The tumor-stroma ratio in giant cell tumor of bone: associations with the immune microenvironment and responsiveness to denosumab treatment.
Denosumab
Giant cell tumor of bone
Prognostic biomarker
The immune microenvironment
Tumor-stroma ratio
Journal
Journal of orthopaedic surgery and research
ISSN: 1749-799X
Titre abrégé: J Orthop Surg Res
Pays: England
ID NLM: 101265112
Informations de publication
Date de publication:
15 Jul 2024
15 Jul 2024
Historique:
received:
31
03
2024
accepted:
27
06
2024
medline:
16
7
2024
pubmed:
16
7
2024
entrez:
15
7
2024
Statut:
epublish
Résumé
Currently, there is limited understanding regarding the clinical significance of the tumor-stroma ratio (TSR) in giant cell tumor of bone (GCTB). Hence, we aimed to investigate the distribution of TSR in GCTB and explore its correlation with various clinicopathologic factors, immune microenvironment, survival prognosis, and denosumab treatment responsiveness. We conducted a multicenter cohort study comprising 426 GCTB patients treated at four centers. TSR was evaluated on hematoxylin and eosin-stained and immunofluorescent sections of tumor specimens. Immunohistochemistry was performed to assess CD3+, CD4+, CD8+, CD20+, PD-1+, PD-L1+, and FoxP3+ TIL subtypes as well as Ki-67 expression levels in 426 tissue specimens. These parameters were then analyzed for their correlations with patient outcomes [local recurrence-free survival (LRFS) and overall survival (OS)], clinicopathological features, and denosumab treatment responsiveness. Low TSR was significantly associated with poor LRFS and OS in both cohorts. Furthermore, TSR was also correlated with multiple clinicopathological features, TIL subtype expression, and denosumab treatment responsiveness. TSR demonstrated similar predictive capabilities as the conventional Campanacci staging system for predicting patients' LRFS and OS. The results of this study provide evidence supporting the use of TSR as a reliable prognostic tool in GCTB and as a predictor of denosumab treatment responsiveness. These findings may aid in developing individualized treatment strategies for GCTB patients in the future.
Sections du résumé
BACKGROUND
BACKGROUND
Currently, there is limited understanding regarding the clinical significance of the tumor-stroma ratio (TSR) in giant cell tumor of bone (GCTB). Hence, we aimed to investigate the distribution of TSR in GCTB and explore its correlation with various clinicopathologic factors, immune microenvironment, survival prognosis, and denosumab treatment responsiveness.
METHODS
METHODS
We conducted a multicenter cohort study comprising 426 GCTB patients treated at four centers. TSR was evaluated on hematoxylin and eosin-stained and immunofluorescent sections of tumor specimens. Immunohistochemistry was performed to assess CD3+, CD4+, CD8+, CD20+, PD-1+, PD-L1+, and FoxP3+ TIL subtypes as well as Ki-67 expression levels in 426 tissue specimens. These parameters were then analyzed for their correlations with patient outcomes [local recurrence-free survival (LRFS) and overall survival (OS)], clinicopathological features, and denosumab treatment responsiveness.
RESULTS
RESULTS
Low TSR was significantly associated with poor LRFS and OS in both cohorts. Furthermore, TSR was also correlated with multiple clinicopathological features, TIL subtype expression, and denosumab treatment responsiveness. TSR demonstrated similar predictive capabilities as the conventional Campanacci staging system for predicting patients' LRFS and OS.
CONCLUSION
CONCLUSIONS
The results of this study provide evidence supporting the use of TSR as a reliable prognostic tool in GCTB and as a predictor of denosumab treatment responsiveness. These findings may aid in developing individualized treatment strategies for GCTB patients in the future.
Identifiants
pubmed: 39010095
doi: 10.1186/s13018-024-04885-8
pii: 10.1186/s13018-024-04885-8
doi:
Substances chimiques
Denosumab
4EQZ6YO2HI
Bone Density Conservation Agents
0
Types de publication
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
405Subventions
Organisme : National Natural Science Foundation of China
ID : 81871821
Organisme : China Scholarship Council
ID : 202106370071
Informations de copyright
© 2024. The Author(s).
Références
He Y, Cheng D, Lian C, et al. Serglycin induces osteoclastogenesis and promotes tumor growth in giant cell tumor of bone. Cell Death Dis. 2021;12(10):868.
doi: 10.1038/s41419-021-04161-1
pubmed: 34556636
pmcid: 8460728
Van der Heijden L, Dijkstra PDS, Blay JY, Gelderblom H. Giant cell tumour of bone in the denosumab era. Eur J Cancer. 2017;77:75–83.
doi: 10.1016/j.ejca.2017.02.021
pubmed: 28365529
Boriani S, Cecchinato R, Cuzzocrea F, Bandiera S, Gambarotti M, Gasbarrini A. Denosumab in the treatment of giant cell tumor of the spine. Preliminary report, review of the literature and protocol proposal. Eur Spine J. 2020;29(2):257–271.
Li H, Gao J, Gao Y, Lin N, Zheng M, Ye Z. Denosumab in giant cell tumor of bone: current status and pitfalls. Front Oncol. 2020;10:580605.
doi: 10.3389/fonc.2020.580605
pubmed: 33123484
pmcid: 7567019
Asano N, Saito M, Kobayashi E, et al. Preoperative denosumab therapy against giant cell tumor of bone is associated with an increased risk of local recurrence after curettage surgery. Ann Surg Oncol. 2022;29(6):3992–4000.
doi: 10.1245/s10434-022-11411-9
pubmed: 35175454
Toda Y, Kohashi K, Yamamoto H, et al. Tumor microenvironment in giant cell tumor of bone: evaluation of PD-L1 expression and SIRPα infiltration after denosumab treatment. Sci Rep. 2021;11(1):14821.
doi: 10.1038/s41598-021-94022-w
pubmed: 34285260
pmcid: 8292371
Zheng BW, Zheng BY, Niu HQ, et al. Tumor growth rate in spinal giant cell tumors of bone and association with the immune microenvironment and denosumab treatment responsiveness: a multicenter study. Neurosurgery. 2023;92(3):524–37.
doi: 10.1227/neu.0000000000002237
pubmed: 36409294
Kairaluoma V, Kemi N, Pohjanen VM, Saarnio J, Helminen O. Tumour budding and tumor-stroma ratio in hepatocellular carcinoma. Br J Cancer. 2020;123(1):38–45.
doi: 10.1038/s41416-020-0847-1
pubmed: 32362654
pmcid: 7341881
Zou MX, Zheng BW, Liu FS, et al. The relationship between tumor-stroma ratio, the immune microenvironment, and survival in patients with spinal chordoma. Neurosurgery. 2019;85(6):E1095–110.
doi: 10.1093/neuros/nyz333
pubmed: 31501892
Gentles AJ, Bratman SV, Lee LJ, et al. Integrating tumor and stromal gene expression signatures with clinical indices for survival stratification of early-stage non-small cell lung cancer. J Natl Cancer Inst. 2015;107(10):djv211.
Natrajan R, Sailem H, Mardakheh FK, et al. Microenvironmental heterogeneity parallels breast cancer progression: a histology-genomic integration analysis. PLoS Med. 2016;13(2):e1001961.
doi: 10.1371/journal.pmed.1001961
pubmed: 26881778
pmcid: 4755617
Finak G, Bertos N, Pepin F, et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med. 2008;14(5):518–27.
doi: 10.1038/nm1764
pubmed: 18438415
Mo F, Lin D, Takhar M, et al. Stromal gene expression is predictive for metastatic primary prostate cancer. Eur Urol. 2018;73(4):524–32.
doi: 10.1016/j.eururo.2017.02.038
pubmed: 28330676
Valkenburg KC, de Groot AE, Pienta KJ. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol. 2018;15(6):366–81.
doi: 10.1038/s41571-018-0007-1
pubmed: 29651130
pmcid: 5960434
Yamamoto H, Iwasaki T, Yamada Y, et al. Diagnostic utility of histone H3.3 G34W, G34R, and G34V mutant-specific antibodies for giant cell tumors of bone. Hum Pathol. 2018;73:41–50.
Khazaei S, De Jay N, Deshmukh S, et al. H3.3 G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in giant cell tumor of bone. Cancer Discov. 2020;10(12):1968–1987.
Campanacci M, Baldini N, Boriani S, Sudanese A. Giant-cell tumor of bone. J Bone Joint Surg Am. 1987;69(1):106–14.
doi: 10.2106/00004623-198769010-00018
pubmed: 3805057
Liu FS, Zheng BW, Zhang TL, et al. Clinicopathological and prognostic characteristics in dedifferentiated/poorly differentiated chordomas: a pooled analysis of individual patient data from 58 studies and comparison with conventional chordomas. Front Oncol. 2021;11:686565.
doi: 10.3389/fonc.2021.686565
pubmed: 34490087
pmcid: 8418060
Rutkowski P, Gaston L, Borkowska A, et al. Denosumab treatment of inoperable or locally advanced giant cell tumor of bone: multicenter analysis outside clinical trial. Eur J Surg Oncol. 2018;44(9):1384–90.
doi: 10.1016/j.ejso.2018.03.020
pubmed: 29650420
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.
doi: 10.1016/j.ejca.2008.10.026
pubmed: 19097774
Zheng BW, Yang ML, Huang W, et al. Prognostic significance of tumor-associated macrophages in chondroblastoma and their association with response to adjuvant radiotherapy. J Inflamm Res. 2021;14:1991–2005.
doi: 10.2147/JIR.S308707
pubmed: 34040412
pmcid: 8139723
Meng T, Yin H, Li B, et al. Clinical features and prognostic factors of patients with chordoma in the spine: a retrospective analysis of 153 patients in a single center. Neuro Oncol. 2015;17(5):725–32.
doi: 10.1093/neuonc/nou331
pubmed: 25488908
Zou MX, Lv GH, Wang XB, et al. Clinical impact of the immune microenvironment in spinal chordoma: immunoscore as an independent favorable prognostic factor. Neurosurgery. 2019;84(6):E318–33.
doi: 10.1093/neuros/nyy274
pubmed: 30032257
Zou MX, Pan Y, Huang W, et al. A four-factor immune risk score signature predicts the clinical outcome of patients with spinal chordoma. Clin Transl Med. 2020;10(1):224–37.
doi: 10.1002/ctm2.4
pubmed: 32508056
pmcid: 7240847
Niu HQ, Zheng BY, Zou MX, Zheng BW. Complex immune microenvironment of chordoma: a road map for future treatment. J Immunother Cancer. 2024;12(6):e009313. https://doi.org/10.1136/jitc-2024-009313
doi: 10.1136/jitc-2024-009313
Wu J, Liang C, Chen M, Su W. Association between tumor-stroma ratio and prognosis in solid tumor patients: a systematic review and meta-analysis. Oncotarget. 2016;7(42):68954–65.
doi: 10.18632/oncotarget.12135
pubmed: 27661111
pmcid: 5356603
Lv Z, Cai X, Weng X, et al. Tumor-stroma ratio is a prognostic factor for survival in hepatocellular carcinoma patients after liver resection or transplantation. Surgery. 2015;158(1):142–50.
doi: 10.1016/j.surg.2015.02.013
pubmed: 25890776
Mao SY, Huang TB, Xiong DB, et al. Prognostic value of the tumorstroma ratio in patients with T1 high-grade bladder cancer undergoing transurethral resection of bladder tumor. Int J Clin Exp Pathol. 2017;10(5):5850–8.
Hansen TF, Kjaer-Frifeldt S, Lindebjerg J, et al. Tumor-stroma ratio predicts recurrence in patients with colon cancer treated with neoadjuvant chemotherapy. Acta Oncol (Madr). 2018;57(4):528–33.
doi: 10.1080/0284186X.2017.1385841
Vangangelt KMH, van Pelt GW, Engels CC, et al. Prognostic value of tumorstroma ratio combined with the immune status of tumors in invasive breast carcinoma. Breast Cancer Res Treat. 2018;168(3):601–12.
doi: 10.1007/s10549-017-4617-6
pubmed: 29273955
Gujam FJ, Edwards J, Mohammed ZM, Going JJ, McMillan DC. The relationship between the tumour stroma percentage, clinicopathological characteristics and outcome in patients with operable ductal breast cancer. Br J Cancer. 2014;111(1):157–65.
doi: 10.1038/bjc.2014.279
pubmed: 24874480
pmcid: 4090742
Zhang J, Liu J. Tumor stroma as targets for cancer therapy. Pharmacol Ther. 2013;137(2):200–15.
doi: 10.1016/j.pharmthera.2012.10.003
pubmed: 23064233
Sebens S, Schafer H. The tumor stroma as mediator of drug resistance: a potential target to improve cancer therapy? Curr Pharm Biotechnol. 2012;13(11):2259–72.
doi: 10.2174/138920112802501999
pubmed: 21605068
Spaw M, Anant S, Thomas SM. Stromal contributions to the carcinogenic process. Mol Carcinog. 2017;56(4):1199–213.
doi: 10.1002/mc.22583
pubmed: 27787930
Saito T, Nishikawa H, Wada H, et al. Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med. 2016;22(6):679–84.
doi: 10.1038/nm.4086
pubmed: 27111280
Wang J, Gong R, Zhao C, Lei K, Sun X, Ren H. Human FOXP3 and tumour microenvironment. Immunology. 2022.
Saleh R, Elkord E. FoxP3 T regulatory cells in cancer: prognostic biomarkers and therapeutic targets. Cancer Lett. 2020;490:174–85.
doi: 10.1016/j.canlet.2020.07.022
pubmed: 32721551
Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179.
doi: 10.1038/srep15179
pubmed: 26462617
pmcid: 4604472
Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 2010;11(2):174–83.
doi: 10.1016/S1470-2045(09)70262-1
pubmed: 20152769
Cowan RW, Singh G. Giant cell tumor of bone: a basic science perspective. Bone. 2013;52(1):238–46.
doi: 10.1016/j.bone.2012.10.002
pubmed: 23063845