal Medicine, Clinic for Internal Medicine IV, Martin-Luther-University Halle/Saale, 06120 Halle, Germany
| | - Richard M Goldberg
- West Virginia University Cancer Institute, West Virginia University, Morgantown, WV 26506, USA
| | - Alan P Venook
- Department of Medicine, The University of California San Francisco, San Francisco, CA 94143, USA
| | - Paulo Hoff
- Department of Clinical Oncology, University of Sao Paulo, Sao Paulo 05508-010, Brazil
| | - Jean-Yves Douillard
- Department of Medical Oncology, University of Nantes Medical School, 44035 Nantes, France
| | | | - Herbert Hurwitz
- Duke Cancer Institute, Duke University, Durham, NC 27710, USA
| | - Cornelis J A Punt
- Julius Center, University Medical Centre Utrecht, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
| | - Carsten Bokemeyer
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | | | - Eduardo Diaz-Rubio
- Department of Oncology, Hospital Clínico San Carlos, 28040 Madrid, Spain
| | - Niall C Tebbutt
- Sydney Medical School, University of Sydney, Sydney, NSW 2050, Australia
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | | | | | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Institute, 92300 Levallois-Perret, France
| | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba 277-8577, Japan
| | - John Zalcberg
- School of Public Health and Preventative Medicine, Monash University, Melbourne, VIC 3004, Australia
| | - Richard A Adams
- Centre for Trials Research, Cardiff University, Cardiff CF14 4YS, UK
- Velindre Cancer Center, Velindre NHS Trust, Cardiff CF14 2TL, UK
| | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Institute, 92300 Levallois-Perret, France
| | - Qian Shi
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA
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8
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Haram M, Hansen R, Bouget D, Myhre OF, Davies CDL, Hofsli E. Treatment of Liver Metastases With Focused Ultrasound and Microbubbles in Patients With Colorectal Cancer Receiving Chemotherapy. ULTRASOUND IN MEDICINE & BIOLOGY 2023:S0301-5629(23)00171-0. [PMID: 37336691 DOI: 10.1016/j.ultrasmedbio.2023.05.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/11/2023] [Accepted: 05/22/2023] [Indexed: 06/21/2023]
Abstract
OBJECTIVE Pre-clinical trials have obtained promising results that focused ultrasound (FUS) combined with microbubbles (MBs) increases tumor uptake and the therapeutic effect of drugs. The aims of the study described here were to investigate whether FUS and MBs could improve the effect of chemotherapy in patients with liver metastases from colorectal cancer and to investigate the safety and feasibility of using FUS + MBs. METHODS We included 17 patients with liver metastases from colorectal cancer, selected two lesions in each patient's liver and randomized the lesions for, respectively, treatment with FUS + MBs or control. After chemotherapy (FOLFIRI or FOLFOXIRI), the lesions were treated with FUS (frequency = 1.67 MHz, mechanical index = 0.5, pulse repetition frequency = 0.33 Hz, 33 oscillations, duty cycle = 0.2%-0.4% and MBs (SonoVue) for 35 min). Nine boluses of MBs were injected intravenously at 3.5 min intervals. Patients were scheduled for four cycles of treatment. Changes in the size of metastases were determined from computed tomography images. RESULTS Treatment with FUS + MBs is safe at the settings used. There was considerable variation in treatment response between lesions and mixed response between lesions receiving only chemotherapy. There is a tendency toward larger-volume reduction in lesions treated with FUS + MBs compared with control lesions, but a mixed response to chemotherapy and lesion heterogeneity make it difficult to interpret the results. CONCLUSION The combination of FUS and MBs is a safe, feasible and available strategy for improving the effect of chemotherapy in cancer patients. Therapeutic effect was not demonstrated in this trial. Multicenter trials with standardized protocols should be performed.
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Affiliation(s)
- Margrete Haram
- Department of Radiology and Nuclear Medicine, St. Olav's Hospital-Trondheim University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Cancer Clinic, St. Olav's Hospital-Trondheim University Hospital, Trondheim, Norway.
| | - Rune Hansen
- Department of Health Research, SINTEF Digital, Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - David Bouget
- Department of Health Research, SINTEF Digital, Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Ola Finneng Myhre
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | | | - Eva Hofsli
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Cancer Clinic, St. Olav's Hospital-Trondheim University Hospital, Trondheim, Norway
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9
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Inchingolo R, Maino C, Cannella R, Vernuccio F, Cortese F, Dezio M, Pisani AR, Giandola T, Gatti M, Giannini V, Ippolito D, Faletti R. Radiomics in colorectal cancer patients. World J Gastroenterol 2023; 29:2888-2904. [PMID: 37274803 PMCID: PMC10237092 DOI: 10.3748/wjg.v29.i19.2888] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/07/2023] [Accepted: 04/25/2023] [Indexed: 05/16/2023] Open
Abstract
The main therapeutic options for colorectal cancer are surgical resection and adjuvant chemotherapy in non-metastatic disease. However, the evaluation of the overall adjuvant chemotherapy benefit in patients with a high risk of recurrence is challenging. Radiological images can represent a source of data that can be analyzed by using automated computer-based techniques, working on numerical information coded within Digital Imaging and Communications in Medicine files: This image numerical analysis has been named "radiomics". Radiomics allows the extraction of quantitative features from radiological images, mainly invisible to the naked eye, that can be further analyzed by artificial intelligence algorithms. Radiomics is expanding in oncology to either understand tumor biology or for the development of imaging biomarkers for diagnosis, staging, and prognosis, prediction of treatment response and diseases monitoring and surveillance. Several efforts have been made to develop radiomics signatures for colorectal cancer patient using computed tomography (CT) images with different aims: The preoperative prediction of lymph node metastasis, detecting BRAF and RAS gene mutations. Moreover, the use of delta-radiomics allows the analysis of variations of the radiomics parameters extracted from CT scans performed at different timepoints. Most published studies concerning radiomics and magnetic resonance imaging (MRI) mainly focused on the response of advanced tumors that underwent neoadjuvant therapy. Nodes status is the main determinant of adjuvant chemotherapy. Therefore, several radiomics model based on MRI, especially on T2-weighted images and ADC maps, for the preoperative prediction of nodes metastasis in rectal cancer has been developed. Current studies mostly focused on the applications of radiomics in positron emission tomography/CT for the prediction of survival after curative surgical resection and assessment of response following neoadjuvant chemoradiotherapy. Since colorectal liver metastases develop in about 25% of patients with colorectal carcinoma, the main diagnostic tasks of radiomics should be the detection of synchronous and metachronous lesions. Radiomics could be an additional tool in clinical setting, especially in identifying patients with high-risk disease. Nevertheless, radiomics has numerous shortcomings that make daily use extremely difficult. Further studies are needed to assess performance of radiomics in stratifying patients with high-risk disease.
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Affiliation(s)
- Riccardo Inchingolo
- Unit of Interventional Radiology, F. Miulli Hospital, Acquaviva delle Fonti 70021, Italy
| | - Cesare Maino
- Department of Radiology, Fondazione IRCCS San Gerardo dei Tintori, Monza 20900, Italy
| | - Roberto Cannella
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, Palermo 90127, Italy
| | - Federica Vernuccio
- Institute of Radiology, University Hospital of Padova, Padova 35128, Italy
| | - Francesco Cortese
- Unit of Interventional Radiology, F. Miulli Hospital, Acquaviva delle Fonti 70021, Italy
| | - Michele Dezio
- Unit of Interventional Radiology, F. Miulli Hospital, Acquaviva delle Fonti 70021, Italy
| | - Antonio Rosario Pisani
- Interdisciplinary Department of Medicine, Section of Nuclear Medicine, University of Bari “Aldo Moro”, Bari 70121, Italy
| | - Teresa Giandola
- Department of Radiology, Fondazione IRCCS San Gerardo dei Tintori, Monza 20900, Italy
| | - Marco Gatti
- Department of Surgical Sciences, University of Turin, Turin 10126, Italy
| | - Valentina Giannini
- Department of Surgical Sciences, University of Turin, Turin 10126, Italy
| | - Davide Ippolito
- Department of Radiology, Fondazione IRCCS San Gerardo dei Tintori, Monza 20900, Italy
| | - Riccardo Faletti
- Department of Surgical Sciences, University of Turin, Turin 10126, Italy
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10
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Beaumont H, Faye N, Iannessi A, Chamorey E, Klifa C, Hsieh C. Differences in sensitivity to new therapies between primary and metastatic breast cancer: A need to stratify the tumor response? Cancer Med 2022; 12:3112-3122. [PMID: 36098367 PMCID: PMC9939226 DOI: 10.1002/cam4.5236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 05/16/2022] [Accepted: 09/02/2022] [Indexed: 11/11/2022] Open
Abstract
OBJECTIVE We compared therapeutic response of Varlitinib + Capecitabine (VC) versus Lapatinib + Capecitabine (LC) in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer after trastuzumab therapy by assessing changes in target lesion (TL) diameter and volume per location. METHODS We retrospectively analyzed the CT data of the ASLAN001-003 study (NCT02338245). We analyzed TL size and number at each location focusing on therapeutic response from baseline to Week 12. We used TL diameter and volume to conduct an inter-arm comparison of the response according to: RECIST 1.1; stratified per TL location and considering TLs independently. Multiple pairwise intra-arm comparisons of therapeutic responses were performed. Considering TL independently, weighted models were designed by adding weighted mean TL responses grouped by location. RESULTS We evaluated 42 patients (88 TL) and 35 patients (74 TL), respectively, at baseline and Week 12. We found reductions in breast TL burden in the VC arm compared to the LC arm (p = 0.002 (diameter), p < 0.001 (volume)). Responses and TL sizes at baseline were not correlated. Explained variabilities of volume change per TL location, patient and patient:TL interaction were 36%, 10% and 4% (VC), and 13%, 1% and 23%, (LC). A test of inter-arm difference of responses yielded p = 0.07 (diameter), and p < 0.001 (volume). CONCLUSIONS The therapeutic responses differed across tumors' locations; the magnitude of the differences of responses across the tumors' locations were drug-dependent. Stratified analysis of the response by tumor location improved drug comparisons and is a powerful tool to understand TL heterogeneity.
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11
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Qi L, Zhou H, Wang Y, Jablonska E, Wang M, Su S, Jia Y, Wang R, Jiang M, Wang Y, Zhang Y, Li Q, Wang T. The role of selenoprotein P in the determining the sensitivity of cervical cancer patients to concurrent chemoradiotherapy: A metabonomics-based analysis. J Trace Elem Med Biol 2022; 73:127041. [PMID: 35905604 DOI: 10.1016/j.jtemb.2022.127041] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 07/08/2022] [Accepted: 07/15/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND The effect of selenoprotein P (SELENOP) levels on the sensitivity of cervical cancer patients to concurrent chemoradiotherapy (CCRT) has not been reported. In this study, the effects of the variations in plasma SELENOP levels on the sensitivity of cervical cancer patients to CCRT were investigated using metabonomics. METHODS Two patient groups were evaluated, i.e., the case group: 11 patients with intermediate to advanced primary squamous cervical cancer, who developed resistance against CCRT, and the sensitivity group: 11 patients who did not develop resistance were matched in a 1:1 ratio (controls). Blood samples were collected before and after CCRT, and the plasma SELENOP levels were measured by ELISA. The different metabolites present in the plasma were analyzed by UPLC-MS-MS. RESULTS SELENOP levels exhibited a significant reduction in both the resistant and sensitive groups after CCRT (F = 50.705, P < 0.001), and interaction effects between sensitivity and pre-and post-treatment on SELENOP levels were observed (F = 7.414, P = 0.013). Further, a more significant reduction in the SELENOP levels was observed in the CCRT-resistant group (mean reduction, 0.028 µg/mL; P < 0.001) than in the sensitive group (mean reduction, 0.013 µg/mL; P = 0.006). Four metabolic biomarkers, i.e., C18, C19, C20 sphingomyelin, and phosphatidylcholine 20:2/22:6, were shown to be differentially expressed between the resistant and sensitive groups pre-and post-treatment. C20 sphingomyelin levels exhibited a significant correlation with SELENOP levels (r = -0.326, P = 0.031). CONCLUSION The levels of plasma SELENOP in the CCRT-resistant group decreased significantly, suggesting that SELENOP might affect the sensitivity by modulating lipid synthesis and metabolism.
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Affiliation(s)
- Lei Qi
- Institute of Keshan Disease, Chinese Center for Endemic Disease Control, Harbin Medical University, Harbin 150081, China
| | - Huihui Zhou
- Department of Public Health, Jining Medical University, Jining 272029, China
| | - Yuanyuan Wang
- Institute of Keshan Disease, Chinese Center for Endemic Disease Control, Harbin Medical University, Harbin 150081, China
| | - Ewa Jablonska
- Department of Translational Research, Nofer Institute of Occupational Medicine, Sw. Teresy 8 Street, Lodz 91-348, Poland
| | - Mingxing Wang
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Shengqi Su
- Institute of Keshan Disease, Chinese Center for Endemic Disease Control, Harbin Medical University, Harbin 150081, China
| | - Yuehui Jia
- Institute of Keshan Disease, Chinese Center for Endemic Disease Control, Harbin Medical University, Harbin 150081, China
| | - Ruixiang Wang
- Institute of Keshan Disease, Chinese Center for Endemic Disease Control, Harbin Medical University, Harbin 150081, China
| | - Meijing Jiang
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin 150081, China
| | - Yanan Wang
- School of Public Health and Management, Binzhou Medical University, No.346 Guanhai Road, Laishan District, Yantai 264003, China
| | - Yiyi Zhang
- Yantai Center for Disease Control and Prevention, No.17 Fuhou Road, Laishan District, Yantai 264003, China
| | - Qi Li
- Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin 150081, China.
| | - Tong Wang
- Institute of Keshan Disease, Chinese Center for Endemic Disease Control, Harbin Medical University, Harbin 150081, China.
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12
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Strömberg C, Martinez de la Maza L, Fernández Moro C, Gerling M, Jorns C, Sparrelid E, Löhr J, Villard C. Prognostic impact of inter-metastatic heterogeneity of viable tumour cells in colorectal liver metastases. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2022; 48:1656-1663. [DOI: 10.1016/j.ejso.2022.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/03/2022] [Accepted: 03/08/2022] [Indexed: 11/16/2022]
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13
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Wesdorp NJ, Bolhuis K, Roor J, van Waesberghe JHTM, van Dieren S, van Amerongen MJ, Chapelle T, Dejong CHC, Engelbrecht MRW, Gerhards MF, Grunhagen D, van Gulik TM, Hermans JJ, de Jong KP, Klaase JM, Liem MSL, van Lienden KP, Molenaar IQ, Patijn GA, Rijken AM, Ruers TM, Verhoef C, de Wilt JHW, Swijnenburg RJ, Punt CJA, Huiskens J, Kazemier G. The Prognostic Value of Total Tumor Volume Response Compared With RECIST1.1 in Patients With Initially Unresectable Colorectal Liver Metastases Undergoing Systemic Treatment. ANNALS OF SURGERY OPEN 2021; 2:e103. [PMID: 37637880 PMCID: PMC10455281 DOI: 10.1097/as9.0000000000000103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/17/2021] [Indexed: 01/20/2023] Open
Abstract
Objectives Compare total tumor volume (TTV) response after systemic treatment to Response Evaluation Criteria in Solid Tumors (RECIST1.1) and assess the prognostic value of TTV change and RECIST1.1 for recurrence-free survival (RFS) in patients with colorectal liver-only metastases (CRLM). Background RECIST1.1 provides unidimensional criteria to evaluate tumor response to systemic therapy. Those criteria are accepted worldwide but are limited by interobserver variability and ignore potentially valuable information about TTV. Methods Patients with initially unresectable CRLM receiving systemic treatment from the randomized, controlled CAIRO5 trial (NCT02162563) were included. TTV response was assessed using software specifically developed together with SAS analytics. Baseline and follow-up computed tomography (CT) scans were used to calculate RECIST1.1 and TTV response to systemic therapy. Different thresholds (10%, 20%, 40%) were used to define response of TTV as no standard currently exists. RFS was assessed in a subgroup of patients with secondarily resectable CRLM after induction treatment. Results A total of 420 CT scans comprising 7820 CRLM in 210 patients were evaluated. In 30% to 50% (depending on chosen TTV threshold) of patients, discordance was observed between RECIST1.1 and TTV change. A TTV decrease of >40% was observed in 47 (22%) patients who had stable disease according to RECIST1.1. In 118 patients with secondarily resectable CRLM, RFS was shorter for patients with less than 10% TTV decrease compared with patients with more than 10% TTV decrease (P = 0.015), while RECIST1.1 was not prognostic (P = 0.821). Conclusions TTV response assessment shows prognostic potential in the evaluation of systemic therapy response in patients with CRLM.
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Affiliation(s)
- Nina J. Wesdorp
- From the Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Karen Bolhuis
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Joran Roor
- Department of Health, SAS Institute B.V., Huizen, The Netherlands
| | - Jan-Hein T. M. van Waesberghe
- Department of Radiology and Molecular Imaging, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Susan van Dieren
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Martin J. van Amerongen
- Department of Medical Imaging, Radboud University Medical Center, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Thiery Chapelle
- Department of Hepatobiliary, Transplantation, and Endocrine Surgery, Antwerp University Hospital, Antwerp, Belgium
| | - Cornelis H. C. Dejong
- Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Surgery, Universitätsklinikum Aachen, Aachen, Germany
| | - Marc R. W. Engelbrecht
- Department of Radiology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Michael F. Gerhards
- Department of Surgery, Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, The Netherlands
| | - Dirk Grunhagen
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands
| | - Thomas M. van Gulik
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - John J. Hermans
- Department of Medical Imaging, Radboud University Medical Center, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Koert P. de Jong
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Joost M. Klaase
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Mike S. L. Liem
- Department of Surgery, Medical Spectrum Twente, Enschede, The Netherlands
| | - Krijn P. van Lienden
- Department of Interventional Radiology, St Antonius Hospital, Nieuwegein, The Netherlands
| | - I. Quintus Molenaar
- Department of Surgery, Regional Academic Cancer Center Utrecht, University Medical Center Utrecht and St Antonius Hospital, Nieuwegein, The Netherlands
| | - Gijs A. Patijn
- Department of Surgery, Isala Hospital, Zwolle, The Netherlands
| | - Arjen M. Rijken
- Department of Surgery, Amphia Hospital, Breda, The Netherlands
| | - Theo M. Ruers
- Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Cornelis Verhoef
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands
| | - Johannes H. W. de Wilt
- Department of Surgery, Radboud University Medical Center, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Rutger-Jan Swijnenburg
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Cornelis J. A. Punt
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Joost Huiskens
- Department of Health, SAS Institute B.V., Huizen, The Netherlands
| | - Geert Kazemier
- From the Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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14
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Ryu WK, Kim JS, Park MH, Lee M, Kim HJ, Ryu JS, Lim JH. Heterogeneous radiological response to chemotherapy is associated with poor prognosis in advanced non-small-cell lung cancer. Thorac Cancer 2021; 12:3333-3339. [PMID: 34693646 PMCID: PMC8671901 DOI: 10.1111/1759-7714.14207] [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: 08/25/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 11/30/2022] Open
Abstract
Background A heterogeneous radiological response is frequently observed in cancer patients and could reflect tumor heterogeneity. We investigated the prognostic impact of heterogeneous radiological responses in patients with advanced non‐small‐cell lung cancer (NSCLC) who received platinum‐based chemotherapy. Methods The treatment response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria was evaluated in 212 patients with advanced NSCLC who received platinum‐based chemotherapy. Patients with partial response (PR) or stable disease (SD) were classified into “PR homo,” “PR hetero,” “SD homo,” and “SD hetero” by the presence of a heterogeneous radiological response, and survival was compared between groups. We also compared survival based on the presence of metabolic responses in lesions with heterogeneous radiological responses. Results Fifty‐two patients (24.5%) were classified as PR, 112 patients (52.8%) as SD, and 48 patients (22.7%) as progressive disease (PD). There was no significant difference in progression‐free survival (PFS) and overall survival (OS) between the PR homo and PR hetero groups. The SD homo group had a longer PFS and OS than the SD hetero group. In the SD hetero group, patients with increased maximum standardized uptake value (SUVmax) in lesions with heterogeneous radiological responses had a shorter PFS than those with a stable SUVmax. Conclusions The presence of lesions with radiological heterogeneity was associated with disease progression and poor prognosis in the SD group. Patients with heterogeneous radiological responses require careful monitoring.
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Affiliation(s)
- Woo Kyung Ryu
- Division of Pulmonology, Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, Incheon, Republic of Korea
| | - Jung Soo Kim
- Division of Pulmonology, Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, Incheon, Republic of Korea
| | - Mi Hwa Park
- Division of Pulmonology, Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, Incheon, Republic of Korea
| | - Minkyung Lee
- Department of Nuclear Medicine, Inha University Hospital, Inha University College of Medicine, Incheon, Republic of Korea
| | - Hyun-Jung Kim
- Division of Pulmonology, Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, Incheon, Republic of Korea
| | - Jeong-Seon Ryu
- Division of Pulmonology, Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, Incheon, Republic of Korea
| | - Jun Hyeok Lim
- Division of Pulmonology, Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, Incheon, Republic of Korea
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15
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Guo JC, Lin CY, Lin CC, Huang TC, Lien MY, Lu LC, Kuo HY, Hsu CH. Response to Immune Checkpoint Inhibitors in Recurrent or Metastatic Esophageal Squamous Cell Carcinoma May Be Affected by Tumor Sites. Oncology 2021; 99:652-658. [PMID: 34340231 DOI: 10.1159/000517738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 06/07/2021] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Heterogeneous tumor response has been reported in cancer patients treated with immune checkpoint inhibitors (ICIs). This study investigated whether the tumor site is associated with the response to ICIs in patients with recurrent or metastatic esophageal squamous cell carcinoma (ESCC). METHODS Patients with ESCC who had measurable tumors in the liver, lung, or lymph node (LN) according to the response evaluation criteria in solid tumors (RECIST) 1.1 and received ICIs at 2 medical centers in Taiwan were enrolled. In addition to RECIST 1.1, tumor responses were determined per individual organ basis according to organ-specific criteria modified from RECIST 1.1. Fisher test or χ2 test was used for statistical analysis. RESULTS In total, 37 patients were enrolled. The overall response rate per RECIST 1.1 was 13.5%. Measurable tumors in the LN, lung, and liver were observed in 26, 17, and 13 patients, respectively. The organ-specific response rates were 26.9%, 29.4%, and 15.4% for the LN, lung, and liver tumors, respectively (p = 0.05). The organ-specific disease control rates were 69.2%, 52.9%, and 21.1% for the LN, lung, and liver tumors, respectively (p = 0.024). Five (27.8%) among 18 patients harboring at least 2 involved organs had heterogeneous tumor response. CONCLUSION The response and disease control to ICIs may differ in ESCC tumors located at different metastatic sites, with a lesser likelihood of response and disease control in metastatic liver tumors than in tumors located at the LNs and lung.
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Affiliation(s)
- Jhe-Cyuan Guo
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan, .,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, .,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan,
| | - Chen-Yuan Lin
- Division of Hematology and Oncology, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Chi Lin
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ta-Chen Huang
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ming-Yu Lien
- Division of Hematology and Oncology, China Medical University Hospital, Taichung, Taiwan
| | - Li-Chun Lu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hung-Yang Kuo
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chih-Hung Hsu
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
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Chen DT, Chan W, Thompson ZJ, Thapa R, Beg AA, Saltos AN, Chiappori AA, Gray JE, Haura EB, Rose TA, Creelan B. Utilization of target lesion heterogeneity for treatment efficacy assessment in late stage lung cancer. PLoS One 2021; 16:e0252041. [PMID: 34197475 PMCID: PMC8248740 DOI: 10.1371/journal.pone.0252041] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
RATIONALE Recent studies have discovered several unique tumor response subgroups outside of response classification by Response Evaluation Criteria for Solid Tumors (RECIST), such as mixed response and oligometastasis. These subtypes have a distinctive property, lesion heterogeneity defined as diversity of tumor growth profiles in RECIST target lesions. Furthermore, many cancer clinical trials have been activated to evaluate various treatment options for heterogeneity-related subgroups (e.g., 29 trials so far listed in clinicaltrials.gov for cancer patients with oligometastasis). Some of the trials have shown survival benefit by tailored treatment strategies. This evidence presents the unmet need to incorporate lesion heterogeneity to improve RECIST response classification. METHOD An approach for Lesion Heterogeneity Classification (LeHeC) was developed using a contemporary statistical approach to assess target lesion variation, characterize patient treatment response, and translate informative evidence to improving treatment strategy. A mixed effect linear model was used to determine lesion heterogeneity. Further analysis was conducted to classify various types of lesion variation and incorporate with RECIST to enhance response classification. A study cohort of 110 target lesions from 36 lung cancer patients was used for evaluation. RESULTS Due to small sample size issue, the result was exploratory in nature. By analyzing RECIST target lesion data, the LeHeC approach detected a high prevalence (n = 21; 58%) of lesion heterogeneity. Subgroup classification revealed several informative distinct subsets in a descending order of lesion heterogeneity: mix of progression and regression (n = 7), mix of progression and stability (n = 9), mix of regression and stability (n = 5), and non-heterogeneity (n = 15). Evaluation for association of lesion heterogeneity and RECIST best response classification showed lesion heterogeneity commonly occurred in each response group (stable disease: 16/27; 59%; partial response: 3/5; 60%; progression disease: 2/4; 50%). Survival analysis showed a differential trend of overall survival between heterogeneity and non-heterogeneity in RECIST response groups. CONCLUSION This is the first study to evaluate lesion heterogeneity, an underappreciated metric, for RECIST application in oncology clinical trials. Results indicated lesion heterogeneity is not an uncommon event. The LeHeC approach could enhance RECIST response classification by utilizing granular lesion level discovery of heterogeneity.
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Affiliation(s)
- Dung-Tsa Chen
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
- * E-mail:
| | - Wenyaw Chan
- Department of Biostatistics and Data Science, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America
| | - Zachary J. Thompson
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
| | - Ram Thapa
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
| | - Amer A. Beg
- Department of Immunotherapy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
| | - Andreas N. Saltos
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
| | - Alberto A. Chiappori
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
| | - Jhanelle E. Gray
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
| | - Eric B. Haura
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
| | - Trevor A. Rose
- Department of Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
| | - Ben Creelan
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
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Gambaro K, Marques M, McNamara S, Couetoux du Tertre M, Diaz Z, Hoffert C, Srivastava A, Hébert S, Samson B, Lespérance B, Ko Y, Dalfen R, St‐Hilaire E, Sideris L, Couture F, Burkes R, Harb M, Camlioglu E, Gologan A, Pelsser V, Constantin A, Greenwood CM, Tejpar S, Kavan P, Kleinman CL, Batist G. Copy number and transcriptome alterations associated with metastatic lesion response to treatment in colorectal cancer. Clin Transl Med 2021; 11:e401. [PMID: 33931971 PMCID: PMC8087915 DOI: 10.1002/ctm2.401] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Therapeutic resistance is the main cause of death in metastatic colorectal cancer. To investigate genomic plasticity, most specifically of metastatic lesions, associated with response to first-line systemic therapy, we collected longitudinal liver metastatic samples and characterized the copy number aberration (CNA) landscape and its effect on the transcriptome. METHODS Liver metastatic biopsies were collected prior to treatment (pre, n = 97) and when clinical imaging demonstrated therapeutic resistance (post, n = 43). CNAs were inferred from whole exome sequencing and were correlated with both the status of the lesion and overall patient progression-free survival (PFS). We used RNA sequencing data from the same sample set to validate aberrations as well as independent datasets to prioritize candidate genes. RESULTS We identified a significantly increased frequency gain of a unique CN, in liver metastatic lesions after first-line treatment, on chr18p11.32 harboring 10 genes, including TYMS, which has not been reported in primary tumors (GISTIC method and test of equal proportions, FDR-adjusted p = 0.0023). CNA lesion profiles exhibiting different treatment responses were compared and we detected focal genomic divergences in post-treatment resistant lesions but not in responder lesions (two-tailed Fisher's Exact test, unadjusted p ≤ 0.005). The importance of examining metastatic lesions is highlighted by the fact that 15 out of 18 independently validated CNA regions found to be associated with PFS in this study were only identified in the metastatic lesions and not in the primary tumors. CONCLUSION This investigation of genomic-phenotype associations in a large colorectal cancer liver metastases cohort identified novel molecular features associated with treatment response, supporting the clinical importance of collecting metastatic samples in a defined clinical setting.
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Affiliation(s)
- Karen Gambaro
- Canadian National Centres of Excellence—Exactis Innovation5450 Cote‐des‐NeigesMontrealQuebecH3T 1Y6Canada
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
| | - Maud Marques
- Canadian National Centres of Excellence—Exactis Innovation5450 Cote‐des‐NeigesMontrealQuebecH3T 1Y6Canada
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
| | - Suzan McNamara
- Canadian National Centres of Excellence—Exactis Innovation5450 Cote‐des‐NeigesMontrealQuebecH3T 1Y6Canada
| | | | - Zuanel Diaz
- Canadian National Centres of Excellence—Exactis Innovation5450 Cote‐des‐NeigesMontrealQuebecH3T 1Y6Canada
| | - Cyrla Hoffert
- Canadian National Centres of Excellence—Exactis Innovation5450 Cote‐des‐NeigesMontrealQuebecH3T 1Y6Canada
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
| | - Archana Srivastava
- Canadian National Centres of Excellence—Exactis Innovation5450 Cote‐des‐NeigesMontrealQuebecH3T 1Y6Canada
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
| | - Steven Hébert
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
| | - Benoit Samson
- Charles LeMoyne Hospital3120 Taschereau Blvd.Greenfield ParkQuebecJ4V 2H1Canada
| | | | - Yoo‐Joung Ko
- Sunnybrook Health Science Centre2075 Bayview Ave.TorontoOntarioM4N 3M5Canada
| | - Richard Dalfen
- St. Mary's Hospital3830 LacombeMontrealQuebecH3T 1M5Canada
| | - Eve St‐Hilaire
- Georges Dumont Hospital220 Avenue UniversiteMonctonNew BrunswickE1C 2Z3Canada
| | - Lucas Sideris
- Hôpital Maisonneuve Rosemont5415 Assumption BlvdMontrealQuebecH1T 2M4Canada
| | - Felix Couture
- Hôtel‐Dieu de Quebec11 Cote du PalaisMontrealQuebecG1R 2J6Canada
| | - Ronald Burkes
- Mount Sinai Hospital600 University AvenueTorontoOntarioM5G 1X5Canada
| | - Mohammed Harb
- Moncton Hospital135 Macbeath AveMonctonNew BrunswickE1C 6Z8Canada
| | - Errol Camlioglu
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
| | - Adrian Gologan
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
| | - Vincent Pelsser
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
| | - André Constantin
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
| | - Celia M.T. Greenwood
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
- Gerald Bronfman Department of OncologyMcGill University3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
- Department of Epidemiology, Biostatistics and Occupational HealthMcGill University3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
| | - Sabine Tejpar
- Digestive Oncology UnitKatholieke Universiteit LeuvenOude Markt 13Leuven3000Belgium
| | - Petr Kavan
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
| | - Claudia L. Kleinman
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
- Department of Human GeneticsLady Davis Research Institute, McGill University3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
| | - Gerald Batist
- McGill University‐Segal Cancer Centre, Jewish General Hospital3755 Côte Ste‐CatherineMontrealQuebecH3T 1E2Canada
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Xie D, Sun Q, Wang X, Zhou J, Fan J, Ren Z, Gao Q. Immune checkpoint inhibitor plus tyrosine kinase inhibitor for unresectable hepatocellular carcinoma in the real world. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:652. [PMID: 33987350 PMCID: PMC8106062 DOI: 10.21037/atm-20-7037] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background This study aimed to evaluate safety and efficacy of programmed death-1 (PD-1) inhibitor sintilimab plus tyrosine kinase inhibitors (TKI) in a real-word cohort of patients with unresectable hepatocellular carcinoma (uHCC). Methods A total of 60 patients treated with sintilimab plus TKI between February 2019 and December 2019 were enrolled. Radiological response was recorded by computed tomography (CT) or magnetic resonance imaging (MRI) at baseline and every 6-12 weeks after treatment initiation. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and HCC-specific modified RECIST (mRECIST). Results As of the data cutoff on September 30st, 2020, the median duration of follow-up was 10.4 (4.3-23.9) months. The objective response rate (ORR) and disease control rate (DCR) were 36.7% (95% CI: 24.9-48.5%), 81.7% (95% CI: 71.9-91.5%) according to the RECIST 1.1, and 52.8% (95% CI: 39.1-66.5%), 83.0% (95% CI: 73.2-93.8%) according to mRECIST criteria. Among 36 HCC patients with multinodular HCC or locally-advanced HCC with portal vein tumor thrombus (PVTT), 14 patients received one session of transarterial chemoembolization (TACE) within 1 month before or after the combinational systemic therapies, and the rest 22 patients did not receive any local regional therapies. After propensity score matching, patients from the TACE group tended to have a longer PFS (median, 10.1 vs. 9.1 months, P=0.73) than those from the non-TACE group but without significant differences. A total of 8 patients received surgical resection after the combined systemic therapies and 3 patients achieved pathological CR. No recurrence or metastasis was observed in 6 patients. A total of 46 (76.7%) patients reported adverse event (AE) with any grade and 8 (13.3%) patients discontinued the combination therapy due to grade 3/4 severe adverse events. Conclusions PD-1-targeted immunotherapy sintilimab plus TKIs exhibited promising efficacy with tolerable toxicity in unresectable HCC. The addition of TACE to the combined systemic therapies also resulted in a favorable tumor control and safety. For select responders, surgical resection might be a choice for radical treatment.
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Affiliation(s)
- Diyang Xie
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Qiman Sun
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Xiaoying Wang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Zhenggang Ren
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Qiang Gao
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
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19
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Zhu HB, Xu D, Ye M, Sun L, Zhang XY, Li XT, Nie P, Xing BC, Sun YS. Deep learning-assisted magnetic resonance imaging prediction of tumor response to chemotherapy in patients with colorectal liver metastases. Int J Cancer 2021; 148:1717-1730. [PMID: 33284998 DOI: 10.1002/ijc.33427] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/03/2020] [Accepted: 10/30/2020] [Indexed: 12/17/2022]
Abstract
Accurate evaluation of tumor response to preoperative chemotherapy is crucial for assigning appropriate patients with colorectal liver metastases (CRLM) to surgery or conservative therapy. However, there is no well-recognized method for predicting pathological response before surgery. Our study constructed and validated a deep learning algorithm using prechemotherapy and postchemotherapy magnetic resonance imaging (MRI) to predict pathological response in CRLM. CRLM patients from center one who had ≤5 lesions and were scheduled to receive preoperative chemotherapy followed by liver resection between January 2013 and November 2016, were included prospectively and chronologically divided into a training cohort (80% of patients) and a testing cohort (20% of patients). Patients from center two were included January 2017 and December 2018 as an external validation cohort. MRI-based models were constructed to discriminate according to pathology tumor regression grade (TRG) between the response (TRG1/2) and nonresponse (TRG3/4/5) groups at the lesion level. From center one, 155 patients (328 lesions) were included; chronologically, 101 (264 lesions) in the training cohort and 54 (64 lesions) in the testing cohort. The model achieved better accuracy (0.875 vs 0.578) and AUC (0.849 vs 0.615) than RECIST for discriminating response; it also distinguished the survival outcomes after hepatectomy better than the RECIST criteria. Evaluations of the external validation cohort (25 patients, 61 lesions) also showed good ability with an AUC of 0.833. In conclusion, the MRI-based deep learning model provided accurate prediction of pathological tumor response to preoperative chemotherapy in patients with CRLM and may inform individualized treatment.
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Affiliation(s)
- Hai-Bin Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Da Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, Beijing, China
| | - Meng Ye
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Li Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiao-Yan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiao-Ting Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Pei Nie
- Department of Radiology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bao-Cai Xing
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, Beijing, China
| | - Ying-Shi Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiology, Peking University Cancer Hospital & Institute, Beijing, China
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20
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Furubayashi N, Negishi T, Sakamoto N, Shimokawa H, Morokuma F, Song Y, Hori Y, Tomoda T, Tokuda N, Seki N, Kuroiwa K, Nakamura M. Organ-Specific Tumor Response to Pembrolizumab in Advanced Urothelial Carcinoma After Platinum-Based Chemotherapy. Onco Targets Ther 2021; 14:1981-1988. [PMID: 33776447 PMCID: PMC7987306 DOI: 10.2147/ott.s299724] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/05/2021] [Indexed: 11/25/2022] Open
Abstract
Background To evaluate the organ-specific therapeutic effect of pembrolizumab after the failure of platinum-based chemotherapy for advanced urothelial carcinoma (UC). Materials and Methods Patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy and who had measurable disease were retrospectively analyzed. The objective response rate (ORR) and organ-specific response rate (OSRR) were evaluated according to Response Evaluation Criteria in Solid Tumors, version 1.1. Results We analyzed 69 patients (male, n=51; median age, 71 years) with 226 metastases. The ORR was 23.2%. In total, 32, 31, 16, 14, 13 and 7 patients had measurable lung (OSSR 31.3%), lymph node (OSSR 29.0%), local recurrence (OSSR 12.5%), primary tumor organ (OSSR 7.1%), liver (OSSR 23.1%) and bone (OSSR 28.6%) disease, respectively. The median overall survival (OS) for pembrolizumab was 10.9 months (95% confidence interval, 5.9‑13.7 months). Regarding organ-specific OS, a Log rank test significant differences in OS were confirmed between patients with and without primary tumor organ disease (p=0.046) and liver metastasis (p<0.001). Conclusion Metastases and primary tumor organ disease showed different tumor responses to pembrolizumab. The most prominent tumor response was found in lung metastasis and the least response was found in primary organ sites. The mechanisms of these different responses were unclear and there does not appear to be a constant trend between tumor shrinkage and OS in tumor sites. Further studies are needed.
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Affiliation(s)
- Nobuki Furubayashi
- Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Takahito Negishi
- Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Naotaka Sakamoto
- Department of Urology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Hozumi Shimokawa
- Department of Medical Oncology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
| | - Futoshi Morokuma
- Department of Urology, Saga-ken Medical Centre Koseikan, Saga, Japan
| | - Yoohyun Song
- Department of Urology, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan
| | - Yoshifumi Hori
- Department of Urology, Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Japan
| | | | - Noriaki Tokuda
- Department of Urology, Saga-ken Medical Centre Koseikan, Saga, Japan
| | - Narihito Seki
- Department of Urology, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan
| | - Kentaro Kuroiwa
- Department of Urology, Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Japan
| | - Motonobu Nakamura
- Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
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21
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Giannini V, Rosati S, Defeudis A, Balestra G, Vassallo L, Cappello G, Mazzetti S, De Mattia C, Rizzetto F, Torresin A, Sartore-Bianchi A, Siena S, Vanzulli A, Leone F, Zagonel V, Marsoni S, Regge D. Radiomics predicts response of individual HER2-amplified colorectal cancer liver metastases in patients treated with HER2-targeted therapy. Int J Cancer 2020; 147:3215-3223. [PMID: 32875550 DOI: 10.1002/ijc.33271] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 08/06/2020] [Accepted: 08/12/2020] [Indexed: 12/20/2022]
Abstract
The aim of our study was to develop and validate a machine learning algorithm to predict response of individual HER2-amplified colorectal cancer liver metastases (lmCRC) undergoing dual HER2-targeted therapy. Twenty-four radiomics features were extracted after 3D manual segmentation of 141 lmCRC on pretreatment portal CT scans of a cohort including 38 HER2-amplified patients; feature selection was then performed using genetic algorithms. lmCRC were classified as nonresponders (R-), if their largest diameter increased more than 10% at a CT scan performed after 3 months of treatment, responders (R+) otherwise. Sensitivity, specificity, negative (NPV) and positive (PPV) predictive values in correctly classifying individual lesion and overall patient response were assessed on a training dataset and then validated on a second dataset using a Gaussian naïve Bayesian classifier. Per-lesion sensitivity, specificity, NPV and PPV were 89%, 85%, 93%, 78% and 90%, 42%, 73%, 71% respectively in the testing and validation datasets. Per-patient sensitivity and specificity were 92% and 86%. Heterogeneous response was observed in 9 of 38 patients (24%). Five of nine patients were carriers of nonresponder lesions correctly classified as such by our radiomics signature, including four of seven harboring only one nonresponder lesion. The developed method has been proven effective in predicting behavior of individual metastases to targeted treatment in a cohort of HER2 amplified patients. The model accurately detects responder lesions and identifies nonresponder lesions in patients with heterogeneous response, potentially paving the way to multimodal treatment in selected patients. Further validation will be needed to confirm our findings.
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Affiliation(s)
- Valentina Giannini
- Radiology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Samanta Rosati
- Department of Electronics and Telecommunications, Polytechnic of Turin, Turin, Italy
| | - Arianna Defeudis
- Radiology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Gabriella Balestra
- Department of Electronics and Telecommunications, Polytechnic of Turin, Turin, Italy
| | | | - Giovanni Cappello
- Radiology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Simone Mazzetti
- Radiology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Cristina De Mattia
- Department of Medical Physics, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Francesco Rizzetto
- Department of Radiology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Alberto Torresin
- Department of Medical Physics, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Physics, Università degli Studi di Milano, Milan, Italy
| | - Andrea Sartore-Bianchi
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Salvatore Siena
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Angelo Vanzulli
- Department of Radiology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Francesco Leone
- Medical Oncology, ASL Biella, Biella, Italy
- Department of Oncology, University of Turin, Turin, Italy
| | - Vittorina Zagonel
- Medical Oncology Unit 1, Istituto Oncologico Veneto-IRCCS, Padova, Italy
| | - Silvia Marsoni
- Precision Oncology, IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy
| | - Daniele Regge
- Radiology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Department of Surgical Sciences, University of Turin, Turin, Italy
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22
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Hall PE, Shepherd STC, Brown J, Larkin J, Jones R, Ralph C, Hawkins R, Chowdhury S, Boleti E, Bahl A, Fife K, Webb A, Crabb SJ, Geldart T, Hill R, Dunlop J, McLaren D, Ackerman C, Wimalasingham A, Beltran L, Nathan P, Powles T. Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy. Eur Urol Focus 2020; 6:999-1005. [PMID: 30738795 DOI: 10.1016/j.euf.2019.01.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 01/07/2019] [Accepted: 01/16/2019] [Indexed: 11/28/2022]
Abstract
BACKGROUND Response evaluation criteria in solid tumours (RECIST) is widely used to assess tumour response but is limited by not considering disease site or radiological heterogeneity (RH). OBJECTIVE To determine whether RH or disease site has prognostic significance in patients with metastatic clear-cell renal cell carcinoma (ccRCC). DESIGN, SETTING, AND PARTICIPANTS A retrospective analysis was conducted of a second-line phase II study in patients with metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions. INTERVENTION The phase II trial assessed vascular endothelial growth factor-targeted therapy±Src inhibition. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS RH at week 8 was assessed within individual patients with two or more lesions to predict overall survival (OS) using Kaplan-Meier method and Cox regression model. We defined a high heterogeneous response as occurring when one or more lesion underwent a ≥10% reduction and one or more lesion underwent a ≥10% increase in size. Disease progression was defined by RECIST 1.1 criteria. RESULTS AND LIMITATIONS In patients with a complete/partial response or stable disease by RECIST 1.1 and two or more lesions at week 8, those with a high heterogeneous response had a shorter OS compared to those with a homogeneous response (hazard ratio [HR] 2.01; 95% confidence interval [CI]: 1.39-2.92; p<0.001). Response by disease site at week 8 did not affect OS. At disease progression, one or more new lesion was associated with worse survival compared with >20% increase in sum of target lesion diameters only (HR 2.12; 95% CI: 1.43-3.14; p<0.001). Limitations include retrospective study design. CONCLUSIONS RH and the development of new lesions may predict survival in metastatic ccRCC. Further prospective studies are required. PATIENT SUMMARY We looked at individual metastases in patients with kidney cancer and showed that a variable response to treatment and the appearance of new metastases may be associated with worse survival. Further studies are required to confirm these findings.
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Affiliation(s)
- Peter E Hall
- Barts Cancer Institute, CRUK Experimental Cancer Medicine Centre, London, UK
| | - Scott T C Shepherd
- Department of Oncology, Royal Free NHS Foundation Trust, London, UK; Department of Medical Oncology, Royal Marsden Hospital, London, UK
| | - Janet Brown
- Department of Medical Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, UK; Academic Unit of Clinical Oncology, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - James Larkin
- Department of Medical Oncology, Royal Marsden Hospital, London, UK
| | - Robert Jones
- Beatson Cancer Centre, University of Glasgow, Glasgow, Scotland, UK
| | - Christy Ralph
- Department of Medical Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Robert Hawkins
- Department of Medical Oncology, Christie Hospital, Manchester, UK
| | - Simon Chowdhury
- Department of Oncology, Guys and St Thomas' NHS Foundation Trust, London, UK
| | - Ekaterini Boleti
- Department of Oncology, Royal Free NHS Foundation Trust, London, UK
| | - Amit Bahl
- Department of Oncology, University Hospital Bristol NHS Foundation trust, Bristol, UK
| | - Kate Fife
- Department of Oncology, Cambridge University Hospitals, Cambridge, UK
| | - Andrew Webb
- Department of Oncology, Brighton and Sussex University Hospital Trust, Brighton, UK
| | - Simon J Crabb
- Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Thomas Geldart
- Department of Oncology, Royal Bournemouth Hospital, Bournemouth, UK
| | - Robert Hill
- Scottish Clinical Trials Research Unit (SCTRU), NHS National Services Scotland, Edinburgh, UK
| | - Joanna Dunlop
- Scottish Clinical Trials Research Unit (SCTRU), NHS National Services Scotland, Edinburgh, UK
| | - Duncan McLaren
- Edinburgh Cancer Centre, Western General Hospital, Edinburgh, UK
| | - Charlotte Ackerman
- Barts Cancer Institute, CRUK Experimental Cancer Medicine Centre, London, UK
| | | | - Luis Beltran
- Barts Cancer Institute, CRUK Experimental Cancer Medicine Centre, London, UK
| | - Paul Nathan
- Department of Oncology, Mount Vernon Cancer Centre, Northwood, UK
| | - Thomas Powles
- Barts Cancer Institute, CRUK Experimental Cancer Medicine Centre, London, UK; Department of Oncology, Royal Free NHS Foundation Trust, London, UK.
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23
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Bruun J, Kryeziu K, Eide PW, Moosavi SH, Eilertsen IA, Langerud J, Røsok B, Totland MZ, Brunsell TH, Pellinen T, Saarela J, Bergsland CH, Palmer HG, Brudvik KW, Guren T, Dienstmann R, Guren MG, Nesbakken A, Bjørnbeth BA, Sveen A, Lothe RA. Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity. Clin Cancer Res 2020; 26:4107-4119. [PMID: 32299813 DOI: 10.1158/1078-0432.ccr-19-3637] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 03/02/2020] [Accepted: 04/10/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE Molecular tumor heterogeneity may have important implications for the efficacy of targeted therapies in metastatic cancers. Inter-metastatic heterogeneity of sensitivity to anticancer agents has not been well explored in colorectal cancer. EXPERIMENTAL DESIGN We established a platform for ex vivo pharmacogenomic profiling of patient-derived organoids (PDO) from resected colorectal cancer liver metastases. Drug sensitivity testing (n = 40 clinically relevant agents) and gene expression profiling were performed on 39 metastases from 22 patients. RESULTS Three drug-response clusters were identified among the colorectal cancer metastases, based primarily on sensitivities to EGFR and/or MDM2 inhibition, and corresponding with RAS mutations and TP53 activity. Potentially effective therapies, including off-label use of drugs approved for other cancer types, could be nominated for eighteen patients (82%). Antimetabolites and targeted agents lacking a decisive genomic marker had stronger differential activity than most approved chemotherapies. We found limited intra-patient drug sensitivity heterogeneity between PDOs from multiple (2-5) liver metastases from each of ten patients. This was recapitulated at the gene expression level, with a highly proportional degree of transcriptomic and pharmacological variation. One PDO with a multi-drug resistance profile, including resistance to EGFR inhibition in a RAS-mutant background, showed sensitivity to MEK plus mTOR/AKT inhibition, corresponding with low-level PTEN expression. CONCLUSIONS Intra-patient inter-metastatic pharmacological heterogeneity was not pronounced and ex vivo drug screening may identify novel treatment options for metastatic colorectal cancer. Variation in drug sensitivities was reflected at the transcriptomic level, suggesting potential to develop gene expression-based predictive signatures to guide experimental therapies.
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Affiliation(s)
- Jarle Bruun
- Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Kushtrim Kryeziu
- Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Peter W Eide
- Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Seyed H Moosavi
- Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | - Ina A Eilertsen
- Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | - Jonas Langerud
- Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | - Bård Røsok
- K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Max Z Totland
- Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Tuva H Brunsell
- Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.,Department of Gastrointestinal Surgery, Ullevål Hospital-Oslo University Hospital, Oslo, Norway
| | - Teijo Pellinen
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Jani Saarela
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Christian H Bergsland
- Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | - Hector G Palmer
- Stem Cells and Cancer Group, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain. CIBERONC, Madrid, Spain
| | - Kristoffer W Brudvik
- K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Tormod Guren
- K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Rodrigo Dienstmann
- Stem Cells and Cancer Group, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain. CIBERONC, Madrid, Spain
| | - Marianne G Guren
- K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Arild Nesbakken
- K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.,Department of Gastrointestinal Surgery, Ullevål Hospital-Oslo University Hospital, Oslo, Norway
| | - Bjørn Atle Bjørnbeth
- K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Anita Sveen
- Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | - Ragnhild A Lothe
- Department of Molecular Oncology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. .,K.G. Jebsen Colorectal Cancer Research Centre, Clinic for Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
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24
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Lu LC, Hsu C, Shao YY, Chao Y, Yen CJ, Shih IL, Hung YP, Chang CJ, Shen YC, Guo JC, Liu TH, Hsu CH, Cheng AL. Differential Organ-Specific Tumor Response to Immune Checkpoint Inhibitors in Hepatocellular Carcinoma. Liver Cancer 2019; 8:480-490. [PMID: 31799205 PMCID: PMC6883443 DOI: 10.1159/000501275] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 06/02/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIMS Immune checkpoint inhibitors (ICIs) exhibit significant clinical activity in patients with advanced hepatocellular carcinoma (HCC). This study explored whether tumor response to ICIs in HCC varies among different organs. METHODS We reviewed the data of patients with advanced HCC who had received ICIs. Patients with measurable diseases were enrolled. Organ-specific response criteria, adapted from RECIST 1.1 and immune-related RECIST, were used to evaluate the objective response to ICIs in tumors located in the liver, lung, lymph node, and other intra-abdominal sites. RESULTS Of the 75 enrolled patients with advanced HCC, 51 and 11 patients had chronic hepatitis B virus and chronic hepatitis C virus infection, respectively. Regarding ICI treatment, 58, 1, and 16 patients had undergone anti-PD-1/anti-PD-L1 monoclonal antibody (mAb) alone, anti-CTLA4 mAb alone, and anti-PD-1 mAb plus anti-CTLA4 mAb, respectively; 20 and 55 patients had received ICIs as first-line or ≥second-line therapy. The overall objective response rate (ORR) was 28.0%. In total, 58, 34, 19, and 18 patients had measurable hepatic tumors and lung, lymph node, and other intra-abdominal metastases, and the corresponding organ-specific ORRs were 22.4, 41.2, 26.3, and 38.9%, respectively. Of the 39 patients who had both hepatic and extrahepatic tumors, 12 had disease control in extrahepatic tumors while progressive disease (PD) in hepatic tumors, whereas only 4 exhibited disease control in hepatic tumors while PD in extrahepatic tumors (p = 0.046, McNemar test). Of the 16 patients with only evaluable tumors in the liver and lungs at baseline, 8 had disease control in the lungs while PD in the liver, and none experienced disease control in the liver while PD in the lungs (p = 0.005). CONCLUSIONS The hepatic tumors of HCC may be less responsive to ICIs than extrahepatic lesions. Lung metastases responded most favorably to ICIs. The mechanisms underlying this differential response to ICIs warrant further investigation.
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Affiliation(s)
- Li-Chun Lu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan,National Taiwan University Cancer Center, Taipei, Taiwan
| | - Chiun Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Yun Shao
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan,National Taiwan University Cancer Center, Taipei, Taiwan
| | - Yee Chao
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chia-Jui Yen
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - I-Lun Shih
- Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Ping Hung
- Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chun-Jung Chang
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Ying-Chun Shen
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan,National Taiwan University Cancer Center, Taipei, Taiwan
| | - Jhe-Cyuan Guo
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan,National Taiwan University Cancer Center, Taipei, Taiwan
| | - Tsung-Hao Liu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan,Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | - Chih-Hung Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan,National Taiwan University Cancer Center, Taipei, Taiwan,*Chih-Hung Hsu, MD, PhD or Ann-Lii Cheng, MD, PhD, Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 10002 (Taiwan), E-Mail or
| | - Ann-Lii Cheng
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan,National Taiwan University Cancer Center, Taipei, Taiwan
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25
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Brunsell TH, Cengija V, Sveen A, Bjørnbeth BA, Røsok BI, Brudvik KW, Guren MG, Lothe RA, Abildgaard A, Nesbakken A. Heterogeneous radiological response to neoadjuvant therapy is associated with poor prognosis after resection of colorectal liver metastases. Eur J Surg Oncol 2019; 45:2340-2346. [PMID: 31350075 DOI: 10.1016/j.ejso.2019.07.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 05/22/2019] [Accepted: 07/08/2019] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Surgery combined with perioperative chemotherapy has become standard of care in patients with resectable colorectal liver metastases. However, poor outcome is expected for a significant subgroup. The clinical implications of inter-metastatic heterogeneity remain largely unknown. In a prospective, population-based series of patients undergoing resection of multiple colorectal liver metastases, the aim was to investigate the prevalence and prognostic impact of heterogeneous response to neoadjuvant chemotherapy. MATERIALS AND METHODS Radiological response to treatment was evaluated in a lesion-specific manner in 2-5 metastases per patient. Change of lesion diameter was evaluated and response/progression was classified according to three different size thresholds; 3, 4 and 5 mm. A heterogeneous response was defined as progression and response of different metastases in the same patient. RESULTS In total, 142 patients with 585 liver metastases were examined with the same radiological method (MRI or CT) before and after neoadjuvant treatment. Heterogeneous response to treatment was seen in 16 patients (11%) using the 3 mm size change threshold, and this group had a 5-year cancer-specific survival of 19% compared to 49% for patients with response in all lesions (p = 0.003). Cut-off values of 4-5 mm were less sensitive for detecting a heterogeneous response, but the survival difference was similar and significant. CONCLUSION A subgroup of patients with multiple colorectal liver metastases had heterogeneous radiological response to neoadjuvant chemotherapy and poor prognosis. The evaluation of response pattern is easy to perform, feasible in clinical practice and, if validated, a promising biomarker for treatment decisions.
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Affiliation(s)
- Tuva Høst Brunsell
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, POB 1171 Blindern, N-0318, Oslo, Norway.
| | - Vanja Cengija
- K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; Department of Radiology and Nuclear Medicine, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway.
| | - Anita Sveen
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, POB 1171 Blindern, N-0318, Oslo, Norway.
| | - Bjørn Atle Bjørnbeth
- K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway.
| | - Bård I Røsok
- K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway.
| | - Kristoffer Watten Brudvik
- K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway.
| | - Marianne Grønlie Guren
- K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; Department of Oncology, Oslo University Hospital, POB 4956 Nydalen, N-0424, Oslo, Norway.
| | - Ragnhild A Lothe
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, POB 1171 Blindern, N-0318, Oslo, Norway.
| | - Andreas Abildgaard
- K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; Department of Radiology and Nuclear Medicine, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway.
| | - Arild Nesbakken
- K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, POB 1171 Blindern, N-0318, Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, POB 4950 Nydalen, N-0424, Oslo, Norway.
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26
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Klaassen R, Larue RTHM, Mearadji B, van der Woude SO, Stoker J, Lambin P, van Laarhoven HWM. Feasibility of CT radiomics to predict treatment response of individual liver metastases in esophagogastric cancer patients. PLoS One 2018; 13:e0207362. [PMID: 30440002 PMCID: PMC6237370 DOI: 10.1371/journal.pone.0207362] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 10/30/2018] [Indexed: 02/06/2023] Open
Abstract
In this study we investigate a CT radiomics approach to predict response to chemotherapy of individual liver metastases in patients with esophagogastric cancer (EGC). In eighteen patients with metastatic EGC treated with chemotherapy, all liver metastases were manually delineated in 3D on the pre-treatment and evaluation CT. From the pre-treatment CT scans 370 radiomics features were extracted per lesion. Random forest (RF) models were generated to discriminate partial responding (PR, >65% volume decrease, including 100% volume decrease), and complete remission (CR, only 100% volume decrease) lesions from other lesions. RF-models were build using a leave one out strategy where all lesions of a single patient were removed from the dataset and used as validation set for a model trained on the lesions of the remaining patients. This process was repeated for all patients, resulting in 18 trained models and one validation set for both the PR and CR datasets. Model performance was evaluated by receiver operating characteristics with corresponding area under the curve (AUC). In total 196 liver metastases were delineated on the pre-treatment CT, of which 99 (51%) lesions showed a decrease in size of more than 65% (PR). From the PR set a total of 47 (47% of RL, 24% of initial) lesions were no longer detected in CT scan 2 (CR). The RF-model for PR lesions showed an average training AUC of 0.79 (range: 0.74-0.83) and 0.65 (95% ci: 0.57-0.73) for the combined validation set. The RF-model for CR lesions had an average training AUC of 0.87 (range: 0.83-0.90) and 0.79 (95% ci 0.72-0.87) for the validation set. Our findings show that individual response of liver metastases varies greatly within and between patients. A CT radiomics approach shows potential in discriminating responding from non-responding liver metastases based on the pre-treatment CT scan, although further validation in an independent patient cohort is needed to validate these findings.
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Affiliation(s)
- Remy Klaassen
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands
- Amsterdam UMC, University of Amsterdam, LEXOR, Laboratory for Experimental Oncology and Radiobiology, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Ruben T. H. M. Larue
- The D-Lab: Decision Support for Precision Medicine, GROW-School for Oncology and Developmental Biology, Maastricht Comprehensive Cancer Centre, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Banafsche Mearadji
- Amsterdam UMC, University of Amsterdam, Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Stephanie O. van der Woude
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Jaap Stoker
- Amsterdam UMC, University of Amsterdam, Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Philippe Lambin
- The D-Lab: Decision Support for Precision Medicine, GROW-School for Oncology and Developmental Biology, Maastricht Comprehensive Cancer Centre, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Hanneke W. M. van Laarhoven
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands
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27
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Stewart CL, Warner S, Ito K, Raoof M, Wu GX, Kessler J, Kim JY, Fong Y. Cytoreduction for colorectal metastases: liver, lung, peritoneum, lymph nodes, bone, brain. When does it palliate, prolong survival, and potentially cure? Curr Probl Surg 2018; 55:330-379. [PMID: 30526930 DOI: 10.1067/j.cpsurg.2018.08.004] [Citation(s) in RCA: 147] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 08/28/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Camille L Stewart
- Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA
| | - Susanne Warner
- Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA
| | - Kaori Ito
- Department of Surgery, Michigan State University, Lansing, MI
| | - Mustafa Raoof
- Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA
| | - Geena X Wu
- Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA
| | - Jonathan Kessler
- Department of Diagnostic Radiology, City of Hope National Medical Center, Duarte, CA
| | - Jae Y Kim
- Division of Thoracic Surgery, City of Hope National Medical Center, Duarte, CA
| | - Yuman Fong
- Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA.
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28
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Mistry HB, Orrell D, Eftimie R. Model based analysis of the heterogeneity in the tumour size dynamics differentiates vemurafenib, dabrafenib and trametinib in metastatic melanoma. Cancer Chemother Pharmacol 2017; 81:325-332. [PMID: 29222604 PMCID: PMC5778167 DOI: 10.1007/s00280-017-3486-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 11/15/2017] [Indexed: 01/15/2023]
Abstract
PURPOSE Explore the heterogeneity in dynamics of tumour response to vemurafenib, dabrafenib and trametinib using routinely collected clinical trial imaging data. METHODS Time-series imaging data from the phase III studies of vemurafenib, dabrafenib and trametinib were collected through a data repository. A mathematical model based on basic mechanisms of tumour growth was placed within a statistical modelling framework to analyse the data. RESULTS The analysis revealed: (1) existence of homogeneity in drug response and resistance development within a patient; (2) tumour shrinkage rate does not relate to rate of resistance development; (3) vemurafenib and dabrafenib, two BRAF inhibitors, have different variability in tumour shrinkage rates. CONCLUSIONS Overall these results show how analysis of the dynamics of individual lesions can shed light on the within and between patient differences in tumour shrinkage and resistance rates, which could be used to gain a macroscopic understanding of tumour heterogeneity.
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Affiliation(s)
- Hitesh B Mistry
- Centre for Drug Disease Modelling and Simulation, Manchester Pharmacy School, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
| | - David Orrell
- Systems Forecasting, 330 Spadina Road, Toronto, ON, M5R 2V9, Canada
| | - Raluca Eftimie
- Department of Mathematics, University of Dundee, Dundee, DD1 4HN, UK
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29
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Sebagh M, Allard MA, Bosselut N, Dao M, Vibert E, Lewin M, Lemoine A, Cherqui D, Adam R, Sa Cunha A. Evidence of intermetastatic heterogeneity for pathological response and genetic mutations within colorectal liver metastases following preoperative chemotherapy. Oncotarget 2017; 7:21591-600. [PMID: 26943031 PMCID: PMC5008308 DOI: 10.18632/oncotarget.7809] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 01/29/2016] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND In patients receiving preoperative chemotherapy, colorectal liver metastases (CLM) are expected to demonstrate a similar behaviour because of similar organ microenvironment and tumour cell chemosensitivity. We focused on the occurrence of pathological and genetic heterogeneity within CLM. METHODS Patients resected for multiple CLM between 2004 and 2011 after > three cycles of chemotherapy were included. Pathological heterogeneity was arbitrarily defined as a > 50% difference in the percentage of remaining tumour cells between individual CLM. In patients with pathological heterogeneity, the mutational genotyping (KRAS, NRAS, BRAF and PIK3CA) was determined from the most heterogeneous CLM. RESULTS Pathological heterogeneity was observed in 31 of 157 patients with multiple CLM (median = 4, range, 2-32) (19.7%). In 72.4% of them, we found a concordance of the mutation status between the paired CLM: both wild-type in 55%, and both mutated in 17.2%. We observed a discordance of the mutation status of 27.6% between CLM: one mutated and the other wild-type. The mutated CLM was the less florid one in 75% of patients with genetic heterogeneity. CONCLUSIONS Pathological heterogeneity is present in 19.7% of patients with multiple CLM. Genetic heterogeneity is present in 27.6% of patients with pathological heterogeneity. Heterogeneity could refine guide management for tissue sampling.
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Affiliation(s)
- Mylène Sebagh
- AP-HP Hôpital Paul Brousse, Department of Pathology, Villejuif, France.,Inserm U1193, Paris-Sud University, Villejuif, France
| | - Marc-Antoine Allard
- AP-HP Hôpital Paul Brousse, Hepatobiliary Centre, Villejuif, France.,Inserm U935, Paris-Sud University, Villejuif, France
| | - Nelly Bosselut
- Inserm U1193, Paris-Sud University, Villejuif, France.,AP-HP Hôpital Paul Brousse, Department of Oncogenetics, Villejuif, France
| | - Myriam Dao
- AP-HP Hôpital Paul Brousse, Department of Pathology, Villejuif, France
| | - Eric Vibert
- Inserm U1193, Paris-Sud University, Villejuif, France.,AP-HP Hôpital Paul Brousse, Hepatobiliary Centre, Villejuif, France
| | - Maïté Lewin
- AP-HP Hôpital Paul Brousse, Radiology, Villejuif, France
| | - Antoinette Lemoine
- Inserm U1193, Paris-Sud University, Villejuif, France.,AP-HP Hôpital Paul Brousse, Department of Oncogenetics, Villejuif, France
| | - Daniel Cherqui
- Inserm U1193, Paris-Sud University, Villejuif, France.,AP-HP Hôpital Paul Brousse, Hepatobiliary Centre, Villejuif, France
| | - René Adam
- AP-HP Hôpital Paul Brousse, Hepatobiliary Centre, Villejuif, France.,Inserm U935, Paris-Sud University, Villejuif, France
| | - Antonio Sa Cunha
- AP-HP Hôpital Paul Brousse, Hepatobiliary Centre, Villejuif, France.,Inserm U935, Paris-Sud University, Villejuif, France
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30
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Franklin JM, Sharma RA, Harris AL, Gleeson FV. Imaging oligometastatic cancer before local treatment. Lancet Oncol 2016; 17:e406-14. [PMID: 27599145 DOI: 10.1016/s1470-2045(16)30277-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 06/21/2016] [Accepted: 06/23/2016] [Indexed: 12/21/2022]
Abstract
With the advent of novel treatment strategies to help widen the therapeutic window for patients with oligometastatic cancer, improved biomarkers are needed to reliably define patients who can benefit from these treatments. Multimodal imaging is one such option and should be optimised to comprehensively assess metastatic sites, disease burden, and response to neoadjuvant treatment in each disease setting. These features will probably remain important prognostic biomarkers, and are crucial in planning multidisciplinary treatment. There are opportunities to extract additional phenotypic information from conventional imaging, while novel imaging techniques can also reveal specific aspects of tumour biology. Imaging can both characterise and localise the phenotypic heterogeneity of multiple tumour sites. Novel approaches to existing imaging datasets and correlation with tumour biology will be important in realising the potential of imaging to guide treatment in the oligometastatic setting. In this Personal View, we discuss the current status and future directions of imaging before treatment in patients with extracranial oligometastases.
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Affiliation(s)
- James M Franklin
- Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Department of Oncology, University of Oxford, UK.
| | | | - Adrian L Harris
- Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Department of Oncology, University of Oxford, UK
| | - Fergus V Gleeson
- Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Department of Oncology, University of Oxford, UK
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31
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Lucidi V, Hendlisz A, Van Laethem JL, Donckier V. Missing metastases as a model to challenge current therapeutic algorithms in colorectal liver metastases. World J Gastroenterol 2016; 22:3937-3944. [PMID: 27099436 PMCID: PMC4823243 DOI: 10.3748/wjg.v22.i15.3937] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
In oncosurgical approach to colorectal liver metastases, surgery remains considered as the only potentially curative option, while chemotherapy alone represents a strictly palliative treatment. However, missing metastases, defined as metastases disappearing after chemotherapy, represent a unique model to evaluate the curative potential of chemotherapy and to challenge current therapeutic algorithms. We reviewed recent series on missing colorectal liver metastases to evaluate incidence of this phenomenon, predictive factors and rates of cure defined by complete pathologic response in resected missing metastases and sustained clinical response when they were left unresected. According to the progresses in the efficacy of chemotherapeutic regimen, the incidence of missing liver metastases regularly increases these last years. Main predictive factors are small tumor size, low marker level, duration of chemotherapy, and use of intra-arterial chemotherapy. Initial series showed low rates of complete pathologic response in resected missing metastases and high recurrence rates when unresected. However, recent reports describe complete pathologic responses and sustained clinical responses reaching 50%, suggesting that chemotherapy could be curative in some cases. Accordingly, in case of missing colorectal liver metastases, the classical recommendation to resect initial tumor sites might have become partially obsolete. Furthermore, the curative effect of chemotherapy in selected cases could lead to a change of paradigm in patients with unresectable liver-only metastases, using intensive first-line chemotherapy to intentionally induce missing metastases, followed by adjuvant surgery on remnant chemoresistant tumors and close surveillance of initial sites that have been left unresected.
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32
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Li G, Wang Z, Xu J, Wu H, Cai S, He Y. The prognostic value of lactate dehydrogenase levels in colorectal cancer: a meta-analysis. BMC Cancer 2016; 16:249. [PMID: 27016045 PMCID: PMC4807548 DOI: 10.1186/s12885-016-2276-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 03/13/2016] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The prognostic value of lactate dehydrogenase levels in the prognosis of colorectal cancer patients has been assessed for years, although the results remain controversial and heterogeneous. Thus, we comprehensively reviewed the evidence from studies that evaluated lactate dehydrogenase levels in colorectal cancer patients to determine their effect. METHODS The following databases were searched in September 2014 to identify studies that evaluated the prognostic value of lactate dehydrogenase levels in colorectal cancer: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. We extracted hazard ratios (HRs) and the associated 95% confidence intervals (CIs) from the identified studies, and performed random-effects model meta-analyses on the overall survival (OS) and progression-free survival (PFS). Thirty-two studies with a cumulative sample size of 8,261 patients were included in our analysis. RESULTS Our meta-analyses revealed that high levels of lactate dehydrogenase were associated with poor OS (HR, 1.75; 95% CI, 1.52-2.02) in colorectal cancer patients. However, this effect was not obvious in the OS of non-metastatic colorectal cancer patients (HR, 1.21; 95% CI, 0.79-1.86). The prognostic value of lactate dehydrogenase levels on PFS was also not confirmed (HR, 1.36; 95% CI, 0.98-1.87). Subgroup analyses revealed that the prognostic significance of lactate dehydrogenase was independent of study location, patient age, number of patients, metastasis, chemotherapy with anti-angiogenesis drugs, study type, or risk of bias. CONCLUSIONS Our results indicate that high lactate dehydrogenase levels are associated with poor OS among colorectal cancer patients, although these levels are not significant predictors of PFS.
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Affiliation(s)
- Guanghua Li
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, 510080 Guangzhou, Guangdong Province People’s Republic of China
| | - Zhao Wang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, 510080 Guangzhou, Guangdong Province People’s Republic of China
| | - Jianbo Xu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, 510080 Guangzhou, Guangdong Province People’s Republic of China
| | - Hui Wu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, 510080 Guangzhou, Guangdong Province People’s Republic of China
| | - Shirong Cai
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, 510080 Guangzhou, Guangdong Province People’s Republic of China
| | - Yulong He
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, 510080 Guangzhou, Guangdong Province People’s Republic of China
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33
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Sturesson C, Nilsson J, Lindell G, Andersson RG, Keussen I. Disappearing liver metastases from colorectal cancer: impact of modern imaging modalities. HPB (Oxford) 2015; 17:983-987. [PMID: 26252426 PMCID: PMC4605336 DOI: 10.1111/hpb.12476] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 06/17/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Chemotherapy is often used before a resection for colorectal liver metastases. After chemotherapy, metastases may disappear on cross-sectional imaging but residual metastatic disease may still exist. The aim of this retrospective study was to investigate the impact of new advancements in imaging technology such as magnetic resonance imaging (MRI) with liver-specific contrast (Gd-EOB-DTPA) and contrast-enhanced intra-operative ultrasound (CE-IOUS) on disappearing liver metastases (DLM). METHODS Twenty-nine patients with one or more DLM undergoing surgical exploration were included. Pre-operative imaging consisted of contrast-enhanced multi-detector computed tomography (MDCT) and/or MRI with liver-specific contrast. At surgery, CE-IOUS was used when tumours known from pre-chemotherapy imaging were not found by inspection or intra-operative ultrasound. RESULTS Patients presented 66 DLM. At surgical exploration, 42 DLM were identified and treated (64%). CE-IOUS detected one additional DLM not found by intra-operative ultrasound. For metastases ≤10 mm on histological analysis, imaging sensitivities for MRI and MDCT before surgery but after chemotherapy were 26/49 (53%) and 24/66 (36%), respectively. CONCLUSION A majority of DLM are identified during surgery using intra-operative ultrasound, with only little additional value of CE-IOUS. The sensitivities of post-chemotherapy imaging modalities for small metastases are low in the setting of DLM. For surgical planning, an optimized pre-chemotherapy imaging is essential.
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Affiliation(s)
- Christian Sturesson
- Department of Clinical Sciences, Lund, Surgery, Lund University, Skåne University HospitalLund, Sweden
| | - Jan Nilsson
- Department of Clinical Sciences, Lund, Surgery, Lund University, Skåne University HospitalLund, Sweden
| | - Gert Lindell
- Department of Clinical Sciences, Lund, Surgery, Lund University, Skåne University HospitalLund, Sweden
| | - Roland G Andersson
- Department of Clinical Sciences, Lund, Surgery, Lund University, Skåne University HospitalLund, Sweden
| | - Inger Keussen
- Department of Radiology, Lund University, Skåne University HospitalLund, Sweden
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Ryu JS, Kim L, Kim WC, Kim JS, Memon A, Yi BR, Kim HJ. Interpretation of a heterogeneous radiological response as tumor heterogeneity or a non-tumor diagnosis: A case report. Oncol Lett 2015; 10:2953-2956. [PMID: 26722270 DOI: 10.3892/ol.2015.3709] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 08/17/2015] [Indexed: 12/20/2022] Open
Abstract
Heterogeneous radiological responses (HRRs) among tumor lesions are usually observed following chemotherapy or radiation treatment in cancer patients. When HRR is observed after chemotherapy or radiation treatment, a change in anticancer treatment is recommended due to the clinically high suspicion of resistance in the majority of cases. The present study reports the case report of a patient with limited-stage small cell lung cancer, diagnosed by bronchoscopy, who received concurrent chemoradiation therapy. Upon response evaluation, the majority of lesions irradiated had nearly completely disappeared following treatment, but one lesion had apparently increased in size. For histological confirmation, a percutaneous needle biopsy for the lesion was performed, however, non-specific necrosis was found and the results were inconclusive for the differentiation of other causes from tumor necrosis. Several acid-fast bacilli were identified on Ziehl-Neelsen staining for the differential diagnosis. This case suggests that a non-tumor diagnosis should be considered when HRR presents after treatment that is expected to result in a higher response rate, particularly in tuberculosis endemic areas.
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Affiliation(s)
- Jeong-Seon Ryu
- Center for Lung Cancer, Inha University Hospital, Incheon 400-711, Republic of Korea ; Department of Internal Medicine, Inha University Hospital, Incheon 400-711, Republic of Korea
| | - Lucia Kim
- Department of Pathology, Inha University Hospital, Incheon 400-711, Republic of Korea
| | - Woo Chul Kim
- Department of Radiation Oncology, Inha University Hospital, Incheon 400-711, Republic of Korea
| | - Jung-Soo Kim
- Center for Lung Cancer, Inha University Hospital, Incheon 400-711, Republic of Korea ; Department of Internal Medicine, Inha University Hospital, Incheon 400-711, Republic of Korea
| | - Azra Memon
- Center for Lung Cancer, Inha University Hospital, Incheon 400-711, Republic of Korea ; Department of Internal Medicine, Inha University Hospital, Incheon 400-711, Republic of Korea
| | - Bo-Rim Yi
- Center for Lung Cancer, Inha University Hospital, Incheon 400-711, Republic of Korea ; Department of Internal Medicine, Inha University Hospital, Incheon 400-711, Republic of Korea
| | - Hyun-Jung Kim
- Center for Lung Cancer, Inha University Hospital, Incheon 400-711, Republic of Korea ; Department of Internal Medicine, Inha University Hospital, Incheon 400-711, Republic of Korea
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Wagner M, Ronot M, Doblas S, Giraudeau C, Van Beers B, Belghiti J, Paradis V, Vilgrain V. Assessment of the residual tumour of colorectal liver metastases after chemotherapy: diffusion-weighted MR magnetic resonance imaging in the peripheral and entire tumour. Eur Radiol 2015; 26:206-15. [DOI: 10.1007/s00330-015-3800-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Revised: 04/07/2015] [Accepted: 04/13/2015] [Indexed: 12/13/2022]
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36
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Prognostic value of pretreatment serum lactate dehydrogenase level in patients with solid tumors: a systematic review and meta-analysis. Sci Rep 2015; 5:9800. [PMID: 25902419 PMCID: PMC5386114 DOI: 10.1038/srep09800] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 02/04/2015] [Indexed: 02/06/2023] Open
Abstract
Although most studies have reported that high serum lactate dehydrogenase (LDH) levels are associated with poor prognosis in several malignancies, the consistency and magnitude of the impact of LDH are unclear. We conducted the first comprehensive meta-analysis of the prognostic relevance of LDH in solid tumors. Overall survival (OS) was the primary outcome; progression-free survival (PFS) and disease-free survival (DFS) were secondary outcomes. We identified a total of 68 eligible studies that included 31,857 patients. High LDH was associated with a HR for OS of 1.48 (95% CI = 1.43 to 1.53; P < 0.00001; I2 = 93%), an effect observed in all disease subgroups, sites, stages and cutoff of LDH. HRs for PFS and DFS were 1.70 (95% CI = 1.44 to 2.01; P < 0.00001; I2 = 13%) and 1.86(95% CI = 1.15 to 3.01; P = 0.01; I2 = 88%), respectively. Analysis of LDH as a continuous variable showed poorer OS with increasing LDH (HR 2.11; 95% CI = 1.35 to 3.28). Sensitivity analyses showed there was no association between LDH cutoff and reported HR for OS. High LDH is associated with an adverse prognosis in many solid tumors and its additional prognostic and predictive value for clinical decision-making warrants further investigation.
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