{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T21:01:55Z","timestamp":1764968515603,"version":"3.46.0"},"reference-count":41,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"9","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO Precis Oncol"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>PURPOSE<\/jats:title>\n                    <jats:p>To determine whether driver gene alterations in metastatic non\u2013small cell lung carcinoma (NSCLC) spine metastases are associated with local tumor control after radiotherapy (RT).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Patients with NSCLC who underwent RT for spine metastasis and tumor genetic profiling were ascertained. Associations between driver gene mutations incidence of local failure were analyzed, followed by competing risk analysis for significant associations. The results were validated using in vitro clonal survival assays of CRISPR-engineered NSCLC cell lines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      A total of 181 patients were analyzed, with a median follow-up of 15.2 months (IQR, 8.0-31.9 months). The 3-year risk of local failure was 0.15 (95% CI, 0.10 to 0.20). Patients harboring\n                      <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                      or\n                      <jats:italic toggle=\"yes\">BRAF<\/jats:italic>\n                      driver alterations experienced higher 3-year local failure rates (\n                      <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                      : 0.33 [0.09-0.61]\n                      <jats:italic toggle=\"yes\">v<\/jats:italic>\n                      0.13 [0.09-0.19];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .002);\n                      <jats:italic toggle=\"yes\">BRAF<\/jats:italic>\n                      : 0.31 [0.08-0.57]\n                      <jats:italic toggle=\"yes\">v<\/jats:italic>\n                      0.13 [0.09-0.19];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .04).\n                      <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                      loss-of-function mutations conferred radioresistance in one of two NSCLC cell lines tested in vitro. Based on the convergence of\n                      <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">BRAF<\/jats:italic>\n                      signaling, the\n                      <jats:italic toggle=\"yes\">RAS-<\/jats:italic>\n                      mitogen-activated protein kinase (\n                      <jats:italic toggle=\"yes\">MAPK<\/jats:italic>\n                      ) pathway was further interrogated.\n                      <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                      mutations overall were not associated with local failure. However, comutation of\n                      <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                      \/\n                      <jats:italic toggle=\"yes\">TP53<\/jats:italic>\n                      exhibited a trend toward elevated 3-year local failure, 0.31 (0.11-0.55) versus 0.13 (0.08\n                      <jats:italic toggle=\"yes\">v<\/jats:italic>\n                      0.19),\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .05.\n                      <jats:italic toggle=\"yes\">RAS-MAPK<\/jats:italic>\n                      pathway driver alterations accounted for 53% of all local failures (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; .0001) and showed an elevated 3-year risk of local failure (0.36 [0.2-0.51]\n                      <jats:italic toggle=\"yes\">v<\/jats:italic>\n                      0.09 [0.05-0.15];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; .001), including when treated with stereotactic body RT (0.28 [0.1-0.5]\n                      <jats:italic toggle=\"yes\">v<\/jats:italic>\n                      0.05 [0.02-0.11];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      Driver alterations in the\n                      <jats:italic toggle=\"yes\">RAS-MAPK<\/jats:italic>\n                      signaling pathway confer radioresistance in metastatic NSCLC. These genetic alterations may serve as biomarkers to personalize RT strategies or as targets to enhance radiosensitivity.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1200\/po-25-00082","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T20:58:07Z","timestamp":1764968287000},"update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Impact of RAS-MAPK Pathway Genetic Alterations on Radiotherapy Response in Metastatic Lung Adenocarcinoma"],"prefix":"10.1200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4749-6093","authenticated-orcid":true,"given":"Gustav Y.","family":"Cederquist","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik S.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Lis","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6279-9987","authenticated-orcid":true,"given":"Lily","family":"Boe","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1775-037X","authenticated-orcid":true,"given":"William C.","family":"Newman","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4037-8716","authenticated-orcid":true,"given":"Ori","family":"Barzilai","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Bilsky","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiya","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6686-7454","authenticated-orcid":true,"given":"Daniel S.","family":"Higginson","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam M.","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"233","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.5351"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.00201"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.3501"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.75.4853"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32487-5"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.0147"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-2859"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0127"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-0282"},{"key":"e_1_3_6_11_2","first-page":"91","article-title":"PIK3CA mutation is associated with increased local failure in lung stereotactic body radiation therapy (SBRT)","volume":"7","author":"Lockney NA","year":"2017","unstructured":"Lockney NA, Yang TJ, Barron D, et al: PIK3CA mutation is associated with increased local failure in lung stereotactic body radiation therapy (SBRT). 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