T R Cottrell1, E D Thompson2, P M Forde3, J E Stein4, A S Duffield1, V Anagnostou5, N Rekhtman6, R A Anders7, J D Cuda8, P B Illei9, E Gabrielson9, F B Askin1, N Niknafs5, K N Smith3, M J Velez6, J L Sauter6, J M Isbell10, D R Jones10, R J Battafarano11, S C Yang11, L Danilova12, J D Wolchok13, S L Topalian14, V E Velculescu3, D M Pardoll3, J R Brahmer3, M D Hellmann15, J E Chaft16, A Cimino-Mathews9, J M Taube17. 1. Department of Pathology, Johns Hopkins University SOM, Baltimore, USA. 2. Department of Pathology, Johns Hopkins University SOM, Baltimore, USA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University SOM, Baltimore, USA; The Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, USA. 3. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University SOM, Baltimore, USA; The Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, USA. 4. Department of Dermatology, Johns Hopkins University SOM, Baltimore, USA. 5. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University SOM, Baltimore, USA. 6. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA. 7. Department of Pathology, Johns Hopkins University SOM, Baltimore, USA; The Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, USA. 8. Department of Pathology, Johns Hopkins University SOM, Baltimore, USA; Department of Dermatology, Johns Hopkins University SOM, Baltimore, USA. 9. Department of Pathology, Johns Hopkins University SOM, Baltimore, USA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University SOM, Baltimore, USA. 10. Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA. 11. Department of Surgery, Johns Hopkins University SOM, Baltimore, USA. 12. The Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, USA; Division of Biostatistics and Bioinformatics, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University SOM, Baltimore, USA. 13. Melanoma and Immunotherapeutics Service, Division of Solid Tumor Oncology, Department of Medicine, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, USA; Weill Cornell Medical College, New York, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, USA. 14. The Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, USA; Department of Surgery, Johns Hopkins University SOM, Baltimore, USA. 15. Weill Cornell Medical College, New York, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, USA; Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. 16. Weill Cornell Medical College, New York, USA; Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. 17. Department of Pathology, Johns Hopkins University SOM, Baltimore, USA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University SOM, Baltimore, USA; The Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, USA; Department of Dermatology, Johns Hopkins University SOM, Baltimore, USA. Electronic address: jtaube1@jhmi.edu.
Abstract
Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed. Patients and methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed. Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002). Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.
Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed. Patients and methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed. Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002). Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.
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