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      Longitudinal Undetectable Molecular Residual Disease Defines Potentially Cured Population in Localized Non–Small Cell Lung Cancer

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          Abstract

          A prospective observational study confirms the value of molecular residual disease (MRD) for patients with stage I–IIIA non–small cell lung cancer after resection, highlighting the negative predictive value of longitudinal undetectable MRD.

          Abstract

          The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non–small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD ( n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC.

          Significance:

          This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection.

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          Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.

          Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow-biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.).
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            Tracking the Evolution of Non–Small-Cell Lung Cancer

            Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC.
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              Osimertinib in Resected EGFR-Mutated Non–Small-Cell Lung Cancer

              Osimertinib is standard-of-care therapy for previously untreated epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC). The efficacy and safety of osimertinib as adjuvant therapy are unknown.
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                Author and article information

                Journal
                Cancer Discov
                Cancer Discov
                Cancer Discovery
                American Association for Cancer Research
                2159-8274
                2159-8290
                06 July 2022
                11 May 2022
                : 12
                : 7
                : 1690-1701
                Affiliations
                [1 ]Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
                [2 ]Geneplus-Beijing Institute, Beijing, China.
                [3 ]Department of Hematology, First Affiliated Hospital, Institute of Hematology, School of Medicine; Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, Guangdong, China.
                [4 ]Chinese Thoracic Oncology Group (CTONG), Guangzhou, Guangdong, China.
                Author notes
                [#]

                J.-T. Zhang, S.-Y. Liu, W. Gao, and S.-Y.M. Liu contributed equally to this article.

                [* ] Corresponding Authors: Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China. Phone: 86-20-83877855; Fax: 86-20-83844620; E-mail: syylwu@ 123456live.cn ; and Xue-Ning Yang, yangxncn@ 123456qq.com
                Author information
                https://orcid.org/0000-0003-4302-9332
                https://orcid.org/0000-0002-5105-6421
                https://orcid.org/0000-0002-6054-382X
                https://orcid.org/0000-0002-3837-0758
                https://orcid.org/0000-0002-6228-2096
                https://orcid.org/0000-0001-5680-9579
                https://orcid.org/0000-0001-7893-2084
                https://orcid.org/0000-0002-0492-1021
                https://orcid.org/0000-0002-4138-8115
                https://orcid.org/0000-0001-7125-9878
                https://orcid.org/0000-0001-9734-5926
                https://orcid.org/0000-0002-0478-176X
                https://orcid.org/0000-0002-3611-0258
                Article
                CD-21-1486
                10.1158/2159-8290.CD-21-1486
                9394392
                35543554
                c5b725e1-7e26-4c66-8b42-006eacb0da89
                ©2022 The Authors; Published by the American Association for Cancer Research

                This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.

                History
                : 14 December 2021
                : 27 February 2022
                : 01 April 2022
                Page count
                Pages: 12
                Funding
                Funded by: Guangdong Science and Technology Department, DOI https://doi.org/10.13039/501100007162, Translational Medicine in Lung Cancer, DOI ;
                Award ID: 2017B030314120
                Funded by: Leading Medical Talents in Guangdong Province, DOI ;
                Award ID: KJ012019426
                Funded by: Guangdong Provincial People's Hospital Young Talent Project, DOI ;
                Award ID: GDPPHYTP201902
                Award ID: KY012021189
                Funded by: China Postdoctoral Science Foundation, DOI https://doi.org/10.13039/501100002858;
                Award ID: 2021M701422
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                Research Articles

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