@article{701761fc8c2b41e5b312d94680925e30,
title = "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)",
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 {\textquoteleft}tumor{\textquoteright} 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 {\textquoteleft}Immune-Related Pathologic Response Criteria{\textquoteright} (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 ¼ 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P ¼ 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.",
keywords = "IrPRC, Lung carcinoma, Neoadjuvant, PD-1, Pathologic response",
author = "Cottrell, {T. R.} and Thompson, {E. D.} and Forde, {P. M.} and Stein, {J. E.} and Duffield, {Amy S} and V. Anagnostou and N. Rekhtman and Anders, {R. A.} and Jonathan Cuda and Illei, {P. B.} and E. Gabrielson and Askin, {F. B.} and N. Niknafs and Smith, {K. N.} and Velez, {M. J.} and Sauter, {J. L.} and Isbell, {J. M.} and Jones, {D. R.} and Battafarano, {R. J.} and Yang, {S. C.} and L. Danilova and Wolchok, {J. D.} and Topalian, {S. L.} and Velculescu, {V. E.} and Pardoll, {D. M.} and Brahmer, {J. R.} and Hellmann, {M. D.} and Chaft, {J. E.} and A. Cimino-Mathews and Taube, {J. M.}",
note = "Funding Information: This work was supported by Bristol-Myers Squibb and the International Immuno-Oncology Network (JMT, SLT, DMP, and clinical trial investigators); Sidney Kimmel Cancer Center Core Grant P30 CA006973 (JMT); National Cancer Institute R01 CA142779 (JMT, SLT, DMP); NIH T32 CA193145 (TRC); LCFA/IASLC grant #125133 (KNS); CA121113 (VEV, VA); CA180950 (VEV); the LUNGevity Foundation (VA, PMF); the V Foundation (VA); the MacMillan Foundation (VA); the International Association for the Study of Lung Cancer, Prevent Cancer & ECOG-ACRIN (PMF); Memorial Sloan Kettering Cancer Center Core Grant NIH P30 CA008748 (all MSKCC investigators). The Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy; and Stand Up To Cancer–Cancer Research Institute Cancer Immunology Translational Cancer Research Grant SU2C-AACR-DT1012. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. Funding Information: EDT, PMF, JDC, EG, JDW, JRB, AC-M: Bristol-Myers Squibb. RAA: Bristol-Myers Squibb, Merck, Five Prime Therapeutics, and Adaptive Biotechnologies. PBI: Genentech; Roche, AstraZeneca, Bristol-Myers Squibb, and AbbVie. JLS: Merck. SLT: Research grants from Bristol-Myers Squibb; consulting and stock, Five Prime Therapeutics. VEV: Personal Genome Diagnostics; Ignyta. DMP: Research grants from Bristol-Myers Squibb; patent royalties through institution, Bristol-Myers Squibb and Potenza Therapeutics; and consulting, Amgen, Merck, MedImmune, Five Prime Therapeutics, and Potenza Therapeutics. MDH: Bristol-Myers Squibb, Merck, AstraZeneca, Genentech/Roche, Janssen, Novartis, Mirati, and Shattuck Labs. JEC: Bristol-Myers Squibb, Merck, AstraZeneca, and Genentech. JMT: Bristol-Myers Squibb, Amgen, AstraZeneca, and Merck. TRC, JES, ASD, VA, NR, FA, NN, KNS, MV, JMI, DRJ, RB, SCY, and LD have declared no conflicts of interest. Publisher Copyright: {\textcopyright} The Author(s) 2018.",
year = "2018",
month = aug,
doi = "10.1093/annonc/mdy218",
language = "English (US)",
volume = "29",
pages = "1853--1860",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "8",
}