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      Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention

      Author(s): 1 , 2 , 3 , 4 , 5 , 5 , 6 , 4 , 5 , 4 , 7 , 4 , 4 , 4 , 8 , 5 , 1 , 9 , 1 , 10 , 11 , 2 , 12 , 1 , 11 , 4 , 5 , 4 , 5 , 1 , 11 , 2 , 1 , 11 , 13 , 4 , 5 , 4 , 5 , 4 , 4 , 4 , 4 , 4 , 4 , 5 , 5 , 6 , 1 , 2 , 14 , 1 , 9 , 15 , 1 , 2 , 3 , 1 , 2 , 16 , 1 , 11 , 2 , 1 , 10 , 11 , 2 , 1 , 11 , 2 , 16
      Publication date (Electronic):
      Journal: Science
      Publisher: American Association for the Advancement of Science (AAAS)

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          Abstract

          Cancer treatments are often more successful when the disease is detected early. We evaluated the feasibility and safety of multi-cancer blood testing coupled with PET-CT imaging to detect cancer in a prospective, interventional study of 10,006 women not previously known to have cancer. Positive blood tests were independently confirmed by a diagnostic PET-CT, which also localized the cancer. Twenty-six cancers were detected by blood testing. Of these, 15 underwent PET-CT imaging and nine (60%) were surgically excised. Twenty-four additional cancers were detected by standard-of-care screening and 46 by neither approach. 1.0% of participants underwent PET-CT imaging based on false positive blood tests, and 0.22% underwent a futile invasive diagnostic procedure. These data demonstrate that multi-cancer blood testing combined with PET-CT can be safely incorporated into routine clinical care, in some cases leading to surgery with intent to cure.

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          Detection and quantification of rare mutations with massively parallel sequencing.

          Isaac Kinde, Jian Wu, Nick Papadopoulos … (2011)
          The identification of mutations that are present in a small fraction of DNA templates is essential for progress in several areas of biomedical research. Although massively parallel sequencing instruments are in principle well suited to this task, the error rates in such instruments are generally too high to allow confident identification of rare variants. We here describe an approach that can substantially increase the sensitivity of massively parallel sequencing instruments for this purpose. The keys to this approach, called the Safe-Sequencing System ("Safe-SeqS"), are (i) assignment of a unique identifier (UID) to each template molecule, (ii) amplification of each uniquely tagged template molecule to create UID families, and (iii) redundant sequencing of the amplification products. PCR fragments with the same UID are considered mutant ("supermutants") only if ≥95% of them contain the identical mutation. We illustrate the utility of this approach for determining the fidelity of a polymerase, the accuracy of oligonucleotides synthesized in vitro, and the prevalence of mutations in the nuclear and mitochondrial genomes of normal cells.
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            Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA

            M. Liu, G. Oxnard, E. Klein … (2020)
            Background: Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888 ) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity. Participants and methods: The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization. Results: Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I–III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ~63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%. Conclusions: cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.
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              High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants

              Pedram Razavi, Bob T. Li, David N. Brown … (2019)
              Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding the various biologic compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white-blood cell (WBC) DNA covering a large genomic region (508 genes, 2Mb, >60,000X raw-depth) in a prospective study of 124 metastatic cancer patients, with contemporaneous matched tumor tissue biopsies, and 47 non-cancer controls. The assay displayed a high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA. The vast majority of cfDNA mutations (81.6% in controls and 53.2% in cancer patients) had features consistent with clonal hematopoiesis (CH). This cfDNA sequencing approach revealed that CH constitutes a pervasive biological phenomenon emphasizing the importance of matched cfDNA-WBC sequencing for accurate variant interpretation.
              Article 0 comments Cited 271 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Title: Science
                Abbreviated Title: Science
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Print): 0036-8075
                ISSN (Electronic): 1095-9203
                Publication date (Electronic): April 28 2020
                Page: eabb9601
                Affiliations
                [1 ]Department of Oncology, the Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
                [2 ]The Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
                [3 ]The Department of Medicine Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
                [4 ]Geisinger, 100 N. Academy Avenue Danville, PA 17822,USA.
                [5 ]Thrive Earlier Detection Corp., 38 Sidney Street Cambridge, MA 02139, USA.
                [6 ]Third Rock Ventures, LLC, 29 Newbury Street Boston, MA 02116, USA.
                [7 ]Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 100 Woodruff Circle Atlanta, GA 30322, USA.
                [8 ]Geisinger Cancer Institute, 100 N. Academy Avenue Danville, PA 17822,USA.
                [9 ]The Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
                [10 ]The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
                [11 ]The Ludwig Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
                [12 ]The Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
                [13 ]The Department of Neurosurgery, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
                [14 ]The Department of Epidemiology, the Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street Baltimore, MD 21205, USA.
                [15 ]The Department of Biostatistics, the Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street Baltimore, MD 21205, USA.
                [16 ]The Department of Pathology, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
                Article
                DOI: 10.1126/science.abb9601
                PMC ID: 7509949
                PubMed ID: 32345712
                SO-VID: 39a211b1-6245-4987-bf67-9c98e77c270e
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