Distribution and prognostic impact of EGFR and KRAS mutations according to histological subtype and tumor invasion status in pTis-3N0M0 lung adenocarcinoma

Abstract

Background: The prognostic impact of EGFR mutation as major targetable somatic gene variant on lung adenocarcinoma is controversial. KRAS is another major somatic variant in lung adenocarcinoma, and a therapeutic agent for KRAS G12C became available in clinical settings. These mutations represent clinicopathological features of lung adenocarcinoma and can guide the treatment choice after recurrence. We evaluated the prognostic impact of EGFR and KRAS mutations by considering other clinicopathological recurrence risks in resected pTis-3N0M0 lung adenocarcinoma.

Methods: Clinicopathological features related to recurrence and genetic status were estimated in consecutive 877 resected cases. Recurrence-free survival (RFS), cumulative recurrence rate (CRR), and overall survival (OS) were compared. Uni- and multivariate analyses for RFS were performed after excluding cases with little or no recurrence risks.

Results: EGFR mutation was more likely to be harbored in female, never-smoker, or patients accompanied by > 5% lepidic component. KRAS mutation was more likely to be harbored in patients with current/ex-smoking history, International Association for the Study of Lung Cancer (IASLC) grade 3, or accompanied lymphatic or vascular invasion. In IASLC grade 2 and 3 patients, EGFR or KRAS mutation cases had significantly worse 5-year RFS than wild type patients (76.9% vs. 85.0%, hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.62-6.41, P < 0.001). EGFR or KRAS mutation cases had significantly higher 5-year CRR than wild type patients (17.7% vs. 9.8%, HR = 1.69, 95% CI = 1.44-6.59, P = 0.0038). KRAS mutation cases had higher 5-year CRR than EGFR mutation cases (16.7% vs. 21.4%, HR = 1.62, 95% CI = 0.96-7.19, P = 0.061). There was no significant difference in OS between cohorts. Multivariate analysis revealed that a positive EGFR/KRAS mutation status was risk factor for worse RFS (HR = 2.007, 95% CI = 1.265-3.183, P = 0.003).

Conclusion: Positive EGFR and KRAS mutation statuses were risk factors for recurrence in resected IASLC grade 2 and 3 patients. KRAS mutations were more likely to be confirmed in cases with an increased risk of recurrence. EGFR and KRAS mutation statuses should be evaluated simultaneously when assessing the risk of recurrence.

Keywords: EGFR; IASLC; KRAS; Lung adenocarcinoma; Prognosis; Recurrence; Staging; Surgery.

Fig. 1

Comparison of prevalence of clinicopathological features according to mutation status. Results from Table 2 were visualized if there were significant differences between groups. A Female; B never-smoker; C > 5% lepidic component; D > 5% solid component; E solid predominance; F IASLC grade 3; G lymphatic invasion; H vascular invasion. **P < 0.01; *P < 0.05; N.S., not significant. Abbreviations: IASLC, International Association for the Study of Lung Cancer

Fig. 2

RFS, CRR, or OS curves established using the Kaplan–Meier method. A RFS curves by AIS, MIA, and IASLC histological grade. B RFS curves by genetic mutation status in IASLC grade 2 and 3 cases. C CRR curves by genetic mutation status in IASLC grade 2 and 3 cases. D OS curves by genetic mutation status in IASLC grade 2 and 3 cases. Abbreviations: AIS, adenocarcinoma in situ; CRR, cumulative recurrence rate; MIA, minimally invasive adenocarcinoma; OS, overall survival; RFS, recurrence-free survival

Fig. 3

Heatmap showing the five-year RFS rate and Bliss images representing the distribution of cases harboring EGFR or KRAS mutations. A Heatmap showing the five-year RFS rate according to pathological T status or histological grade. B, C Bliss images representing the distribution of cases harboring EGFR (B) or KRAS mutations C according to pathological T status or histological grade. Abbreviations: AIS, adenocarcinoma in situ; G1, grade 1; G2, grade 2; G3, grade 3 MIA, minimally invasive adenocarcinoma; RFS, recurrence-free survival