JOP. J Pancreas (Online) 2014 Jul 28;
15(4):289-291.
Risk Determination for Pancreatic Cancer
Highlights
from the “50th ASCO Annual Meeting”. Chicago, IL, USA. May 30 - June
3, 2014
Maria I
Toki1, Konstantinos N Syrigos1, Muhammad Wasif Saif2
1Oncology Unit, 3rd
Department of Medicine, National and Kapodistrian University of Athens, Medical
School, Sotiria General Hospital. Athens, Greece
2Department of Medicine and
Cancer Center, Tufts Medical Center. Boston, MA, USA
ABSTRACT
Pancreatic cancer represents one of the leading causes of cancer
related deaths worldwide and constitutes a major public health problem. Despite
the advances in diagnosis and treatment, the overall five-year survival remains
low, thus leading the focus of medical research towards the identification and modification
of potential risk factors. This year, in ASCO Annual Meeting two interesting studies
were presented. Ghani et al. (Abstract #e15183) sought to investigate the
effect of smoking on chemotherapy response in patients with metastatic pancreatic
cancer, while Walker et al. (Abstract #4117) presented the results of their
study regarding the effect of statin use in the prevention of pancreatic cancer.
Both studies concluded to useful results that along with the existing literature
may further stimulate medical research towards better recognition of risk factors
and the application of this knowledge in the clinical practice.
Introduction
Pancreatic cancer is the
13th most common type of cancer worldwide and the fourth leading cause of cancer-related mortality in the
United States [1]. Approximately 45,220 people were diagnosed with pancreatic
adenocarcinoma and 38,460 died from it in 2013 [2]. Despite the ongoing
advances in diagnosis and treatment of pancreatic cancer, the overall five-year
survival rate from all stages of the disease remains as low as 5% [3]. Therefore,
the determination and modification of potential risk factors, is imperative in the
effort to improve the outcomes of this disease.
What We Knew Before 2014 ASCO Annual Meeting?
Numerous,
putative risk factors have been identified and associated with the development of
pancreatic carcinoma. These factors are summarized in Table 1. Smoking has been
found to play a predominant role among them, although the increase in risk is
relatively small [4-6]. Importantly, smoke cessation can reduce the conferred
risk. It has been reported that the risk of developing cancer after cessation
of tobacco use for 5 year, is comparable to the risk of a never-smoker [6].
Table 1. Risk factors
implicated in the development for pancreatic carcinoma.
|
Risk Factors For Pancreatic Cancer
|
Tobacco
smoking
|
· Carbon
monoxide, nicotine, cyanide, ammonia, benzene, nitrosamines, vinyl chloride
|
Occupational
factors
|
· Chlorinated
hydrocarbon solvents, nickel compounds, chromium compounds, polycyclic
aromatic hydrocarbons, organochlorine insecticides, aliphatic solvents,
silica dust
|
Demographic
factors
|
· Older
age, African American race, Ashkenazic Jewish race
|
Host
factors
|
· Diabetes
mellitus, chronic liver cirrhosis, pancreatitis, high-cholesterol diet,
consumption of red/processed meat and dietary products, obesity, prior
cholecystectomy
|
Infectious
diseases
|
· Helicobacter
pylori infection, hepatitis B virus infection
|
Genetic
predisposition
|
· Mutations:
K-ras, p53, DPC4, p16, BRCA2, MLH1, FANC-G, PALB2
|
·
Inherited
syndromes: hereditary pancreatitis, Peutz-Jeghers, ataxia-telangiectasia,
familial atypical multiple mole melanoma, nonpolyposis colorectal cancer
(Lynch II type), hereditary breast and ovarian cancer
|
Apart
from the identification of risk factors that are associated with the development
of pancreatic cancer, it is of great importance to also recognize factors that can
reduce this risk. To this direction, the use of agents that reduce plasma cholesterol,
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, commonly known
as statins, has shown encouraging results in chemoprevention of pancreatic cancer
[7]. However, several epidemiological studies have evaluated the relationship
between the use of statins and the risk to develop pancreatic cancer with
ambiguous findings [8-12].
What We Learnt At 2014
ASCO Annual Meeting?
The
Impact of Cigarette Smoking On Treatment Outcome in Metastatic Pancreatic Cancer
Patients
Smoking
has been identified as one of the main risk factors that contribute in the development
of pancreatic cancer [4-6]. However, the association between tobacco use and survival
of patients with metastatic pancreatic cancer remains unclear. This topic was the
subject of an abstract presented by Ghani et al. [13]. The authors conducted
a retrospective study including 445 patients managed in their institution during
a 13-year period. The patients were allocated into 2 groups, namely “current smokers”
and “non-smokers” based on their tobacco use habits and the overall survival was
analyzed.
The
presented results showed a trend towards decreased overall survival in “current
smokers” who received chemotherapy (p=0.069). This adverse outcome seemed to be
more pronounced in male patients, under the age of 60, but this correlation was
not statistically significant (p=0.06). Additionally the authors found that the
survival of patients who received chemotherapy was superior to those who did not.
These results suggest a potential adverse implication of smoking in chemotherapy
response of patients with metastatic pancreatic carcinoma.
Statin
Use and Risk of Pancreatic Cancer
Statins
are widely used for the control of cholesterol levels. These drugs have emerged
as potential chemopreventive agents through a variety of anti-proliferative and
tumor-suppressor mechanisms. However, their use in the clinical setting has led
to contradictory results regarding their efficacy in reducing the risk of developing
pancreatic cancer [8-12].
In
this year’s ”ASCO Annual Meeting”, Walker et al. presented the results of
their study regarding the association between statin use and the development of
pancreatic cancer [14]. They included 536 patients with pancreatic cancer and 869
matched control cases. Their results showed that the use of statins (for more than
1 year prior to interview/diagnosis, for ≥4 days/week for ≥ 3 months) was associated
with a 34% risk reduction to develop pancreatic cancer (OR=0.66, 95% CI: 0.47-0.92).
Subgroup analysis according to sex, revealed a statistically significant risk reduction
in men (OR=0.50, 95% CI: 0.32-0.79). Additionally, for duration of use > 120
months, the researchers found a 49% risk reduction (OR=0.51, 95% CI: 0.31-0.85)
which again in subgroup analysis based on sex was found to be statistically significant
only in men (OR=0.41, 95% CI: 0.21-0.80). Finally the authors tried to investigate
the differential effect of the various statins used, based on their pharmacologic
characteristics. The results showed that exclusive use of pravastatin was associated
with reduced risk (OR=0.22, 95% CI: 0.06-0.82). Moreover, the use of high bioavailability
statins resulted in statistically significantly reduced risk compared to the use
of low bioavailability statins (p=0.01). These results suggest that the use of high
bioavailability statins, especially in men and specifically in the long term, could
be associated with a decrease in the risk to develop pancreatic cancer.
Discussion
Smoking
has been established as a major risk factor for pancreatic cancer although the increase
in risk is reported to be relatively small [4-6]. Recent data suggest that
tobacco compounds do not only contribute to the development of cancer but also
to the progression of the disease, rendering cancer cells more metastatic and
more resistant to drugs. It has been reported that nicotine may stimulate the
growth, invasion and resistance of pancreatic cells to chemotherapy through Src
pathway and inhibitor of differentiation-1 (Id1) transcription factor induced
mechanisms [15].
In
the 2014 ASCO Annual Meeting, Ghani et al. presented the results of their
retrospective study regarding the effect of smoking on treatment outcome in patients
with metastatic pancreatic cancer [13]. Their findings are in line with the existing
literature. They came to the conclusion that smoking may be adversely correlated
with the response to chemotherapy. However, there are some concerns regarding the
study. First of all, the data derive from a retrospective analysis. Moreover, the
study design is not very clear. The authors arbitrarily divided the study population
into “current smokers” and “non-smokers” based on cessation of smoking ≤ 2 years
before the diagnosis. There are however no data regarding the number of active smokers
and previous smokers in the “current smokers” group. It has been shown that the
risk to develop pancreatic cancer after discontinuation of tobacco use for 5 years
is reduced and is comparable to the risk of a never smoker [6]. Additionally, the
results did not present any statistically significant differences between the studied
groups. However, this could be attributed to the fact that the authors included
previous smokers in their “current smokers group”. Nonetheless, these findings are
very interesting and need to be further investigated in order to elucidate the impact
of smoking on the management of pancreatic cancer patients.
Apart
from the factors that are associated with the development of pancreatic cancer,
such as smoking, there are also factors that may confer a degree of protection.
Among them, statins, a class of cholesterol lowering drugs have emerged as potential
chemopreventive agents. Their mechanism of action is mediated through various pathways
and there are promising results from experimental data. However, their use in the
clinical setting has not proven to be beneficial since the results from epidemiological
studies are inconsistent [8-12].
The issue of statin use regarding the risk of pancreatic cancer
was the topic of an abstract presented in the 2014 ASCO Annual Meeting by Walker
et al. [14]. The authors found that the use of statins was associated with
a 34% risk reduction to develop pancreatic cancer. This effect was more pronounced
in men and especially when these agents were used in the long term (> 120 months).
Moreover, the authors reported that the use of high bioavailability statins was
more effective in reducing the risk of cancer compared to low bioavailability ones.
The main limitation of this study is that it is based on case-control derived data.
Nonetheless, these results are very important and are in line with previously published
data. Khurana et al. [8] reported that statins reduce the risk of pancreatic
cancer and the magnitude of this effect was associated with the duration of statin
use. Similarly, Carey et al. [12] showed in a recent case-control study
that statins may decrease the risk of pancreatic cancer in male smokers.
However, other authors argue these findings [9-11] while the available meta-analyses
[16, 17] failed to demonstrate any clear benefit from the use of statins in
terms of risk reduction for the development of pancreatic cancer. The aforementioned
highlight the importance of the findings by Walker et al. [14]. However,
the controversy in the existing literature, mandates further research in this promising
filed, especially in the clinical setting, in order to better assess the effect
of statins on the risk of pancreatic cancer development.
Key
words
Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pancreatic Neoplasms; Risk Factors;
Smoking
Conflicts
of Interest
Authors report no conflict of interest.
Correspondence
Maria I
Toki
Oncology Unit
3rd Department of Medicine
National and Kapodistrian University of Athens
Medical School
Sotiria General Hospital
152 Mesogeionave
11527, Athens
Greece
Phone:
+30-210.770.0220
Fax: +30-210.778.1035
E-mail: maria_toki@yahoo.com
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