title: Tumor Hypoxia Response After Targeted Therapy in EGFR-Mutant Non-Small Cell Lung Cancer: Proof of Concept for FMISO-PET.
abstract: Hypoxia is associated with resistance to radiotherapy and chemotherapy. Functional imaging of hypoxia in non-small cell lung cancer (NSCLC) could allow early assessment of tumor response and guide subsequent therapies. Epidermal growth factor receptor (EGFR) inhibition with erlotinib reduces hypoxia in vivo. [18F]-Fluoromisonidazole (FMISO) is a radiolabeled tracer that selectively accumulates in hypoxic cells. We sought to determine whether FMISO positron emission tomography (FMISO-PET) could detect changes in hypoxia in vivo in response to EGFR-targeted therapy. In a preclinical investigation, nude mice with human EGFR-mutant lung adenocarcinoma xenografts underwent FMISO-PET scans before and 5 days after erlotinib or empty vehicle initiation. Descriptive statistics and analysis of variance (ANOVA) tests were used to analyze changes in standardized uptake value (SUV), with pooled analyses for the mice in each group (baseline, postvehicle, and posterlotinib). In a small correlative pilot human study, patients with EGFR-mutant metastatic NSCLC underwent FMISO-PET scans before and 10 to 12 days after erlotinib initiation. Changes in SUV were compared to standard chest computed tomography (CT) scans performed 6 weeks after erlotinib initiation. The mean (±standard error of the mean; SUVmean) of the xenografts was 0.17 ± 0.014, 0.14 ± 0.008, and 0.06 ± 0.004 for baseline, postvehicle, and posterlotinib groups, respectively, with lower SUVmean among the posterlotinib group compared to other groups (P < .05). Changes on preclinical PET imaging were striking, with near-complete disappearance of FMISO uptake after erlotinib initiation. Two patients were enrolled on the pilot study. In the first patient, SUVmean increased by 21% after erlotinib, with progression on 6-week chest CT followed by death after 4.8 months. In the second patient, SUVmean decreased by 7% after erlotinib, with regression on 6-week chest CT accompanied by clinical improvement; the patient had stable disease at 14.5 months. In conclusion, we observed that FMISO-PET can detect changes in hypoxia levels after EGFR-directed therapy in EGFR-mutant NSCLC. Further study is warranted to determine its utility as an imaging biomarker of early response to EGFR-directed therapy.
authors.affiliation: Department of Radiation Oncology, Dana-Farber/Brigham & Women's Cancer Center, Boston, MA, USA narvold@partners.org.
authors.forename: Nils D
authors.initials: ND
authors.lastname: Arvold
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Pedram
authors.initials: P
authors.lastname: Heidari
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Anchisa
authors.initials: A
authors.lastname: Kunawudhi
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000188:drug therapy*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008819:Mice, Nude; D008920:Misonidazole / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D058990:Molecular Targeted Therapy; D010865:Pilot Projects; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019275:Radiopharmaceuticals; C031843:fluoromisonidazole; D008920:Misonidazole; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; FMISO; PET; erlotinib; hypoxia; lung cancer