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Cited by 20Sarcoma Diagnosis and TreatmentHER2/EGFR in Cancer ResearchBone Tumor Diagnosis and Treatments

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Prognostic significance of the expression of HER family members in primary osteosarcoma

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Wang, Sheng‑Lin, Zhong, Guang‑Xian, Wang, Xin‑Wen, Yu, Feng‑Qiang, Weng, Dan‑Feng, Wang, Xin‑Xing, Lin, Jian‑Hua·2018·Oncology Letters
DOI 10.3892/ol.2018.8931PMC PMC6036504
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Abstract

The prognosis of patients with metastatic osteosarcoma is poor and has shown no significant improvement in nearly 20 years. The human epidermal growth factor (EGF) receptor (HER) family is frequently overexpressed in the majority of human carcinomas, and is involved in promoting the proliferation and survival of cancer cells. However, the role of EGFR and HER‑2 expression in osteosarcoma survival remains controversial and no previous study has simultaneously investigated the association of the expression of all the four HER family members with the prognostic significance of osteosarcoma. Therefore, the present study investigated the expression levels of the complete members of the HER family in osteosarcoma specimens, as well as their associations with the clinicopathological parameters, progression‑free survival (PFS) and overall survival (OS) time of patients with osteosarcoma. The expression of HER family members was detected in osteosarcoma tumor specimens from 60 patients using immunohistochemistry. The association of the expression of HER receptors in osteosarcoma with clinicopathological parameters was analyzed using χ2 test and Fishers exact test. Survival analyses were evaluated by Kaplan‑Meier method and Cox proportional hazards regression model. Overall, 18 (30%), 13 (22%), 23 (38%) and 19 (32%) patients presented with high expression of EGFR, HER‑2, HER‑3 and HER‑4, respectively, and the co‑expression of 2, 3 and all 4 members of the HER family was observed. High expression of EGFR and HER‑4 was associated with distant metastasis. High HER‑3 expression was significantly associated with an advanced Enneking stage and distant metastasis. Multivariate analysis demonstrated that the expression of EGFR, HER‑3, HER‑4, EGFR/HER‑3, EGFR/HER‑4 and HER‑3/HER‑4 was an independent predictor of poor PFS and OS time in osteosarcoma patients with stage I‑IIB disease. In patients with stage IIB osteosarcoma, the expression of HER‑4 and EGFR/HER‑4 demonstrated a more significant effect on PFS and OS time. In conclusion, therapies targeting EGFR, HER‑3 and HER‑4 may provide promising strategies for primary osteosarcoma.

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Figure 1. Immunohistochemical expression of HER family members in osteosarcoma specimens. (A) High EGFR expression: Predominantly membranous with some cytoplasmic brown staining (arrow). (B) Low EGFR expression. (C) High HER-2 expression: Predominantly cytoplasmic brown staining (arrow). (D) Low HER-2 expression. (E) High HER-3 expression: Predominantly nuclear and cytoplasmic brown staining (arrow). (F) Low HER-3 expression. (G) High HER-4 expression: Predominantly nuclear and cytoplasmic brown staining (arrow). (H) Low HER-4 expression. (I) Final HER expression score demonstrating no significant difference among the expression levels of the HER family members. The box-plot was obtained using GraphPad Prism 5.0 (GraphPad Software Inc., San Diego, CA, USA) (original magnification of Fig. A-H, ×200). HER, human epidermal growth factor receptor.
Figure 1. Immunohistochemical expression of HER family members in osteosarcoma specimens. (A) High EGFR expression: Predominantly membranous with some cytoplasmic brown staining (arrow). (B) Low EGFR expression. (C) High HER-2 expression: Predominantly cytoplasmic brown staining (arrow). (D) Low HER-2 expression. (E) High HER-3 expression: Predominantly nuclear and cytoplasmic brown staining (arrow). (F) Low HER-3 expression. (G) High HER-4 expression: Predominantly nuclear and cytoplasmic brown staining (arrow). (H) Low HER-4 expression. (I) Final HER expression score demonstrating no significant difference among the expression levels of the HER family members. The box-plot was obtained using GraphPad Prism 5.0 (GraphPad Software Inc., San Diego, CA, USA) (original magnification of Fig. A-H, ×200). HER, human epidermal growth factor receptor.CC BY-NC-ND · PubMed Central
Figure 2. Kaplan-Meier analyses of PFS and OS time in stage I–IIB osteosarcoma patients. Significant differences in (A) PFS (P=0.033) and (B) OS (P=0.041) time were found between the high and low EGFR expression groups. Significant differences in (C) PFS (P=0.001) and (D) OS (P=0.006) time were found between the high and low HER-3 expression groups. Significant differences in (E) PFS (P=0.010) and (F) OS (P=0.015) time were found between the high and low HER-4 expression groups. HER, human epidermal growth factor receptor; PFS, progression-free survival; OS, overall survival.
Figure 2. Kaplan-Meier analyses of PFS and OS time in stage I–IIB osteosarcoma patients. Significant differences in (A) PFS (P=0.033) and (B) OS (P=0.041) time were found between the high and low EGFR expression groups. Significant differences in (C) PFS (P=0.001) and (D) OS (P=0.006) time were found between the high and low HER-3 expression groups. Significant differences in (E) PFS (P=0.010) and (F) OS (P=0.015) time were found between the high and low HER-4 expression groups. HER, human epidermal growth factor receptor; PFS, progression-free survival; OS, overall survival.CC BY-NC-ND · PubMed Central
Figure 3. Kaplan-Meier analyses of PFS and OS time in stage IIB osteosarcoma patients. Significant differences of PFS time were found between the high and low (A) HER-4 (P=0.002) expression groups and (B) EGFR/HER-4 (P<0.001) expression groups. Significant differences of OS time were found between the high and low (C) HER-4 (P=0.011) expression groups and (D) EGFR/HER-4 (P<0.001) expression groups. HER, human epidermal growth factor receptor; PFS, progression-free survival; OS, overall survival.
Figure 3. Kaplan-Meier analyses of PFS and OS time in stage IIB osteosarcoma patients. Significant differences of PFS time were found between the high and low (A) HER-4 (P=0.002) expression groups and (B) EGFR/HER-4 (P<0.001) expression groups. Significant differences of OS time were found between the high and low (C) HER-4 (P=0.011) expression groups and (D) EGFR/HER-4 (P<0.001) expression groups. HER, human epidermal growth factor receptor; PFS, progression-free survival; OS, overall survival.CC BY-NC-ND · PubMed Central

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Citations

Cites

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Metadata

Authors
Wang, S., Zhong, G., Wang, X., Yu, F., Weng, D., Wang, X., & Lin, J.
Affiliations
  • Department of Orthopedics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
  • First Affiliated Hospital of Fujian Medical University (CN)
ORCID
Zhong, Guang‑Xian
Venue
Oncology Letters
Publisher
Spandidos Publications
Published
2018-06-08
Volume
16
Issue
2
Pages
2185-2194
ISSN
  • 1792-1074 (ISSN-L)
  • 1792-1082
DOI
10.3892/ol.2018.8931
PMC
PMC6036504
OpenAlex
W2807420926
Cited by
20
References
1
Citations by year
2024: 2 · 2023: 7 · 2021: 7 · 2020: 2 · 2019: 1 · 2018: 1
FWCI
2.07
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Oncology Letters (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (31571292)
  • Fujian Medical University
Topics
  • Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone Tumor Diagnosis and Treatments
Keywords
primary osteosarcoma, ErbB receptors, EGFR, HER2, HER3, ErbB4, prognostic factors, progression-free survival, overall survival, distant metastasis, Enneking stage, targeted therapy

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