Pharmacogenetics and Other Molecular

Eirini Merika
1
, Konstantinos N Syrigos
2
, Muhammad Wasif Saif
3
1
West London Renal and Transplant Centre, Hammersmith Hospital, Imperial College London.
London, United Kingdom.
2
Oncology Unit, Third Department of Medicine, Athens Medical School. Athens, Greece.
3
Section of Medical Oncology, Yale University School of Medicine. New Haven, CT, USA
Summary
Among various abstracts presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) held in Chicago,
June 2010, four interesting abstracts focusing on pancreatic cancer merit further discussion in this post-ASCO commentary as they
potentially provide insight to clinicians and hope to patients. These abstracts point to the future of pancreatic cancer management
through identification of molecular targets and prognostic factors to overcome the limits of efficacious chemotherapy delivery.
What We Knew before ASCO 2010
Pancreatic cancer remains the most lethal, aggressive
abdominal malignancy, frequently presenting at the
metastatic stage. This renders treatment extremely
difficult, leading to poor prognosis and five-year
survival of 15% for early stage disease and life
expectancy of 6-11 months for locally advanced
disease [1]. The main challenges in the treatment of
locally advanced pancreatic adenocarcinoma are
understanding pancreatic tumour behaviour and
microenvironment, overcoming the limits of delivery
and efficacy of chemotherapy and identifying
biomarkers for prediction of outcome success.
What We Learnt at ASC0 2010
Pancreatic Microenvironment
It is well recognised that the pervasive growth of
dense, collagen-rich, fibrous tissue around pancreatic
tumours, known as the desmoplastic reaction, forms a
barrier to chemotherapy penetration and hence efficacy.
Many matrix metalloproteinases (MMPs) have been
associated with the extent of the desmoplastic reaction
as well as enhanced adhesion and invasion of
pancreatic tumours [2, 3]. Protein membrane type 1-
matrix metalloproteinase (MT1-MMP) is over-
expressed in colorectal [4] and lung tumour cells [5]
and serves as a key protein for tumour growth and
invasiveness. MT1-MMP appears to activate MMP-2,
which has a catalytic function in the basement
membrane degradation (Figure 1), leading to increased
Key words BRAF protein, human; epidermal growth factor
receptor-neu receptor; KRAS protein, human; Pancreatic
Neoplasms; Pharmacogenetics; Polymorphism, Single Nucleotide
Abbreviations ASCO: American Society of Clinical Oncology;
MMP: matrix metalloproteinase; MT1-MMP: membrane type 1-
matrix metalloproteinase
Correspondence Muhammad Wasif Saif
Yale Cancer Center, Yale University School of Medicine, 333
Cedar Street, FMP 116, New Haven, CT, USA
 
Figure 1. Matrix degradation by MT1-MMP (with permission of
Yoshifumi Itoh Lab Imperial College. London, UK).

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pancreatic cancer cell invasiveness but their expression
is also directly linked with the extent of the
desmoplastic reaction in pancreatic cancer tissue [6].
New evidence in the 2010 American Society of
Clinical Oncology (ASCO) Annual Meeting shows that
these MMPs may also be implicated in the tumour
microenvironment and pose an obstacle to treatment
penetration to the tumour. Krantz et al (Abstract
#4158) demonstrated that MT1-MMP over-expression
in transgenic mice led to an increase not only of pre-
cancerous lesions and metaplasia but also in tumour
invasiveness [7]. They also showed that MT1-MMP is
linked to more peripancreatic tumour fibrosis.
This study comes to support our knowledge of the role
of MMPs in tumour progression and the desmoplastic
reaction. MMPs seem to play multiple roles in tumour
progression and further investigation has the potential
of serving as a molecular target for treatment delivery.
Molecular Targets and Pancreatic Cancer
One of the most interesting studies presented at ASCO
Annual Meeting in relation to pancreatic cancer,
showed an association between certain KRAS
mutations and reduction in overall survival in
pancreatic cancer patients after surgery. Recent
research, as seen in the CRYSTAL [8], OPUS [9] and
CAIRO 2 [10] trials, suggests that genetic
polymorphisms can be used to predict treatment
outcome, such as KRAS and BRAF mutations in
colorectal cancer and response to monoclonal
antibodies against EGFR, such as cetuximab or
panitumumab. Certain mutations in particular serve as
negative predictive factors for therapy success, as
expressed in the provisional clinical opinion in the
ASCO 2009 Gastrointestinal Meeting [11]. The
KRAS/BRAF pathway has also been shown to play a
key role in the development of pancreatic ductal
adenocarcinoma [12].
The investigators from Denmark looked at the presence
of KRASBRAF and HER2 mutations in patients
operated for pancreatic adenocarcinoma and their link
to overall survival (Abstract #4043 [13]). Certain
variations in the KRAS genotype could be correlated
with a poorer overall survival (hazard ratio, HR: 1.48;
95% CI: 1.07-2.05; P=0.02). In fact the HR for overall
survival was 1.79 in patients who had certain KRAS
mutations compared to patients with normal variations
of KRAS. The majority of mutations occurred in codons
12 and 13, as in colorectal cancer patients.
Whether this gene analysis will lead to better future
treatment outcomes by targeting EGFR in the subgroup
of patients with these mutations remains to be seen.
Analysis of a single gene is unlikely to be fully
informative of the exact pharmacogenetic mechanism.
However, the results suggest it is worth pursuing the
route of analysis and genotyping of specific oncogenes
present in pancreatic cancer patients, which can
subsequently serve as molecular targets for successful
treatment. Needless to say this will be true for other
cancers, such as breast and gastric. The KRAS/BRAF
pathway has potential to serve as predictive factor for
anti-EGFR therapy in various gastrointestinal tumours.
Pharmacogenetics
Two papers look into the prognostic significance
between gene polymorphisms and treatment success.
One of the main challenges in the treatment of
pancreatic cancer patients is overcoming resistance to
chemotherapeutic agents. Traditional and even newer
pharmaceutical therapeutic regimens are limited in
terms of tolerance, efficacy and cross-resistance.
Resistance is multifaceted and stems from both tumour
immunosuppressive mechanisms as well as genetic
polymorphisms.
Various genes have been characterised that contribute
to tumour cell protection against immune defence
mechanisms, such as the xCT gene, which codes for
part of the plasma membrane cysteine/glutamate
transporter [14]. This balance is critical for protection
of tumour cells against the immune system [15].
In the first paper Huang et al. (Abstract #4065 [16]),
looked at the prognostic significance of single
nucleotide polymorphisms in the xCT gene in patients
with advance pancreatic cancer treated with
gemcitabine and platinum. They identified specific
polymorphisms that correlated with better overall
survival in patients receiving treatment, with maximum
median survival time of 13.6 months for specific
genotypes alone and even higher at 14.1 months in
patients receiving the combination treatment.
In the second paper Pacetti et al (Abstract #4098 [17])
exploited polymorphisms in genes involved in activity
and resistance to drugs, mainly DNA repair gene
polymorphisms, in an effort to link them to treatment
response. The substitution of Gln for Lys in position
751 of the XPD gene (Figure 2) led to increased overall
survival from 262 days (95% CI: 202-423 days) to 446
(95% CI: 346-446 days).
Figure 2. XPD protein (with permission of Department of Energy
Lawrence Berkeley National Laboratory, CA, USA).

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JOP. J Pancreas (Online) 2010 Jul 5; 11(4):328-330.
JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 11, No. 4 - July 2010. [ISSN 1590-8577]
330
Both papers suggest that genetic variants in genes like
xCT have the potential to serve as predictors of
treatment outcome and to the development of
personalised chemotherapeutic therapy.
Conclusion
The 2010 ASCO Annual Meeting in relation to
pancreatic cancer focuses towards the emerging field of
identification of molecular biomarkers and molecular
profiling in treatment selection and highlights the
challenges this emerging field presents. These
advances in genomic, transcriptomic and proteomic
technologies have led to a step towards materialisation
of the concept of personalised medicine. There is still a
significant gap between literature and routine clinical
practice, which needs to start bridging.
Conflict of interest The authors have no potential
conflicts of interest
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