Journal of Cancer Therapy, 2012, 3, 435-441
http://dx.doi.org/10.4236/jct.2012.324056 Published Online September 2012 (http://www.SciRP.org/journal/jct) 435
Smoking Cause Specific Lung Cancer—Evidence from
Non-Smoking Lung Adenocarcinoma
Ning Li, Bin Qu, Kang Shao, Zhaoli Chen, Fengwei Tan, Xiaogang Tan, Baozhong Li, Jiwen Wang,
Jie He*
Department of Thoracic Surgery, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, China.
Received July 13th, 2012; revised August 25th, 2012; accepted September 16th, 2012
ABSTRACT
Introduction: Smoking and non-smoking lung cancer have many differences in clinical feature. But those may be the
result of interference due to differences in pathological type, as most smoking patients suffer squmous cell lung cancer
and non-smokings tend to get adenocarcinoma. This study was conducted on the specific histological type—lung ade-
nocarcinoma—to avoid histological bias and to reveal the true effect of smoking. Methods: A total of 2222 patients
with lung adenocarcinoma confirmed by histological or cytological evidence were enrolled from January 1, 1999 to
December 31, 2004. Differences in clinical features and prognosis between non-smoking and smoking patients were
analyzed. Chi-square test was used for univariate comparisons. Univariate probability of survival was computed using
Kaplan-Meier estimate and compared to using the log-rank test. Cox proportional hazards regression analysis was used
to evaluate the risk of death. Results: There were 777 current smokers (34.96%), 197 former smokers (8.87%) and
1248 non-smoking patients (56.17%). 860 non-smoking patients (68.91%) were female, compared with 6.31% among
current smokers and 4.06% among former smokers (p < 0.001). Non-smoking patients had an earlier age at diagnosis (p
< 0.001) and a better response to chemotherapy (p < 0.001) compared to current smoking patients. Current smoking
correlated with lower cell differentiation (p < 0.001) and worse prognosis (p = 0.0024). After multivariate analysis,
smoking was identified as an independent negative prognostic factor (HR, 1.302; 95% CI, 1.011 - 1.6780, p = 0.041).
No difference in prognosis was observed according to smoking conditions in smoking patients. Conclusions: Signifi-
cent differences exist in clinical features and prognosis between non-smoking and smoking lung adenocarcinoma pa-
tients. There is a strong evidence that non-smoking lung adenocarcinoma should be regard as different disease.
Keywords: Lung Adenocarcinoma; Cigarette Smoke; Differentiation; Chemotherapy; Prognosis
1. Introduction
Lung cancer is the most lethal cancer in the world with
over 1 million deaths each year [1]. Cigarette smoking
was regarded as the most important carcinogenic factor
of lung cancer, which has been well established from
epidemiological evidence [2]. However, over 50 percent
of female and 15 percent of male lung cancer patients
never smoke cigarette [3]. The incidence of lung cancer
in non-smoker was even higher than several high inci-
dence cancers, such as: cervix, pancreas and prostate
cancer worldwide [3].
Smoking can not only increase the lung cancer inci-
dence but also affect the lung cancer patient’s clinical
feature and prognosis. Smoking lung cancer patients have
many differences in gender distribution, clinical features,
pathology result and molecular mechanism comparing to
non-smoking lung cancer [4,5]. Smoking lung cancer
patients tend to be diagnosed at older age, present with
early stage, usually be afflicted with squamous cell lung
cancer, and have a better prognosis [6-8]. Non-smoking
lung cancer have a higher rate of mutation in Epidermal
growth factor receptor (EGFR) and a better response to
the EGFR Tyrosine Kinase Inhibitor: Gifitinib and Er-
lotinib [9,10], while have less mutations in P53 com-
pared with smoking lung cancer [4,11]. Therefore, many
scholarssuggested that lung cancer in never smokers is a
“different” disease, with a different aetiology and a dif-
ferent natural history [5,6].
A small defect exists in the evidences of this hypothe-
sis. Previous researches about clinical features and sur-
vival analysis mostly focus on all categories of lung can-
cer [7] or non-small cell lung cancer (NSCLC) [6,8,12].
Over 70 percent smoking patients suffer from squamous
cell lung cancer and most non-smoking patients suffer
from lung adenocarcinoma [13]. Many distinctions exist
in clinical features between subtypes of lung cancer, and
*Corresponding autho
r
.

Smoking Cause Specific Lung Cancer—Evidence from Non-Smoking Lung Adenocarcinoma 436
histology, such as squamous cell or adenocarcinoma
have been recognized as a predictive factor for response
to chemotherapy and prognosis [14]. So, differences be-
tween smoking and non-smoking lung cancer might be
confounded by the differences between squamous cell
cancer and adenocarcinoma.
To avoid any bias, we performed a retrospective study
of lung adenocarcinoma, which contains the most part of
non-smoking patients. We compared all detectable vari-
ance in clinical features and prognosis between non-
smoking and smoking patients, to investigate the true
effect of smoking to the lung adenocarcinoma.
2. Patients and Methods
Current respective study was conducted in the Cancer
hospital, Chinese Academy of Medical Sciences (CAMS).
Patients had primary lung adenocarcinoma diagnosed
between 1 January 199 9 a n d 3 1 December 2004.
All patients diagnosed consecutively with primary
lung adenocarcinoma, which was confirmed by histo-
logical or cytological examination. To avoid the influ-
ence from different histological subtype, adenosquamous
carcinoma and bronchiolo-alveolar carcinoma were ex-
cluded. To avoid the influence form different ethnic
groups, only Chinese patients were enrolled. Patients
were excluded if smoking history was not available in
case record. Individual case records were reviewed. In
addition to smoke history, age, gender, lung cancer fa-
mily history, American Joint Committee on Cancer
(AJCC) stage at diagnosis and type of treatment were
recorded. When surgery was performed as initial treat-
ment, the metastasis of lymph nodes (N stage), differen-
tiation of adenocarcinoma cells were collected as well.
When chemotherapy was performed as initial treatment
in advanced patients (Stage IIIB and IV), the clinical
response after four cycles to first-line chemotherapy were
also recorded as four levels: Complete Response (CR),
Partial Response (PR), Stable Disease (SD) and Progr ess
Disease (PD), according to RECIST critical. Survival
data were obtained from follow-up group in thoracic de-
partment cancer hospital CAMS. All patients were noti-
fied and understand that their clinical information might
be used for clinical research and analysis, before they got
the therapy. And all included in this study signed the
authorizations form. The study was approved by the me-
dical ethics committee of Cancer Institute and Hospital,
CAMS.
Smoking history contains smok ing condition s, such as:
how many years of smoking, how many cigarettes smoked
per day, and how many years since quitting smoke. Pa-
tients who were smokers during diagnosis or stop smok-
ing less than 1 year were collected in “current smoker”
group [5]. Patients who quit smoking more than one year
were classified as “former smoker”. Patients who have a
lifetime exposure of less than 100 cigarettes or never
smoked in the past were termed as “never smoker”.
According to smoking habits, chi-square test was used
for univariate comparisons of patients, disease and treat-
ment-related characteristics. Cox proportional hazards
regression analysis w as used to evaluate the risk of death
between current, former and never smoking patients,
while adjusting for othe r prognostic factors in cluding age
at diagnosis, gender, lung cancer family history, disease
stage at diagnosis and initial treatment. Univariate prob-
ability of survival was computed using Kaplan-Meier
estimate and compared using the log-rank test. P-Value
of 0.05 was considered significant for all analysis.
3. Results
A total of 2222 patients were enrolled and met study se-
lection criteria. 777 patients (34.96%) were current smo-
kers, 1248 patients (56.17%) were never smokers, and
197 patients (8.87%) who quit smoking for at least one
year were termed as “former smokers”. Demographic
and clinical features of each group were listed in Table
1. The overwhelming majority of current smokers and
former smokers were males, 93.69% in current smokers
and 95.94% in former smokers. On the other hand, only
31.09% patients in never smoker group were males.
Non-smoking patients were diagnosed at median age of
56 years old, which was younger than current and former
smokers (p < 0.001). Former smokers tend to present
with earlier disease than current and never smokers (p =
0.016). Operations were preformed in 503 current smo-
kers (64.74%), 153 former smokers (77.66%) and 794
never smokers (63.62%). Differentiation in adenocarci-
noma cells was evaluated in the tissue samples resects in
operations. More proportion of poor differentiation was
found in current smoking patients (56.39%) than former
(47.37%) and never (35.87%) smokers (p < 0.001). There
was a weak significant difference in N2 lymph nodes
metastasis (p = 0.146) between three groups. Complete
response and partial response were seen in 165 (41.88%)
non-smoking patients, but only in 41(23.56%) current
and 8 (26.67%) former smoking patients (p < 0.001).
Overall survival is shown in Figure 1. The 3-year
overall survival rates for current smoker, former smoker
and never smoker were 23.63%, 28.15% and 33.55%.
The 5-year overall survival rate were 19.85%, 23.06%
and 22.93%, respectively (p = 0.0024). Interestingly,
former smokers had similar survival as never smokers,
and much better than current smokers in patients with
early stage (stage I and II) (Figure 2).
As smoking patients had different smoking conditio ns,
additional analysis were performed out within the current
smoking group to examine the impact of smoking co ndi-
tions on prognosis of smoking patients. There were no

Smoking Cause Specific Lung Cancer—Evidence from Non-Smoking Lung Adenocarcinoma 437
Table 1. The clinical features of lung adenocarcinoma patients.
Current Smokers (n = 777) Former Smokers (n = 197) Never Smokers (n = 1248)
Variable
No. % No. % No. %
p value
Gander
Male 728 93.69% 189 95.94% 388 31.09%
Female 49 6.31% 8 4.06% 860 68.91%
p < 0.001
Age at diagnosis
Median 59 66 56
Range 23 - 86 40 - 83 20 - 84
p < 0.001
AJCC stage at diagnosis (n = 2144)
I 200 26.74% 57 31.32% 278 22.90%
II 64 8.56% 17 9.34% 108 8.90%
III 176 23.53% 54 29.67% 342 28.17%
IV 308 41.18% 54 29.67% 486 40.03%
p = 0.016
Treatment
Operation 503 64.74% 153 77.66% 794 63.62%
Chemotherapy/Others 274 35.26% 44 22.34% 454 36.38%
p = 0.001
Differentiation of adenocarcinoma cells (n = 1323)
Low differentiation 256 56.39% 63 47.37% 264 35.87%
Middle differentiatio n 166 36.56% 57 42.86% 404 54.89%
High differentiation 32 7.05% 13 9.77% 68 9.24%
p < 0.001
Metastasis of lymph nodes (n = 1298)
N0 205 46.49% 59 45.74% 288 39.56%
N1 69 15.65% 17 13.18% 117 16.07%
N2 167 37.87% 53 41.09% 323 44.37%
p = 0.146
significant difference in prognosis of smokers according
to years of smoking, number of cigarettes smoked per
day and the smoking index (Figure 3).
Table 2 summarized the hazard ratios and significance
of the impact of clinical features. The risk of dying for
current smokers remained higher compared with never-
smokers after adjusting for gender, clinical stage, treat-
ment and family history (HR: 1.302; 95% CI: 1.011 -
1.678; p = 0.041). Current smoking status was an inde-
pendent variable for poor prognosis in lung adenocarci-
mona.
4. Discussion
Non-smoking lung related cancer has many differences
compared with smoking related lung cancer, from etio-
logical factors to biological behavior. Non-smoking lung
cancer might result from other risk factors, such as: pre-
existing lung disease, endocrine factors, family history,
radiation, air pollution and environmental tobacco smok-
ing [13]. Cancers induced by different carcinogenic
agents might be variables in biological behavior. With
different ability of proliferation, differentiation, migra-

Smoking Cause Specific Lung Cancer—Evidence from Non-Smoking Lung Adenocarcinoma 438
Table 2. Cox proportional hazards regression analysis of factors associated with survival in patients with lung adenocarci-
noma.
Variable Cate
g
ories/UniteHazard Ratio 95% CI
p
value
Never smoke
r
1
Former smoker 1.289 0.894 - 1.858 0.175
Cigarette smoke
Current smoker 1.302 1.011 - 1.678 0.041
Female 1
Gender
Male 1.129 0.875 - 1.457 0.352
Negative 1
Family histor y
Positive 0.635 0.699 - 1.244 0.635
Operation 1
Treatment
Others 1.410 0 .925 - 2.151 0.110
Stage I 0.132 0.081 - 0.215 <0.001
Stage II 0.419 0 .246 - 0.713 0.001
Stage III 0.752 0 .490 - 1.154 0.192
TNM stage
Stage IV 1
Figure 1. Kaplan-Meier survival curves stratified by smok-
ing status in patients with lung adenocarcinoma.
tion and invasion, even though cancer cells had similar
appearance, they could be regarded as “different cancer”.
It is a feasible method to investigate the biological fea-
tures of non-smoking related lung cancer, to analyze the
clinical features of patients, and then compare with
smoking patients. Differences in age, gender, initial stage,
response to chemotherapy and prognosis between non-
smoking and smoking patients had been found in previ-
ous studies [5,6].
However, several influencing factors should not be
ignored. Distinctions in pathology have been established
by previous studies. Non-smoking lung cancer patients
tend to suffer from adenocarcinoma. Patients with lung
adenocarcinoma have many differences in gender, age at
diagnosis, response to chemotherapy and prognosis com-
pared to those with squamous cell lung cancer [14]. The
ethnic difference is another important factor. Asian fe-
male had much lower smoking rate and higher lung can-
cer incidence compared to American and European fe-
male, and they are more sensitive to the EGFR Tyrosine
Kinase Inhibitor [5]. Japanese ethnicity is independent
favorable prognostic factors when compared with Cauca-
sian ethnicity in NSCLC [15]. Another factor is the
choice of the treatment: each institution or oncologist
chose method mainly based on local policies, cost or con-
venience of the therapeutic schedule, which could affect
the prognosis of the patients. Therefore, we conducted
current study in a specific histological pathology, in a
specific ethnic group and in a specific institute, to avoid
those influences.
Non-smoking patients were diagnosed earlier at me-
dian age of 56 years old compared with current and for-
mer smoking patients. Former studies from Asia coun-
tries had similar results [6], while studies from United
States and Europe did not [5]. Those facts indicate that
non-smoking lung cancer in Asia might not be resulted
from environment tobacco smoking, as patients do not
have enough exposure to tobacco smoking [16]. Diffe-
rences between those two cohorts, such as genetic factors

Smoking Cause Specific Lung Cancer—Evidence from Non-Smoking Lung Adenocarcinoma 439
Figure 2. Kaplan-Meier survival curves stratified by smok-
ing status in patients with Stages I and II, III, and IV.
and environment factors are important in lung cancer
carcinogenesis. Most patients in never smoking group are
female. Similar results were obtained in many previous
studies [6], which indicated the female is more sensitive
to carcinogen among non-smokers. Direct evidence comes
from incidence investigation: incidence of female patients
with non-smoking lung cancer is 14.4 - 20.8/100000,
while 4.8 - 13.7/100000 in male [17,18].
Here we reported that histological differentiation of
cancer cells is different among patients with diverse
Figure 3. Kaplan-Meier survival curves stratified by smok-
ing conditions in smoking patients.
smoking conditions. Non-smoking patients usually had a
better differentiation than smokers, which was a direct
pathomorphological evidence for “different cancer”. The
smoke of cigarette contains more than 4500 chemical
compounds. Many of them affect the cell differentiation
in vitro and in vivo [19], which could explain poorer dif-
ferentia tion in smoking pati ents.
We demonstrated patients in never smoker group had
better response to front line chemotherapy than those in
the other two groups. Tsao et al. had similar results. They
analyzed 873 advanced non small cell lung cancer pa-
tients who received chemotherapy, and found never-

Smoking Cause Specific Lung Cancer—Evidence from Non-Smoking Lung Adenocarcinoma 440
smokers had higher response rates and lower rates of
progressive disease than former and current smokers [8].
As chemotherapy drugs work directly on the cancer cells,
different responses indicate different intracellular mecha-
nisms [20]. Previous study shows, compared with people
who never smoke, people with lung adenocarcinoma who
smoked or stopped smoking less than 25 years ago have
significant less EGFR mutations in exons 19 and 21 [21].
A study of comparing gene expression profiles in never
smokers and smokers with lung adenocarcinoma by
Powell et al. reported that there might be different path-
ways of cell transformation and tumor formation in two
groups, with many differences in gene expression. [22]
Those are strong evidences for the “different cancers”.
Surviving time of patients is considered as the most
important characteristics in cancer research. Different
subtypes of cancer usually have dissimilar prognosis,
such as: lung squamous cell cancer and adenocarcinoma;
gastric signet-ring cell carcinoma and adenocarcinoma;
hepatic cellular cancer and hepatobiliary cancer. Non-
smoking lung adenocarcinoma patients had a better prog-
nosis than current and former smokers. Interestingly,
former smoking patients had similar survival with non-
smoking patients and much better than current smoking
patients in the early stage, which is a good message for
patients who quit smoking. Study from Nordquist et al.
reported 5 years survival were 16% for current smokers
and 23% for never-smokers in 654 patients with lung
adenocarcinoma [23]. Similar results were reported by
Tammemagi et al., they studied 1155 lung cancer pa-
tients and found cigarette smoking was an important in-
dependent pred ictor of shor tened lung can cer surviv al [7].
Bryant et al. also found never smoker patients with early-
stage cancer have a significantly b etter survival rate than
smokers [24]. As expected, in current study, we found
smoking conditions such as the number of cigarettes
smoked per day, years of smoking and the smoking index
do not affect the prognosis. The comorbidity of smoking
such as chronic obstructive pulmonary disease, hyperten-
sion, atherosclerosis and aortic aneurysm are more seri-
ous in heavy smoker; which may indicate that the diffe-
rence in prognosis was not because of the comorbidities
but the nature of cancer. We can infer that lung cancer
caused by smoking is the same type of cancer, which has
no correlation in prognosis with cigarette smoke burden.
With difference in prognosis, non-smoking lung adeno-
carcinoma could be considered as a different cancer.
In summary, we demonstrate significant differences
between non-smoking and smoking patients with lung
adenocarcinoma in age at diagnosis, gender, initial stage
at diagnosis, cell differentiation, response to chemothe-
rapy and prognosis. Furthermore, we suggest non-smok-
ing and smoking lung adenocarcinoma could be consi-
dered as different cancers with many distinctions in clin i-
cal features.
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