Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers.
Aparna Raj Parikh,Ignaty Leshchiner,Liudmila Elagina,Lipika Goyal,Chaya Levovitz,Giulia Siravegna,Dimitri Livitz,Kahn Rhrissorrakrai,Elizabeth E. Martin,Emily E. Van Seventer,Megan Hanna,Kara Slowik,Filippo Utro,Christopher J. Pinto,Alicia Wong,Brian P. Danysh,Ferran Fece de la Cruz,Isobel J Fetter,Brandon Nadres,Heather A. Shahzade,Jill N. Allen,Lawrence S. Blaszkowsky,Jeffrey W. Clark,Bruce J. Giantonio,Janet E. Murphy,Ryan D. Nipp,Eric Roeland,David P. Ryan,Colin D. Weekes,Eunice L. Kwak,Jason E. Faris,Jennifer Y. Wo,François Aguet,Ipsita Dey-Guha,Mehlika Hazar-Rethinam,Dora Dias-Santagata,David T. Ting,Andrew X. Zhu,Theodore S. Hong,Todd R. Golub,Todd R. Golub,Todd R. Golub,A. John Iafrate,Viktor A. Adalsteinsson,Alberto Bardelli,Laxmi Parida,Dejan Juric,Gad Getz,Ryan B. Corcoran +48 more
TLDR
Direct prospective comparison of circulating tumor DNA and tissue biopsy sequencing shows the superiority of liquid biopsies for capturing clinically relevant alterations mediating resistance to targeted therapies in cancer patients.Abstract:
During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1–3. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4–8. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the ‘rule’ rather than the ‘exception’. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance. Direct prospective comparison of circulating tumor DNA and tissue biopsy sequencing shows the superiority of liquid biopsies for capturing clinically relevant alterations mediating resistance to targeted therapies in cancer patients.read more
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Liquid biopsy enters the clinic - implementation issues and future challenges.
TL;DR: In this article, the authors discuss key issues and gaps in technology, clinical trial methodologies and logistics for the eventual integration of liquid biopsy into the clinical workflow, and discuss the potential applications of this technology in cancer screening and diagnosis.
Journal ArticleDOI
High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants.
Pedram Razavi,Bob T. Li,David N Brown,Byoungsok Jung,Earl Hubbell,Ronglai Shen,Wassim Abida,Krishna Juluru,Ino de Bruijn,Chenlu Hou,Oliver Venn,Raymond S. Lim,Aseem Anand,Tara Maddala,Sante Gnerre,Ravi Vijaya Satya,Qinwen Liu,Ling Shen,Nicholas Eattock,Jeanne Yue,Alexander W. Blocker,Mark Lee,Amy J. Sehnert,Hui Xu,Megan P. Hall,Angie Santiago-Zayas,William Novotny,James M. Isbell,Valerie W. Rusch,George Plitas,Alexandra S. Heerdt,Marc Ladanyi,David M. Hyman,David R. Jones,Monica Morrow,Gregory J. Riely,Howard I. Scher,Charles M. Rudin,Mark E. Robson,Luis A. Diaz,David B. Solit,Alex Aravanis,Jorge S. Reis-Filho +42 more
TL;DR: Ultra-sensitive cell-free DNA (cfDNA) sequencing uncovers clonal hematopoiesis as a major source of somatic cfDNA variants in healthy individuals and patients with cancer, and underscores the importance of matched white blood cell DNA sequencing in liquid biopsy procedures.
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Targeting metastatic cancer.
TL;DR: A review of recent progress that is enabling therapeutic advances in treating both micro- and macrometastases can be found in this paper, where the authors reveal both the origins and nature of metastases and identify new opportunities for developing more effective strategies to target metastatic relapse and improve patient outcomes.
Journal ArticleDOI
Exosome-based liquid biopsies in cancer: opportunities and challenges.
W. Yu,James Hurley,D. Roberts,Sudipto K. Chakrabortty,D. Enderle,Mikkel Noerholm,Xandra O. Breakefield,Johan Skog +7 more
TL;DR: In this article, the authors discuss the advantages and challenges of exosome-based liquid biopsies for tumor biomarkers and clinical implementation in the context of circulating tumor DNA and circulating tumor cells.
Journal ArticleDOI
Targeted therapy for hepatocellular carcinoma.
TL;DR: Combination therapies, including anti-angiogenesis agents with ICIs, dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies, have shown promise and provided the basis for exciting clinical trials.
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TL;DR: The ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types was evaluated and suggested that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes.
Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples
Kristian Cibulskis,Andrey Sivachenko,David B. Jaffe,Carrie Sougnez,Stacey Gabriel,Matthew Meyerson,Gad Getz,Eric S. Lander,Michael S. Lawrence,Scott L. Carter +9 more
TL;DR: MuTect is presented, a method that applies a Bayesian classifier to detect somatic mutations with very low allele fractions, requiring only a few supporting reads, followed by carefully tuned filters that ensure high specificity.
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Absolute quantification of somatic DNA alterations in human cancer
Scott L. Carter,Kristian Cibulskis,Elena Helman,Elena Helman,Aaron McKenna,Hui Shen,Travis I. Zack,Peter W. Laird,Robert C. Onofrio,Wendy Winckler,Barbara A. Weir,Rameen Beroukhim,Rameen Beroukhim,Rameen Beroukhim,David Pellman,Douglas A. Levine,Eric S. Lander,Eric S. Lander,Eric S. Lander,Matthew Meyerson,Matthew Meyerson,Gad Getz +21 more
TL;DR: A computational method that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations is described, revealing that genome-doubling events are common in human cancer, likely occur in cells that are already aneuploid, and influence pathways of tumor progression.
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