Abstract:

Objective To explore the prognostic value of epidermal growth factor receptor （EGFR） co-mutation status in patients with advanced lung adenocarcinoma. Methods Clinical data of patients with stage ⅢB-Ⅳ lung adenocarcinoma who were first diagnosed in the Department of Respiratory and Critical Care Medicine， First Affiliated Hospital of Hebei North University from January 2019 to December 2022 were collected prospectively. Patients were divided into EGFR mutation group （n=82） and EGFR co-mutation group （n=74） according to whether EGFR was combined with other gene mutations. The level of circulating tumor DNA （ctDNA） in peripheral blood was measured by real time fluorescence quantitative PCR. Objective response rate （ORR）， disease control rate （DCR）， the levels of ctDNA in peripheral blood， and progression-free survival （PFS） were compared between two groups of patients before and after 1 month of treatment. The univariate and multivariate analyses were conducted by Cox proportional hazards regression model. Results In the EGFR mutation group， there were 45 cases of EGFR19 deletion mutation and 37 cases of EGFR21 mutation. In the EGFR co-mutation group， there were 41 cases of EGFR19 deletion mutation， 33 cases of EGFR21 mutation， 46 cases of TP53 mutation， 16 cases of RB1 mutation， 6 cases of PTEN mutation， 2 cases of MET amplification， 1 case of ERBB2 mutation， 1 case of KRAS mutation， 1 case of RET rearrangement， and 1 case of ALK rearrangement. There were statistically significant differences between the EGFR mutation group and the EGFR co-mutation group in the maximum tumor diameter （χ²=5.04， P=0.025） and stage （χ²=3.92， P=0.048）. The ORRs of the two groups were 64.63% （53/82） and 37.84% （28/74）， respectively， with a statistically significant difference （χ²=11.19， P<0.001）. The DCRs were 96.34% （79/82） and 86.49% （64/74）， respectively， with a statistically significant difference （χ²=4.95， P=0.026）. The ctDNA levels in the EGFR mutation group and EGFR co-mutation group after one month of treatment decreased compared to before treatment [2.63 （1.83， 3.30） ng/μl vs. 4.73 （3.92， 5.49） ng/μl， Z=-7.06， P<0.001； 4.26 （2.26， 6.07） ng/μl vs. 5.28 （4.37， 6.09） ng/μl， Z=-5.15， P<0.001]， the ctDNA levels in the EGFR co-mutation group were higher than those in the EGFR mutation group before treatment and after 1 month of treatment （Z=-2.47， P=0.013； Z=-4.29， P<0.001）. In the EGFR co-mutation group， the ctDNA levels in peripheral blood of patients who were effectively treated with targeted therapy decreased after 1 month of treatment compared to before treatment [（2.03±0.63） ng/μl vs. （3.92±0.82） ng/μl， t=42.94， P<0.001]， the levels of ctDNA in peripheral blood of ineffectively treated patients before and after 1 month of treatment were higher than those of effectively treated patients [（5.84±0.57） ng/μl vs. （3.92±0.82） ng/μl， t=-11.91， P<0.001； （5.87±1.64） ng/μl vs. （2.03±0.63） ng/μl， t=-14.43， P<0.001]. The median PFS of the EGFR mutation group and the EGFR co-mutation group of patients were 10.4 and 8.3 months， respectively， with a statistically significant difference （χ²=22.28， P<0.001）. Univariate analysis suggested that the maximum tumor diameter （HR=0.10， 95%CI： 0.06-0.16， P<0.001）， performance status （PS） score （HR=0.09， 95%CI： 0.06-0.15， P<0.001）， stage （HR=0.09， 95%CI： 0.05-0.14， P<0.001）， pre-treatment ctDNA level （HR=12.04， 95%CI： 8.21-17.65， P<0.001）， ctDNA level after 1 month of treatment （HR=3.75， 95%CI： 3.10-4.54， P<0.001） and EGFR co-mutations （HR=2.21， 95%CI： 1.57-3.12， P<0.001） were found to be significant factors affecting the PFS of stage ⅢB -Ⅳ lung adenocarcinoma patients receiving targeted therapy； Multivariate analysis demonstrated that PS score （HR=0.25， 95%CI： 0.14-0.47， P<0.001）， stage （HR=0.49， 95%CI： 0.24-0.98， P=0.044）， pre-treatment ctDNA level （HR=4.73， 95%CI： 3.08-7.28， P<0.001）， ctDNA level after 1 month of treatment （HR=2.15， 95%CI： 1.65-2.80， P<0.001）， and EGFR gene co-mutation （HR=2.26， 95%CI： 1.40-3.64， P<0.001） were independent risk factors for PFS in stage ⅢB -Ⅳ lung adenocarcinoma patients receiving targeted therapy. Conclusion Both the EGFR mutation group and EGFR co-mutation group show a decrease in ctDNA levels after targeted therapy for one month compared to before treatment. The median PFS of EGFR co-mutation patients is shorter than that of patients with a single EGFR mutation. PS score， stage， ctDNA levels before and after treatment， and EGFR gene co-mutation are all independent factors affecting PFS in stage ⅢB-Ⅳ lung adenocarcinoma patients after targeted therapy.

Key words: Adenocarcinoma of lung, Genes， erbB-1, Circulating tumor DNA, Prognosis