Patient Characteristics
We retrospectively analyzed 146 patients diagnosed stage IIIB-C or IV lung adenocarcinoma at Daping tumor Center General Hospital between April 2011 and April 2018. The clinic pathological characteristics were shown in Table 1. The population were included 73 males and 73 females, with a meanage of 51.1 years (range from 28 years to 80 years). Of 146 patients, 21 (14.38 %) patients had stage IIIB-C disease, and EGFR Mutations were detected in 61.64% (90/146) adenocarcinoma cases. Among the 90 EGFR mutations, 37 were 19 exon del and 40 were L858R. Of the whole study population, 75 (51.37%) were bone metastasis and 46(31.51%)were brain metastasis. At the end of the last follow up, 100 patients had died and the median overall survival was 26.9 months, and the 2-year survival rate was 48.63 % for the whole group
Table 1
Clinic-pathological characteristics in 146 LAC patients.
Variable | Patients | % |
Gender | | |
Male | 73 | 50.00 |
Female | 73 | 50.00 |
Age at diagnosis | | |
༜60 | 88 | 60.27 |
≥ 60 | 58 | 39.73 |
Smoking history | | |
Never | 99 | 67.81 |
Former/Current | 47 | 32.19 |
T stage | | |
T1 | 27 | 18.49 |
T2 T3 | 55 28 | 37.67 19.18 |
T4 | 36 | 24.66 |
N stage | | |
N0 | 17 | 11.64 |
N1 | 18 | 12.33 |
N2 | 62 | 42.47 |
N3 M stage | 49 | 33.56 |
M0 | 21 | 14.38 |
M1 | 125 | 85.62 |
Bone metastasis | | |
Absent | 71 | 48.63 |
Present | 75 | 51.37 |
Brain metastasis | | |
Absent | 100 | 68.49 |
Present | 46 | 31.51 |
EGFR mutation | | |
Wild-type | 56 | 38.36 |
Positive | 90 | 61.64 |
Exon 19 deletion | 37 | 25.34 |
L858R substitution | 34 | 23.29 |
Others | 19 | 13.01 |
Total | 146 | 100 |
Association of CA153/CYFRA21-1/CA125 with PFS and OS in advanced NSCLC
Six serum tumor markers such as CYFRA21-1, CEA, NSE, CA125, CA199 and
CA153 were routinely assessed during the visits of LUAD and predict the overall
survival time. Among the 146 patients, 26 (17.8%) had high CA153 levels, 83(47.9%)
had high CA125 levels, 24 (16.4%) elevated Cyfra21-1, 85(51.8%) had high CEA
levels, 8(5.4%) elevated NSE 34༈23.2%༉ elevated CA199 respectively (Table 2).
Table 2
Clinical characteristics of patients with advanced lung adenocarcinoma for further analysis.
Variable | LAC |
n | Median PFS(mo) | P-value | Median OS(mo) | P-value |
Gender |
Male | 73 | 8 | 0.010 | 26 | 0.010 |
Female | 73 | 13 | | 37 | |
Age at diagnosis |
༜60 | 88 | 9 | 0.367 | 31 | 0.324 |
≥ 60 | 58 | 8 | | 37 | |
Smoking history |
Never | 99 | 10 | 0.025 | 36 | 0.028 |
Former/Current | 47 | 8 | | 25 | |
Clinical stage |
Ⅲ | 21 | 6 | 0.000 | 22 | 0.000 |
Ⅳ | 125 | 10 | | 36 | |
CEA |
༜5ng/ml | 61 | 8.5 | 0.944 | 32 | 0.922 |
≥ 5ng/ml | 85 | 10 | | 28 | |
CA153 |
༜31.3U/ml | 120 | 9 | 0.037 | 36 | 0.003 |
≥ 31.3U/ml | 26 | 7 | | 25 | |
CA125 |
༜35 U/ml | 77 | 10 | 0.074 | 37 | 0.062 |
≥ 35 U/ml | 69 | 8 | | 26 | |
CA199 |
༜35U/ml | 112 | 9 | 0.208 | 35 | 0.249 |
≥ 35U/ml | 34 | 6.5 | | 25 | |
NSE |
༜25ng/ml | 138 | 9 | 0.011 | 31 | 0.168 |
≥ 25ng/ml | 8 | 4 | | 18 | |
Cyfra21-1 |
༜7 ng/ml | 122 | 10 | 0.010 | 32 | 0.044 |
≥ 7 ng/ml | 24 | 6 | | 22 | |
Total | 146 | | | | |
Out of the serum markers only CA 15 − 3 (7 versus 9 months, P = 0.037 for PFS,
; 25 months versus 36 month, P = 0.003 for OS, Fig. 1A, Table 2) and
Cyfra21-1 (7.0 versus 9.0 months, P = 0.010 for PFS, Fig. 2C; 25 months versus
36 months, P = 0.044 for OS, Fig. 1B; Table 2) showed a negatively significant
correlation with overall survival and Progression free survival.
However,Elevated CEA、CA199、CA125 patients did not exhibit any difference in
OS nor PFS as compared with those with normal levels (Supplementary Fig. 1
Table 2). Furthermore, we found the patients with high level of NSE showed shorter
PFS as compared with low level of NSE (Supplementary Fig. 1).
Correlation ship of increased CA125/CYFRA21-1/CA153 with PFS and OS based on EGFR mutation status.
In order to explore serum tumor biomarker in LUAD with different EGFR status, the population were divided into two groups: EGFR-mutant LUAD and EGFR-wild type LUAD We found that the positive rate of CEA was significantly higher in EGFR-MT LUAD than that in EGFR-WT LUAD (63.33% versus 46.55%,P = 0.027). However༌No significantly difference in others were observed in EGFR-MT LUAD group as compared with EGFR-WT NSCLC group(Table 4).
Table 4
Association between clinical characteristics and progression-free survival or overall survival among 90 patients with advanced stage lung adenocarcinoma with EGFR-mutant
Variable | EGFR mutation |
n | Median PFS(mo) | P-value | Median OS(mo) | P-value |
Gender |
Male | 35 | 7 | 0.005 | 36 | 0.086 |
Female | 55 | 16 | | 43 | |
Age at diagnosis |
༜60 | 51 | 14 | 0.318 | 36 | 0.227 |
≥ 60 | 39 | 17 | | 42 | |
Smoking history |
Never | 71 | 15 | 0.058 | 39 | 0.365 |
Former/Current | 23 | 7 | | 37 | |
Clinical stage |
Ⅲ | 9 | 6 | 0.087 | 23 | 0.084 |
Ⅳ | 85 | 15 | | 39 | |
CEA |
༜5ng/ml | 32 | 13 | 0.629 | 39 | 0.705 |
≥ 5ng/ml | 58 | 15 | | 37 | |
CA153 |
༜31.3U/ml | 75 | 15 | 0.022 | 39 | 0.006 |
≥ 31.3U/ml | 15 | 10 | | 24 | |
CA125 |
༜35 U/ml | 45 | 16 | 0.205 | 42 | 0.223 |
≥ 35 U/ml | 45 | 11 | | 37 | |
CA199 |
༜35U/ml | 71 | 14 | 0.524 | 39 | 0.528 |
≥ 35U/ml | 19 | 15 | | 32 | |
NSE |
༜25ng/ml | 86 | 15 | 0.077 | 39 | 0.481 |
≥ 25ng/ml | 4 | 4 | | 22 | |
Cyfra21-1 |
༜7 ng/ml | 74 | 15 | 0.008 | 43 | 0.017 |
≥ 7 ng/ml | 16 | 6 | | 31 | |
Total | 90 | | | | |
EGFR-mutated LUAD patients with either elevated CA153 or Cyfra21-1exhibited
both shorter DFS and OS (CA153: 10.0 versus 15 months, P = 0.022 for PFS, Figure
2A; 24 months versus 39 month, P = 0.006 for OS, Fig. 2A; CYFRA21-1: 6.0
versus 15.0 months, P = 0.008 for PFS, Fig. 2C; 31 months versus 43 months, P=
0.017 for OS, Fig. 2B; Table 4). Abnormal CA125 levels were not correlated with
DFS or OS in EGFR-mutated NSCLC (Fig. 2C;Table 4).
On the Contrary, EGFR-WT NSCLC patients with high expression of CA125
showed worse PFS and OS(CA125: 5 month versus 8 months, P = 0.013 for DFS, Fig. 3A,18 months versus 24 month, P = 0.016 for OS, Fig. 3B;Table 5)No relationship was found between increased CA153 or CYFRA21-1 in PFS or OS (Table 3).
Table 3
Tumor biomarker in EGFR-MT LUAD and EGFR-WT LUAD
Variable | EGFR mutation N = 90 | EGFR Wild-type N = 56 | P-value |
Positive (n) |
CEA | 57 | 27 | 0.027 |
CA153 | 15 | 11 | 0.684 |
CA125 | 45 | 24 | 0.401 |
CA199 | 19 | 15 | 0.430 |
NSE | 4 | 4 | 0.486 |
Cyfra21-1 | 16 | 8 | 0.580 |
Table 5
Association between clinical characteristics and progression-free survival or overall survival among 56 patients with advanced stage LUAD with EGFR-wildtype
Variable | EGFR wild-type |
n | Median PFS(mo) | P-value | Median OS(mo) | P-value |
Gender |
Male | 38 | 8 | 0.189 | 22 | 0.748 |
Female | 18 | 5.5 | | 21 | |
Age at diagnosis |
༜60 | 37 | 7 | 0.748 | 24 | 0.363 |
≥ 60 | 19 | 5 | | 19 | |
Smoking history |
Never | 29 | 6 | 0.800 | 22 | 0.444 |
Former/Current | 27 | 8 | | 21 | |
Clinical stage |
Ⅲ | 13 | 4 | 0.005 | 16 | 0.044 |
Ⅳ | 43 | 8 | | 24 | |
CEA |
༜5ng/ml | 29 | 6 | 0.914 | 22 | 0.626 |
≥ 5ng/ml | 27 | 8 | | 22 | |
CA153 |
༜31.3U/ml | 45 | 6.5 | 0.964 | 22 | 0.355 |
≥ 31.3U/ml | 11 | 7 | | 25 | |
CA125 |
༜35 U/ml | 32 | 8 | 0.013 | 24 | 0.031 |
≥ 35 U/ml | 24 | 5 | | 18 | |
CA199 |
༜35U/ml | 41 | 7 | 0.621 | 22 | 0.576 |
≥ 35U/ml | 15 | 6 | | 19 | |
NSE |
༜25ng/ml | 52 | 7 | 0.087 | 22 | 0.259 |
≥ 25ng/ml | 4 | 4 | | 8.5 | |
Cyfra21-1 |
༜7 ng/ml | 48 | 6.5 | 0.307 | 22 | 0.524 |
≥ 7 ng/ml | 8 | 5 | | 15 | |
Total | 56 | | | | |
Multivariate analysis of prognostic factors in EGFR-MT NSCLC and EGFR-WT advanced NSCLC
Multivariate analysis showed that CA153 (HR = 3.227 for DFS; P = 0.011 HR = 2.940, P = 0.015 for OS) and Cyfra21-1 (HR = 2.768 for DFS; P = 0.027 HR = 2.343, P = 0.027 for OS) were independent prognostic factors in all EGFR-mutated NSCLC patients. Furthermore, For EGFR-WT patients, CA125 (HR = 3.917 for PFS; P = 0.001 HR = 2.350, P = 0.018 for OS) and metastasis stage (HR = 3.917, P = 0.001 for PFS) were independent predictive and prognostic factors (Table 6).
Table 6
Multivariate analysis of PFS and OS for LUAD patients
Variable | PFS | | OS | |
HR(95%CI) | P-value | HR(95%CI) | P-value |
EGFR mutation(N = 90) |
Gender | 2.399(1.118–5.151) | 0.025 | 1.839(0.874–3.870) | 0.109 |
Age at diagnosis | 0.883(0.462–1.686) | 0.706 | 0.654(0.338–1.267) | 0.208 |
Smoking history | 0.766(0.281–2.086) | 0.602 | 0.877(0.363–2.120) | 0.771 |
T stage | 1.814(0.989–3.328) | 0.054 | 1.245(0.666–2.325) | 0.493 |
N stage | 0.581(0.280–1.203) | 0.144 | 0.906(0.450–1.826) | 0.783 |
M stage | 2.674(1.141–3.086) | 0.003 | 2.509(1.762–3.211) | 0.050 |
CA153 | 3.227(1.310–7.952) | 0.011 | 2.940(1.232–7.019) | 0.015 |
Cyfra21-1 | 2.768(1.122–6.828) | 0.027 | 2.343(1.104–4.971) | 0.027 |
EGFR wild-type(N = 56) |
Gender | 0.875(0.341–2.247) | 0.782 | 1.141(0.452–2.875) | 0.780 |
Age at diagnosis | 1.359(0.681–2.713) | 0.385 | 1.241(0.642-2.400) | 0.522 |
Smoking history | 0.669(0.270–1.658) | 0.385 | 0.997(0.410–2.425) | 0.994 |
T stage | 1.149(0.597–2.211) | 0.677 | 1.366(0.722–2.587) | 0.338 |
N stage | 1.203(0.493–2.935) | 0.684 | 0.935(0.398–2.195) | 0.877 |
M stage | 0.198(0.082–0.482) | 0.000 | 0.366(0.169–0.793) | 0.011 |
Patients Harboring Egfr-mutant Treated With Egfr-tki Therapy
In all EGFR-mutant LUAD patients,82(87.2%)patients were treated with EGFR-TKI therapy and/without chemotherapy༌either gefitinib 250 mg/d༌erlotinib 150 mg/d༌econtinib 375mg/d. 27 as a second-linetherapy, and 9 as third-line or thereafter. After fourth-cycle treatment༌39 (47.56%) patients were PR༌13༈15.85%༉were SD, 30(36.59%) were PD respectively. PR and SD were defined as effective ༌while PD were regard as ineffective. It is noteworthy that serum CEA、 NSE、CA153、CA125、CA199 could not predict therapeutic effect for patients treated with EGFR-TKIs, while elevated CYFR21-1 showed lower efficacy for EGFR-TKI resistance༈66.65% VS 85.64%;P < 0.05 Fig. 4༉