Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC)

被引：471

作者：

Cottrell, T. R. ^{[1
]}

Thompson, E. D. ^{[1
,2
,3
]}

Forde, P. M. ^{[2
,3
]}

Stein, J. E. ^{[4
]}

Duffield, A. S. ^{[1
]}

Anagnostou, V. ^{[2
]}

Rekhtman, N. ^{[5
]}

Anders, R. A. ^{[1
,3
]}

Cuda, J. D. ^{[1
,4
]}

Illei, P. B. ^{[1
,2
]}

Gabrielson, E. ^{[1
,2
]}

Askin, F. B. ^{[1
]}

Niknafs, N. ^{[2
]}

Smith, K. N. ^{[2
,3
]}

Velez, M. J. ^{[5
]}

Sauters, J. L. ^{[5
]}

Isbell, J. M. ^{[6
]}

Jones, D. R. ^{[6
]}

Battafarano, R. J. ^{[7
]}

Yang, S. C. ^{[7
]}

Danilova, L. ^{[3
,8
]}

Wolchok, J. D. ^{[9
,10
,11
]}

Topalian, S. L. ^{[3
,7
]}

Velculescu, V. E. ^{[2
,3
]}

Pardoll, D. M. ^{[2
,3
]}

Brahmer, J. R. ^{[2
,3
]}

Hellmann, M. D. ^{[10
,11
,12
]}

Chaft, J. E. ^{[10
,12
]}

Cimino-Mathews, A. ^{[1
,2
]}

Taube, J. M. ^{[1
,2
,3
,4
]}

机构：

[1] Johns Hopkins Univ, Dept Pathol, SOM, Baltimore, MD USA

[2] Johns Hopkins Univ, Dept Oncol, Sidney Kimmel Comprehens Canc Ctr, SOM, Baltimore, MD USA

[3] Johns Hopkins Bloomberg Kimmel Inst Canc Immunoth, Baltimore, MD USA

[4] Johns Hopkins Univ, Dept Dermatol, SOM, Baltimore, MD 21218 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[6] Mem Sloan Kettering Canc Ctr, Dept Surg, Thorac Surg Serv, 1275 York Ave, New York, NY 10021 USA

[7] Johns Hopkins Univ, Dept Surg, SOM, Baltimore, MD USA

[8] Johns Hopkins Univ, Div Biostat & Bioinformat, Sidney Kimmel Comprehens Canc Ctr, SOM, Baltimore, MD USA

[9] Mem Sloan Kettering Canc Ctr, Dept Med, Div Solid Tumor Oncol, Ludwig Ctr Canc Immunotherapy,Melanoma & Immunoth, New York, NY 10021 USA

[10] Weill Cornell Med Coll, New York, NY USA

[11] Mem Sloan Kettering Canc Ctr, Parker Inst Canc Immunotherapy, 1275 York Ave, New York, NY 10021 USA

[12] Mem Sloan Kettering Canc Ctr, Dept Med, Div Solid Tumor Oncol, Thorac Oncol Serv, New York, NY 10021 USA

来源：

ANNALS OF ONCOLOGY | 2018年 / 29卷 / 08期

关键词：

neoadjuvant; PD-1; lung carcinoma; pathologic response; irPRC; INFLAMED TUMOR MICROENVIRONMENT; BREAST-CANCER; DYING CELLS; MELANOMA; CHEMOTHERAPY; SURVIVAL; THERAPY; DRIVERS;

D O I：

10.1093/annonc/mdy218

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：1853 / 1860

页数：8

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