{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T07:09:03Z","timestamp":1784790543439,"version":"3.55.0"},"reference-count":27,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Oncol.","Current Oncology"],"abstract":"<jats:p>Introduction: The prognostic significance of EGFR variant allele frequency (VAF) remains unclear in advanced EGFR-mutant (EGFR-mt) NSCLC. We examined the relationship of EGFR VAF and clinical outcomes in patients treated with first-line osimertinib. Methods: This retrospective cohort study evaluated patients with advanced EGFR-mt NSCLC treated at the Ottawa Hospital between July 2021 and June 2023. Baseline characteristics were collected from electronic medical records. Adjusted VAF (aVAF) was calculated by normalizing EGFR VAF to tumor cellularity and analyzed according to predefined thresholds: aVAF &lt; 50% (low) and aVAF &gt; 100% (high). The primary outcome was progression-free survival (PFS). Results: Of 141 patients diagnosed with EGFR-mt NSCLC, 59 were included. The median age was 70 years, and 70% were females. There were 23 (39.0%) cases with low aVAF and 16 (27.1%) with high aVAF. Neither aVAF &lt; 50% (HR = 1.01; p = 0.76) or aVAF &gt; 100% (HR = 0.81; p = 0.57) was associated with PFS. However, ECOG performance status \u2265 2 (vs 0\u20131; HR = 3.63, p &lt; 0.001), EGFR exon 19 deletion (vs. L858R; HR = 0.50, p = 0.021), and liver involvement (HR = 2.65, p = 0.005) were associated with PFS on multivariable analysis. Discussion: EGFR aVAF was not associated with clinical outcomes. However, established prognostic factors including ECOG performance status, EGFR mutation subtype, and liver involvement were associated with PFS.<\/jats:p>","DOI":"10.3390\/curroncol33080439","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T06:11:42Z","timestamp":1784787102000},"page":"439","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Prognostic Significance of EGFR Adjusted Variant Allele Frequency on First-Line Osimertinib Efficacy in Advanced EGFR-Mutant NSCLC"],"prefix":"10.3390","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6097-1808","authenticated-orcid":false,"given":"William J.","family":"Phillips","sequence":"first","affiliation":[{"name":"University of Colorado Cancer Center, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5030-7487","authenticated-orcid":false,"given":"Russell","family":"Leong","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Yeung","sequence":"additional","affiliation":[{"name":"Molecular Oncology Diagnostics Laboratory, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Al Lawati","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Ross","family":"Camidge","sequence":"additional","affiliation":[{"name":"University of Colorado Cancer Center, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Lo","sequence":"additional","affiliation":[{"name":"Molecular Oncology Diagnostics Laboratory, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3725-9767","authenticated-orcid":false,"given":"Paul","family":"Wheatley-Price","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"78985","DOI":"10.18632\/oncotarget.12587","article-title":"The prevalence of EGFR mutation in patients with non-small cell lung cancer: A systematic review and meta-analysis","volume":"7","author":"Zhang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_2","first-page":"2892","article-title":"EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: A systematic review and global map by ethnicity (mutMapII)","volume":"5","author":"Midha","year":"2015","journal-title":"Am. J. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S1556-0864(15)31573-2","article-title":"Clinicopathologic characteristics of the EGFR gene mutation in non-small cell lung cancer","volume":"1","author":"Tsao","year":"2006","journal-title":"J. Thorac. Oncol."},{"key":"ref_4","first-page":"2191","article-title":"Next-generation sequencing-based detection of EGFR, KRAS, BRAF, NRAS, PIK3CA, Her-2 and TP53 mutations in patients with non-small cell lung cancer","volume":"18","author":"Jing","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1001\/jama.2014.3741","article-title":"Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs","volume":"311","author":"Kris","year":"2014","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/j.trecan.2023.08.011","article-title":"Variant allele frequency: A decision-making tool in precision oncology?","volume":"9","author":"Trapani","year":"2023","journal-title":"Trends Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"i28","DOI":"10.1093\/annonc\/mdx705","article-title":"Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer","volume":"29","author":"Ricordel","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Yang, H., Wen, L., Zhao, C., Li, X., Shan, C., Liu, D., Hong, W., Zhou, Z., Zhou, C., and Cai, L. (2022). EGFR amplification is a putative resistance mechanism for NSCLC-LM patients with TKI therapy and is associated with poor outcome. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.902664"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1056\/NEJMoa1913662","article-title":"Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC","volume":"382","author":"Ramalingam","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1056\/NEJMoa1713137","article-title":"Osimertinib in Untreated EGFR-Mutated Advanced Non\u2013Small-Cell Lung Cancer","volume":"378","author":"Soria","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1056\/NEJMoa2403614","article-title":"Amivantamab Plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC","volume":"391","author":"Cho","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1056\/NEJMoa2306434","article-title":"Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC","volume":"389","author":"Planchard","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Friedlaender, A., Tsantoulis, P., Chevallier, M., De Vito, C., and Addeo, A. (2021). The Impact of Variant Allele Frequency in EGFR Mutated NSCLC Patients on Targeted Therapy. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.644472"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"662","DOI":"10.21037\/tlcr-20-814","article-title":"EGFR variant allele frequency predicts EGFR-TKI efficacy in lung adenocarcinoma: A multicenter study","volume":"10","author":"Gieszer","year":"2021","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1093\/annonc\/mdu251","article-title":"Mutant allele frequency predicts the efficacy of EGFR-TKIs in lung adenocarcinoma harboring the L858R mutation","volume":"25","author":"Ono","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/s41586-023-05729-x","article-title":"The evolution of non-small cell lung cancer metastases in TRACERx","volume":"616","author":"Huebner","year":"2023","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13039-025-00718-3","article-title":"What the VAF? A guide to the interpretation of variant allele fraction, percent mosaicism, and copy number in cancer","volume":"18","author":"Smith","year":"2025","journal-title":"Mol. Cytogenet."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zarabi, S.K., Zhai, L., and Cheng, Y.-W. (2024). A Challenging Correlation between Tumor Cellularity and Somatic Variant Allele Fraction in Lung and Colorectal Cancers\u2014Specimens of Low Tumor Percentage Should Be Analyzed with Caution. Biomolecules, 14.","DOI":"10.3390\/biom14020168"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s11684-022-0946-x","article-title":"Potential unreliability of ALK variant allele frequency in the efficacy prediction of targeted therapy in NSCLC","volume":"17","author":"Rao","year":"2023","journal-title":"Front. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nrm2858","article-title":"Genomic instability\u2014An evolving hallmark of cancer","volume":"11","author":"Negrini","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"75ra26","DOI":"10.1126\/scitranslmed.3002003","article-title":"Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors","volume":"3","author":"Sequist","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.jtho.2022.11.022","article-title":"Molecular Biomarkers of Disease Outcomes and Mechanisms of Acquired Resistance to First-Line Osimertinib in Advanced EGFR-Mutant Lung Cancers","volume":"18","author":"Choudhury","year":"2023","journal-title":"J. Thorac. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.cllc.2025.08.014","article-title":"Refining High-Risk EGFR-Mutant Lung Cancer Patients: The Role of Adjusted Variant Allele Frequency in First-Line Osimertinib Therapy","volume":"27","author":"Brambilla","year":"2025","journal-title":"Clin. Lung Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s11060-017-2590-x","article-title":"High probability and frequency of EGFR mutations in non-small cell lung cancer with brain metastases","volume":"135","author":"Ge","year":"2017","journal-title":"J. Neurooncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100051","DOI":"10.1016\/j.gmg.2025.100051","article-title":"Real-world prognostic factors for first-line EGFR-TKI efficacy in advanced NSCLC patients harboring EGFR 21 L858R mutation","volume":"12","author":"Liu","year":"2025","journal-title":"Glob. Med. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1158\/1078-0432.CCR-05-1846","article-title":"Clinical Course of Patients with Non\u2013Small Cell Lung Cancer and Epidermal Growth Factor Receptor Exon 19 and Exon 21 Mutations Treated with Gefitinib or Erlotinib","volume":"12","author":"Riely","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1007\/s11912-025-01723-w","article-title":"Who Truly Benefits From First-Line Intensification in EGFR-Mutant NSCLC?","volume":"27","author":"Maffezzoli","year":"2025","journal-title":"Curr. Oncol. Rep."}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/33\/8\/439\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T06:33:39Z","timestamp":1784788419000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/33\/8\/439"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,23]]},"references-count":27,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["curroncol33080439"],"URL":"https:\/\/doi.org\/10.3390\/curroncol33080439","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,23]]}}}