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

Abstract

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. 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. 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). 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.