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. 2019 Dec;8(6):967-978.
doi: 10.21037/tlcr.2019.12.02.

Patterns and risks of postoperative recurrence in completely resected EGFR-mutant non-small cell lung cancer: prognostic significance of routine immunohistochemical markers

Jianjiao Ni  1   2   3 , Tiantian Guo  1   2   3 , Yuan Li  2   3   4 , Xi Yang  1   2   3 , Yida Li  1   2   3 , Liqing Zou  1   2   3 , Li Chu  1   2   3 , Xiao Chu  1   2   3 , Shuyan Li  1   2   3 , Luxi Ye  1   2   3 , Yawei Zhang  2   3   5 , Zhengfei Zhu  1   2   3
Affiliations

Patterns and risks of postoperative recurrence in completely resected EGFR-mutant non-small cell lung cancer: prognostic significance of routine immunohistochemical markers

Jianjiao Ni et al. Transl Lung Cancer Res. 2019 Dec.

Abstract

Background: Recent studies indicate that EGFR-mutant non-small cell lung cancer (NSCLC) is a heterogeneous disease with varying prognosis. In order to design an optimized surveillance strategy and identify potential candidates for adjuvant therapy, the patterns and risks of postoperative recurrence in completely resected EGFR-mutant NSCLC should be investigated, which are currently largely unknown.

Methods: Consecutive patients with curatively resected EGFR-positive NSCLC receiving standard adjuvant chemotherapy without EGFR tyrosine kinase inhibitors (TKI), with or without adjuvant radiotherapy, from January 2007 to December 2017 in our cancer center, were retrospectively reviewed. Prognostic significance of ten routine immunohistochemical (IHC) markers were examined.

Results: After a median follow-up of 32 (range, 5-122) months, disease recurrence occurred in 197 (37.1%) of the 531 enrolled patients. The frequencies of thoracic recurrence, brain recurrence, bone recurrence, abdominal recurrence and neck recurrence, were 69.0%, 20.8%, 20.8%, 7.1% and 6.6%, respectively. Using the Cox regression model, tumor size, Ki67, CK20, and N stage were identified as independent predictors of overall recurrence. A nomogram predicting the 1-, 2-, and 3-year cumulative rate of overall recurrence was then developed and internally validated, with a bias-corrected C-index of 0.723 (95% CI, 0.675 to 0.771) and a small extent of "over-fitting" (0.8%). Risk factors of site-specific recurrence were also discovered. Additionally, using competing risk analyses, N stage, lymphovascular invasion (LVI) and CK5/6 were found as independent predictors of loco-regional recurrence. Among patients with N2-positive disease (n=91), adjuvant radiotherapy tended to prolong disease free survival (DFS) (P=0.067), but not overall survival (OS) (P=0.271).

Conclusions: This study provides the proof of concept of using routine IHC markers, along with common clinical-pathological parameters, in predicting postoperative recurrence among completely resected EGFR-mutant NSCLC. Adjuvant radiotherapy may improve DFS, but hard to prolong OS in N2-positive EGFR-mutant NSCLC without further biomarker-guided patients' selection.

Keywords: EGFR mutation; Non-small cell lung cancer (NSCLC); adjuvant therapy; immunohistochemical markers; recurrence.

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Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Patterns of initial recurrence in EGFR-mutant NSCLC after curative resection. (A) Pie chart demonstrating the distribution of initial recurrence site; (B) cumulative incidence of overall and site-specific recurrence. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.
Figure 2
Figure 2
Postoperative nomogram predicting 1-, 2-, 3-year RFS probability. To predict the recurrence risk, users can obtain the score of each indicator first by drawing a line vertically to the scale labeled “Points”. Then, add up the corresponding scores of all the indicators. Finally, identify the position of the total score on the “Total Points” scale and draw a line vertically to the “1-Year RFS Probability”, “2-Year RFS Probability” and “3-Year RFS Probability” axes to estimate the probability of RFS. RFS, recurrence-free survival; CK20, cytokeratin 20.
Figure 3
Figure 3
Calibration curves of the nomogram. (A) Comparing nomogram-predicted and actual observed 1-year RFS probability; (B) comparing nomogram-predicted and actual observed 2-year RFS probability; (C) comparing nomogram-predicted and actual observed 3-year RFS probability. The RFS probability predicted by the nomogram is plotted on the X-axis. The actual observed RFS probability is plotted on the Y-axis. The dashed line indicates the ideal concordance of this predictive model. NSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor; RFS, recurrence-free survival.
Figure 4
Figure 4
Prognostic significance of adjuvant radiotherapy in EGFR-mutant NSCLC. Kaplan-Meier survival curve stratified by the status of adjuvant radiotherapy among patients with N2-positive disease. (A) disease free survival; (B) overall survival. RT, patients who received adjuvant radiotherapy; No-RT, patients who did not receive adjuvant radiotherapy.
Figure S1
Figure S1
Flowchart of patient enrollment. NSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor.
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References

    1. Owonikoko TK, Ragin CC, Belani CP, et al. Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database. J Clin Oncol 2007;25:5570-7. 10.1200/JCO.2007.12.5435 - DOI - PubMed
    1. Donington JS, Kim YT, Tong B, et al. Progress in the Management of Early-Stage Non-Small Cell Lung Cancer in 2017. J Thorac Oncol 2018;13:767-78. 10.1016/j.jtho.2018.04.002 - DOI - PubMed
    1. Sugimura H, Nichols FC, Yang P, et al. Survival after recurrent nonsmall-cell lung cancer after complete pulmonary resection. Ann Thorac Surg 2007;83:409-17; discussioin 417-8. - PubMed
    1. Burdett S, Pignon JP, Tierney J, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev 2015;(3):CD011430. - PMC - PubMed
    1. Mikell JL, Gillespie TW, Hall WA, et al. Postoperative radiotherapy is associated with better survival in non-small cell lung cancer with involved N2 lymph nodes: results of an analysis of the National Cancer Data Base. J Thorac Oncol 2015;10:462-71. 10.1097/JTO.0000000000000411 - DOI - PMC - PubMed