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ISSUE 5
Keeping your finger
on the pulse
Personalized Medicine
eNewsletter
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Welcome to issue 5 of Adis in-touch Personalized Medicine.
We must first apologize for the delay in sending you this issue but we have all
been very busy getting our journal content ready to appear on Springer’s new
platform. You will be hearing more from us about this very soon.
In this bumper issue Michelle Wilde, Commissioning Editor for Oncology at Adis,
reports back from the ESMO congress which took place in Vienna last month with
record numbers of attendees. We also bring you an update on industry news as
well as an overview of recently published and upcoming relevant content from
Adis journals.
As always, we are keen to hear your feedback and suggestions for future issues, so
please get in touch and share your thoughts!
Enjoy!
The Adis in-touch team

Welcome Contents
3 Announcement
4 Featured Content
Polymorphisms of Estrogen Receptors and Risk of
Depression: Therapeutic Implications
Molecular Characterization of Head and Neck Cancer:
How Close to Personalized Targeted Therapy?
Individualized Therapy for Gastroesophageal Reflux
Disease: Potential Impact of Pharmacogenetic Testing

based on CYP2C19
Individualized Therapy for Type 2 Diabetes: Clinical
Implications of Pharmacogenetic Data
6 How to download free content
7 ESMO Meeting Report
13 Personalized Medicine News
Lower Toxicity with Targeted Anticancer Agents in Phase I
Trials
Antipsychotic-Associated Weight Gain: Genetic Link
Identified
PARP Inhibitors: Mechanism of Action and Their Potential
Role in the Prevention and Treatment of Cancer
Genetic Interaction between NAT2, GSTM1, GSTT1,
CYP2E1, and Environmental Factors is Associated with
Adverse Reactions to Anti-Tuberculosis Drugs
Influence of an Interaction between Lithium Salts and a
Functional Polymorphism in SLC1A2 on the History of
Illness in Bipolar Disorder
Cost Effectiveness of Genetic Testing for CYP2C19 Variants
to Guide Thienopyridine Treatment in Patients with Acute
Coronary Syndromes
19 Articles coming soon
20 Upcoming Events
21 Opportunity to Publish
3
Announcement
Jamie, originally from the UK, completed his PhD in
Biochemistry at the University of Strathclyde in Glasgow in
1985. This was followed by a five-year stint at the Royal Post
Graduate Medical School, London working on the hormonal

control of gynaecological malignancies and other reproductive
pathologies. In 1990, he joined the newly established William
Harvey Research Institute at St. Bartholomew’s Hospital,
London working on many aspects of cell signalling processes
underlying tumour cell proliferation and inflammatory and cardiovascular diseases.
Jamie relocated to New Zealand in 2007 and joined Adis as a medical writer in the
Periodicals Writing Group.
In total, he has authored almost 90
peer-reviewed publications both
as a researcher and medical writer.
Jamie joined the Commissioning
Services Group at Adis in 2012 and
is now the Editor for BioDrugs and
Molecular Diagnosis & Therapy.
Adis welcomes Jamie Croxtall, the new Editor of
BioDrugs and Molecular Diagnosis & Therapy
Download our FREE
Glossary of terms
used in Diabetes
and Genetics &
Genomics
Diabetes:
/>Genetics & Genomics:
/>4
Polymorphisms of Estrogen Receptors and Risk of Depression:
Therapeutic Implications
Ryan, J. and Ancelin, M.; Drugs. 72(13):1725-1738, September 10, 2012.
Accumulating evidence suggests the involvement of estrogen in depression.
Estrogen can modulate neurotransmitter turnover, enhancing the levels
of serotonin and noradrenaline (norepinephrine), and it is involved in

the regulation of serotonin receptor number and function. Across the
female reproductive life, fluctuating estrogen levels and low levels have
been associated with depressed mood, and there is strong support for a
beneficial effect of estrogen-containing hormone treatment in depressed
peri-menopausal women. Estrogen exerts its biological effects in large part
through intracellular activation of its principal receptors, estrogen receptor
α (ESR1) and estrogen receptor β (ESR2). Genetic variation in the estrogen
receptors may therefore modify estrogen signalling, thus influencing a
woman’s susceptibility to developing depression. This review provides a
synthesis of studies that have examined the association between estrogen
receptor polymorphisms and depression-related mood disorders across the
lifetime. The studies conducted to date have produced inconsistent findings,
which likely relates to the large heterogeneity in terms of the populations,
study design and depression measures used. If it is confirmed that specific
estrogen receptor polymorphisms are associated with the risk of depression,
this could have important preventive and therapeutic implications, with the
potential to develop targeted estrogen receptor agonists and antagonists.
Furthermore, it is possible that such therapies may be more effective in
treating particular people with depression based on their genetic profile,
which is an exciting prospect given that many people do not respond to
current antidepressant treatments.
Molecular Characterization of Head and Neck Cancer: How
Close to Personalized Targeted Therapy?
Worsham, M. J., Ali, H., Dragovic, J. and Schweitzer, V. P.; Molecular Diagnosis & Therapy.
16(4):209-222, August 1, 2012.
Molecular targeted therapy in head and neck squamous cell carcinoma
(HNSCC) continues to make strides, and holds much promise. Cetuximab
remains the sole US FDA-approved molecular targeted therapy available
for HNSCC, though several new biologic agents targeting the epidermal
growth factor receptor (EGFR) and other pathways are currently in the

regulatory approval pipeline. While targeted therapies have the potential
to be personalized, their current use in HNSCC is not personalized. This
is illustrated for EGFR-targeted drugs, where EGFR as a molecular target
has yet to be individualized for HNSCC. Future research needs to identify
factors that correlate with response (or lack of one) and the underlying
genotype–phenotype relationship that dictates this response. Comprehensive
exploration of genetic and epigenetic landscapes in HNSCC is opening new
frontiers to further enlighten and mechanistically inform newer as well as
existing molecular targets, and to set a course for eventually translating
these discoveries into therapies for patients. This opinion offers a snapshot
of the evolution of molecular subtyping in HNSCC and its current clinical
applicability, as well as new emergent paradigms with implications for
controlling this disease in the future.
Featured Content
Download any of the featured content for free before December 10th 2012
- Click on the links above and enter the voucher code 5F54NU during checkout to redeem this offer.
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Featured Content
Download any of the featured content for free before December 10th 2012
- Click on the links above and enter the voucher code 5F54NU during checkout to redeem this offer.
Individualized Therapy for Gastroesophageal Reflux Disease:
Potential Impact of Pharmacogenetic Testing based on
CYP2C19
Furuta, T., Sugimoto, M. and Shirai, N.; Molecular Diagnosis & Therapy. 16(4):223-234,
August 1, 2012.
The main therapeutic agent for gastroesophageal reflux disease (GERD) is
a proton pump inhibitor (PPI). Plasma levels and the acid inhibitory effect
of PPIs depend on the activity of cytochrome P450 (CYP) 2C19, which is
polymorphic. Genotypes of CYP2C19 are classified into three groups: rapid
metabolizers (RMs: *1/*1), intermediate metabolizers (IMs: *1/*X), and poor

metabolizers (PMs: *X/*X), where *1 and X represent the wild type and the
mutant allele, respectively. RMs include ultra-rapid metabolizers, who possess
the CYP2C19*17 allele. The pharmacokinetics and pharmacodynamics of
PPIs differ among different CYP2C19 genotype groups. Plasma PPI levels
and intragastric pH values during PPI treatment are lowest in the RM
group, intermediate in the IM group, and highest in the PM group. These
CYP2C19-genotype-dependent differences in the pharmacokinetics and
pharmacodynamics of PPIs influence the healing and recurrence of GERD
during PPI treatment, suggesting the need for CYP2C19 genotype-based
tailored therapy for GERD. CYP2C19 pharmacogenetics should be taken into
consideration for the personalization of PPI-based therapy. However, the
clinical usefulness of CYP2C19 genotype testing in GERD therapy should be
verified in clinical studies.
Individualized Therapy for Type 2 Diabetes: Clinical
Implications of Pharmacogenetic Data
Mannino, G. C. and Sesti, G.; Molecular Diagnosis & Therapy. 16(5):285-302, October 1, 2012.
Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance,
abnormally elevated hepatic glucose production, and reduced glucose-
stimulated insulin secretion. Treatment with antihyperglycemic agents is
initially successful in type 2 diabetes, but it is often associated with a high
secondary failure rate, and the addition of insulin is eventually necessary
for many patients, in order to restore acceptable glycemic control and to
reduce the risk of development and progression of disease complications.
Notably, even patients who appear to have similar requirements of
antidiabetic regimens show great variability in drug disposition, glycemic
response, tolerability, and incidence of adverse effects during treatment.
Pharmacogenomics is a promising area of investigation and involves the
search for genetic polymorphisms that may explain the interindividual
variability in antidiabetic therapy response. The initial positive results portend
that genomic efforts will be able to shed important light on variability in

pharmacologic traits. This review summarizes the current understanding of
genetic polymorphisms that may affect the responses of subjects with T2DM
to antidiabetic treatment. These genes belong to three major classes: genes
involved in drug metabolism and transporters that influence pharmacokinetics
(including the CYP superfamily and the OATP and OCT families); genes
encoding drug targets and receptors (including PPARG, KATP, and incretin
receptors); and genes involved in the causal pathway of T2DM that are able
to modify the effects of drugs (including adipokines, TCF7L2, IRS1, NOS1AP,
and SLC30A8). In addition to these three major classes, available evidence
is reviewed for novel genes that have recently been proposed as possible
modulators of therapeutic response in T2DM.
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Meeting Report
The conference was hugely exciting, over 16,000 delegates attended with
2,000 abstracts presented that included data from more than 100,000
patients who had participated in well-designed clinical trials.
Targeted therapies continue to be central to the move towards personalized
treatment of cancer patients. In fact, it is increasingly apparent that we are
now entering a very important period of tumor sequencing and stratifying

in oncology. This is being achieved through a more detailed classification
of tumor subtypes, through individualized genome profiling to identify the
presence of genetic alterations unique to a particular patient’s tumor and
quantification of gene expression (DNA and RNA and protein analysis) to
identify key oncogenic drivers. The aim of this “precision medicine” is to
improve patient selection or, in other words, identify those patients who
are most likely to respond to a particular therapy.
Dr Douglas Hanahan (Lausanne, Switzerland) gave an excellent keynote
presentation on recent perspectives on the acquired hallmark capabilities
of cancer and implications for targeted therapies. In addition to genetic
and epigenetic changes in cancer cells, stromal cells in the tumor micro-
environment also contribute to the hallmark capabilities. Although we
have drugs that target all of the hallmarks of cancer, targeting an individual
hallmark is not very effective. `Hallmark multi-targeting’ is required.
Unfortunately, development of resistance to targeted therapy is currently
the rule. A wide range of adaptive resistance mechanisms can develop,
including hallmark switching and activation of alternative pathways.
A Report from the European Society
of Medical Oncology (ESMO)
Vienna, Austria, 28 Sept- 2 Oct, 2012
Michelle Wilde,
Oncology Commissioning Editor,
Adis Journals
8
Meeting Report - continued
Heterogeneity, in both inter- and intra-patient characteristics and tumor
genetics, was a big theme at this year’s ESMO congress. The need for
accurate genomic characterization of tumors is essential for tailoring
treatment, determining resistance mechanisms, and for biomarker and
drug development. Using single tumor biopsy samples is not sufficient.

There was much discussion on how we deal with this in the clinic. Current
thinking included the use of one drug that blocks many pathways,
combination therapy to block many targets, destroying resistant clones
before they develop, and optimising treatment duration to avoid
cultivating resistance.
Central to this is the critical and difficult task of target/biomarker
identification, reproducibility and validation. We need more predictive
biomarkers, biomarker-driven studies to assess combination therapies, and
comparisons of methods for diagnosis. Biomarker-dependent therapy and
biomarker-guided patient selection is the way forward. Multiple/composite
biomarkers will be increasingly needed to assess new generations of drugs.
Bidirectional molecular data sharing will be key, and the availability of
results from negative studies is important for retrospective identification
of subpopulations likely to benefit.
There were a number of indications for which actual and potential practice-
changing results were presented. Some of these are detailed below.
Melanoma
Dr Keith T Flaherty (Boston, USA) explained that there is a wide range
of resistance mechanisms with BRAF inhibitors. Although we have a
`druggable’ molecular alteration in melanoma (BRAF V600 mutation),
BRAF inhibitors have a limited duration of efficacy because the tumors
upregulate other pathways, and MAPK reactivation is common. Current
evidence suggests that combination targeted therapy, rather than second-
line therapy, could be the optimal approach to overcoming or delaying
the development of resistance. There are a wide range of BRAF inhibitor-
containing combination therapies currently being investigated.
9
Meeting Report - continued
Of particular excitement was the dual-therapy study in BRAF V600E
mutation-positive metastatic melanoma, reported by Dr. Georgina Long

(Melanoma Institute Australia, and Westmead Hospital, University of
Sydney, Australia). The combination of dabrafenib 150mg twice daily
(an inhibitor of BRAF V600 mutations) and tremetinib 2mg once daily (a
selective MEK inhibitor) significantly increased progression-free survival
(PFS) [median 9.4 mo vs 5.8 mo; HR 0.39, 95% CI 0.25-0.62, p<0.0001]
and the confirmed response rate (76 vs 54%; p=0.03) compared with
dabrafenib monotherapy, and the duration of response was longer
with combination therapy (median 10.5 vs 5.6 mo). The 12-month
overall survival (OS) was 79% with the combination (crossover to the
combination was allowed on progression); however, the median OS had
not been reached.
[1]
Importantly, the incidence of hyperproliferative skin
lesions was lower with combination therapy; the incidence and severity of
pyrexia was greater, but this was manageable. This combination is the first
kinase-kinase combination to show benefit in melanoma.
Another possible future BRAF/MEK inhibitor combination could be
vemurafenib (BRAF inhibitor) plus GDC-0973 (MEK inhibitor)
[2]
. Professor
Rene Gonzalez (Division of Medical Oncology, University of Colorado,
Aurora, USA) presented results from the BRIM7 study, a phase I dose
escalation trial of patients with unresectable or metastatic BRAF V600-
mutated melanoma. The combination was tolerable with adverse events
being manageable. Although tumor size reduction was reported, further
study is required.
Lung cancer
We clearly know that lung cancer is not a single disease entity. It remains
important to first determine the histology of nonsmall-cell lung cancer
(NSCLC), followed by identification of genetic mutations. Excellent keynote

presentations on the molecular characterization of lung cancer in multiple
different diseases were given. Professor Jean-Charles Soria (Institute
Gustave Roussy, Villejuif, France) explained that molecular abnormalities
that could allow the identification of new molecular subtypes of NSCLC
and potential targets for the development of therapeutic agents have
been identified in many genes, in addition to the known EGFR (mutations)
and ALK (translocations); these include FGFR1 and HER2 (amplifications),
and ROS and RET (translocations), among many others. Professor Soria
emphasised that for optimal management of patients with NSCLC and
development of targeted therapies, characterization of the genomic
changes that drive an individual patient’s disease is critical.
At the same keynote, Dr Jeffrey Engelman (Massachusetts General
Hospital, Charlestown, MA, USA) spoke about the evolution of lung cancers
upon treatment with targeted therapies. Development of resistance is the
rule; the duration of response is months not years. Dr Engelman explained
that resistance may develop because of alterations in the gene target or
amplification of the gene itself; bypass track resistance; or continuation
of proliferation despite the signalling pathway being inhibited. While
we do not know how to overcome this, current and potential strategies
include the use of combination therapies, pulsatile treatment and varying
regimens; killing resistant clones before they develop; and stopping
10
treatment before resistance is cultivated. An added complication is that,
in the case of EGFR mutations, these mutations can also be seen in
the resistant biopsy. Furthermore, EGFR-resistant adenocarcinoma can
become small cell lung cancer. We do not yet know why this is happening,
although epithelial-mesenchymal transition (EMT) is seen in many cancers
that acquire resistance.
Both `microscopic’ and `macroscopic’ heterogeneity may also explain
clinical observations in NSCLC. For example, cancers that progress on

EGFR inhibitor therapy will often flare when the inhibitor is discontinued;
it may be that we are selecting for a different clone of the cancer rather
than the cancer histology changing. Furthermore, different parts of a
lesion can have different histologies, and there can be different resistance
mechanisms within a sample. Instead of repeat biopsies, other approaches
such as serial monitoring of circulating tumor cells (CTCs), and monitoring
for KRAS mutations in the serum may be more useful.
We now have several targeted drugs for molecularly defined subsets of
patients with NSCLC. The most recent development is crizotinib, which
is now the standard of care for previously treated patients with advanced
anaplastic lymphoma kinase-positive (ALK+) NSCLC. As presented by
Dr. Alice Shaw (Massachusetts General Hospital Cancer Center, Boston,
MA, USA), the phase III Profile 1007 study showed crizotinib to be
significantly superior to standard second-line chemotherapy (pemetrexed
or docetaxel) in increasing the primary endpoint, PFS (median 7.7 mo vs
3 mo; HR 0.49; 95% CI 0.37-0.64, p<0.0001), as well as the secondary
endpoint, objective response rate (65 vs 20%; p<0.0001), in patients with
advanced ALK+ NSCLC who had received one previous platinum-based
regimen.
[3]
Patient-reported outcomes based on lung cancer symptoms
revealed significantly improved quality of life (QOL) with crizotinib.
Interim analysis of OS showed no statistically significant difference but
data are immature and significant crossover occurred in the study. There
was a similar incidence of grade 3 and 4 treatment-related adverse events.
As with all targeted therapies, patients develop resistance to crizotinib.
There are several ongoing trials of second-generation ALK inhibitors
including AP26113.
Meeting Report - continued
11

Breast cancer
T-DM1 (trastuzumab emtansine), an antibody-drug conjugate, significantly
reduced the risk of death by 32% (OS 30.9 vs 25.1mo at median follow-up
of about 20 months; HR 0.68, 95% CI 0.55-0.85, p<0.001), increased PFS
(median 9.6 vs 6.4mo; HR 0.65, 95% CI 0.55-0.77, p<0.0001) and improved
tolerability in the phase III EMILIA study, compared with capecitabine plus
lapatinib in HER2-positive (HER2+) patients with unresectable locally
advanced/metastatic breast cancer previously treated with trastuzumab
and taxane.
[4]
This updated analysis from EMILIA, was presented by Dr
Sunil Verma (Sunnybrook Odette Center, Toronto, Canada), who concluded
that T-DM1 should be an important therapeutic option in the treatment
of metastatic HER2+ breast cancer. This degree of improvement in OS
in metastatic breast cancer is unprecedented. Importantly, the rates of
cardiac dysfunction were low with both treatment arms. Final OS data are
expected in 2014.
There has been much debate about the optimal duration of trastuzumab
therapy in HER2+ early breast cancer. One year of trastuzumab remains
the standard of care in the adjuvant treatment of HER2+ early breast
cancer. This was confirmed on the basis of the phase III HERA (2 vs 1
year of treatment with trastuzumab; median 8-year follow up]
[5]
and
PHARE (6 vs 12 months’ treatment with trastuzumab; median follow-up
42.5 months)
[6]
trial data, presented by Professors Richard Gelber (Dana
Farber Cancer Institute, Boston, USA) and Xavier Pivot (Besancon, France),
respectively. In the HERA trial, there was no evidence of long term benefit

in terms of disease-free survival (DFS) or OS of 2 versus 1y of trastuzumab
administration. The primary cardiac endpoint was similar in both groups
but the secondary cardiac endpoint was higher in the 2 year arm. In the
PHARE study, noninferiority for DFS with 6 months’ treatment could not
be demonstrated. However, the hazard ratio for DFS (1.28) suggests a
trend favoring 12 months’ therapy.
Renal cancer
Pazopanib appears to be the preferred treatment in the first-line treatment
of metastatic renal cell carcinoma, according to the results of the COMPARZ
trial.
[7]
As presented by Professor Robert Motzer (Memorial Sloan-Kettering
Cancer Center, New York, USA), this phase III head to head trial of pazopanib
and sunitinib, in combination with bevacizumab and interferon, showed
noninferiority of pazopanib in PFS in patients with treatment-naïve
metastatic renal cell carcinoma. Pazopanib also demonstrated a more
favourable QOL profile, and the differentiated safety profile of pazopanib
included a decreased incidence of hand/foot syndrome.
GI
There is a high unmet clinical need for treatment options in metastatic
colorectal cancer. Drs Heinz-Joseph Lenz (Univeristy of Southern
California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA),
Axel Grothey (Mayo Clinic, Rochester, MN, USA) and George Demetri
(Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA, USA)
gave highly entertaining and accomplished presentations on translating
advances in molecular oncology to the clinic for the treatment of
metastatic colorectal cancer and GIST.
Meeting Report - continued
12
Meeting Report - continued

These authors confirmed the potential of mechanism-guided combination
therapies in selective co- targeting of multiple hallmark capabilities seen in
colorectal cancer and GIST. The example of regorafenib was given, an oral
multikinase agent that inhibits both oncogenic (proliferation and tumor
microenvironment signalling) and angiogenic kinases, that has potential in
the management of metastatic colorectal cancer and refractory GIST. This
agent was approved by the US FDA in September 2012 as a monotherapy
for patients with metastatic colorectal cancer who progressed with
current standard therapies.
Other developments for patients with progressive metastatic colorectal
cancer include continuation of treatment with bevacizumab beyond
progression, and aflibercept, an antiangiogenic agent. Continuation of
bevacizumab administered with second-line chemotherapy significantly
increased PFS (median 6.77 vs 4.97 mo; HR 0.65, 95% CI 0.48-0.89; p
= 0.0062) compared with second-line chemotherapy alone in patients
with disease progression who had received bevacizumab as part of first-
line therapy.
[8]
Dr Gianluca Masi (University Hospital of Pisa, Italy), who
presented the results of this phase III trial, concluded that the continuation
of bevacizumab in combination with second-line chemotherapy represents
a new treatment option for these patients. Mature OS survival data are
not yet available.
As further confirmation of the usefulness of prolonged VEGF inhibition, Dr
Grothey reviewed the data on aflibercept, a soluble fusion protein and novel
VEGF receptor antagonist. This agent was recently approved by the US FDA as
a treatment option in combination with FOLFIRI for patients with metastatic
colorectal cancer previously treated with an oxaliplatin-based regimen.
References
1. Long GV, Sosman JA, Daud AI, et al. Phase II three arm randomised study of the BRAF inhibitor (BRAFI) dabrafenib alone vs combination with MEK1/2 inhibitor (MEKI) trametinib in patients with

BRAF V600 mutation-positive metastatic melanoma (MM) [abstract no. LBA27_PR]. European Society for Medical Oncology 2012 Congress; 2012 Sep 28 – 2 Oct, Vienna, Austria
2. Gonzalez R, Ribas A, Daud A, et al. Phase IB Study of Vemurafenib in Combination with the MEK inhibitor, GDC-0973, in Patients (PTS) with Unresectable or Metastatic BRAFV600 Mutated
Melanoma [abstract no. LBA28_PR]. European Society for Medical Oncology 2012 Congress; 2012 Sep 28 – 2 Oct, Vienna, Austria
3. Shaw AT, Kim DW, Nakagawa T, et al. Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer (NSCLC)
(PROFILE 1007) [abstract no. LBA1_PR]. European Society for Medical Oncology 2012 Congress; 2012 Sep 28 – 2 Oct, Vienna, Austria
4. Verma S, Miles D, Gianni L, et al. Results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic
breast cancer (MBC) [abstract no. LBA12]. European Society for Medical Oncology 2012 Congress; 2012 Sep 28 – 2 Oct, Vienna, Austria.
5. Goldhirsch A, Piccart M, Procter M, et al. HERA TRIAL: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median
follow up [abstract no. LBA6_PR]. European Society for Medical Oncology 2012 Congress; 2012 Sep 28 – 2 Oct, Vienna, Austria
6. Pivot X, Romieu G, Bonnefoi H, et al. PHARE Trial results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer [abstract no. LBA5_PR]. European Society for Medical
Oncology 2012 Congress; 2012 Sep 28 – 2 Oct, Vienna, Austria
7. Motzer R, Hutson TE, Reeves J, et al. Randomized, Open label, Phase III Trial of Pazopanib versus Sunitinib in First-line Treatment of Patients with Metastatic Renal Cell Carcinoma (mRCC):
rResults of the COMPARZ Trial [abstract no. LBA8_PR]. European Society for Medical Oncology 2012 Congress; 2012 Sep 28 – 2 Oct, Vienna, Austria .
8. Masi G, Loupakis F, Salvatore L, et al. A randomized phase III study evaluating the continuation of bevacizumab (BV) beyond progression in metastatic colorectal cancer (MCRC) patient (PTS)
who received BV as part of first-line treatment: results of the BEBYP trial by the Gruppo Oncologico Nord Ovest (GONO [abstract no. LBA17]. European Society for Medical Oncology 2012
Congress; 2012 Sep 28 – 2 Oct, Vienna, Austria.
13
Personalized Medicine News
Originally published as a Forum piece in Pharmaceutical Medicine 26(6):411-420, December
1, 2012
Molecularly targeted agents (MTAs) are associated with a lower risk of
serious toxicity than conventional chemotherapy drugs in phase I trials,
according to two studies published in the Annals of Oncology.
Both studies retrospectively assessed the rates of National Cancer
Institute - Common Toxicity Criteria (NCI-CTC) grade 3−4 adverse events
in patients with advanced cancers enrolled in phase I trial programmes at a
single centre. Multivariate analyses were conducted to identify predictive
factors for serious toxicity.
The first study was an analysis of data from 687 patients enrolled in 36
trials of targeted agents at the Royal Marsden Hospital (RMH) in the UK

from January 2005 through December 2009.
[1]
Grade 3−4 adverse events occurred in 110 patients (16.0%) and three
deaths (0.43%) were considered to be at least possibly treatment related.
Independent predictors of serious toxicity were Eastern Cooperative
Oncology Group (ECOG) performance status (PS) of 2 versus PS 0−1
(odds ratio [OR] 2.6; 95% CI 1.1, 6.1; p = 0.032) and administration of
>100% of the maximum tolerated dose (MTD) or maximum administered
dose (OR 2.5; 95% CI 1.6, 3.9; p < 0.001).
The second study was conducted at the MD Anderson Cancer Center in
Houston, Texas, USA.
[2]
Database records of 1181 consecutive patients
enrolled in 82 trials of predominantly targeted agents (84% of trials
included at least one MTA) between 1 January 2006 and 31 December
2008 were examined.
Grade 3−4 adverse events occurred in 122 patients (10.3%). There were
five deaths (0.4%) that were considered possibly related to treatment.
Two independent predictors of serious toxicity were identified: ECOG PS
>0 (relative risk [RR] 1.7; p = 0.011), and treatment on a first phase I study
involving a conventional chemotherapeutic agent (RR 1.8; p = 0.001).
Neither study found the RMH score or its component variables to be
independently predictive of toxicity, indicating that predictors of toxicity
differed from those for survival.
An accompanying editorial, noting the difference between toxicity
patterns involved in phase I trials of targeted agents and those of
conventional chemotherapy drugs, comments that these studies highlight
the need for the continued evolution of the design of phase I trials to
meet the challenges encountered in the era of MTAs and personalized
medicine.

[3]
The authors suggest that, due to the increasing number of
MTAs in development, the regulations for determining starting doses for
phase I studies may need to change, and longer-term toxicity may need
to be considered when determining MTDs.
Lower Toxicity with Targeted Anticancer Agents in Phase I Trials
1. Molife LR, Alam S, Olmos D, et al. Defining the risk of toxicity in phase I oncology trials of novel molecularly targeted agents: a single centre experience. Ann Oncol 2012; 23 (8): 1968-73
2. Wheler JJ, Tsimberidou AM, Hong DS, et al. Risk of serious toxicity in 1181 patients treated in phase I clinical trials of predominantly targeted anticancer drugs: the M. D. Anderson Cancer Center
experience. Ann Oncol 2012; 23 (8): 1963-7
3. Greystoke A, Ranson M. Learning from toxicity patterns in phase I trials during the era of mechanism targeted agents. Ann Oncol 2012; 23(8): 1934-6
14
Originally published as a Forum piece in Pharmaceutical Medicine 26(6):411-420, December
1, 2012
A genome-wide association study has further implicated the melanocortin
4 receptor gene (MC4R) in severe drug-induced weight gain associated
with second generation antipsychotics (SGA).
[1]
The discovery cohort included 139 paediatric patients undergoing initial
treatment with an SGA. The study identified genetic variants (single
nucleotide polymorphisms, or SNPs) at a single locus downstream of
MC4R that were linked to significantly greater weight gain during the
12-week treatment period. The results were confirmed in three additional
patient cohorts involving 205 patients in total from the USA and Europe.
The SGAs are associated with substantial weight gain in approximately
40% of patients, and prior identification of at-risk patients could help
physicians prescribe more effectively. The current study is the second
involving scientists from the Centre for Addiction and Mental Health
(CAMH) to implicate the MC4R gene, according to a CAMH media
release.
[2]

The earlier study, published in The Pharmacogenomics Journal,
[3]

identified a different variation near MC4R. The receptor encoded by MC4R
is involved in the brain pathways that regulate weight, appetite and
satiety. We don’t know exactly how the atypical antipsychotics disrupt
this pathway, or how this variation affects the receptor, says CAMH
scientist Dr Daniel Müller. We need further studies to validate this result
and eventually turn this into a clinical application.
1. Malhotra AK, Correll CU, Chowdhury NI, et al. Association between common variants near
the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch
Gen Psychiatry. Epub 2012 May 7
2. Centre for Addiction and Mental Health. Genetic link to rapid weight gain from
antipsychotics discovered [media release]. 2012 Jul 17 [online]. Available from URL:
[Accessed 2012 Sept 12]
3. Chowdhury NI, Tiwari AK, Souza RP, et al. Genetic association study between antipsychotic-
induced weight gain and the melanocortin-4 receptor gene. Pharmacogenomics J. Epub
2012 Feb 7
Antipsychotic-Associated Weight Gain: Genetic Link Identified
Personalized Medicine News - continued
15
Originally published in the Journal Watch piece of Pharmaceutical Medicine 26(6):411-420,
December 1, 2012
The use of poly(ADP-ribose) polymerase (PARP) inhibitors provided proof-
of-concept for a synthetic lethal anti-cancer strategy as a result of their
efficacy and favourable toxicity profile in BRCA1/2 mutation carriers.
Efforts are underway to identify a broader group of patients with genomic
susceptibility that may benefit from these agents. In an endeavour to
enhance anti-tumour effects, PARP inhibitors have been combined with
traditional cytotoxic therapy and radiotherapy; however, optimization

of dosing schedules for these combination regimens remains key to
maximizing benefit whilst mitigating the potential for increased toxicity.
With ongoing clinical experience of PARP inhibition, mechanisms of
resistance to these therapies are being elucidated and specific challenges
to long-term administration of these drugs will need to be addressed.
Development of robust predictive biomarkers of response for optimal
patient selection and rational combination strategies must be pursued if
the full potential of these agents is to be realized.
Basu B, Sandhu SK, de Bono JS. PARP inhibitors: mechanism of action and their potential role in
the prevention and treatment of cancer. Drugs 2012; 72 (12): 1579-1590
Personalized Medicine News - continued
PARP Inhibitors: Mechanism of Action and Their Potential Role in the Prevention and Treatment of Cancer
16
Originally published in the Journal Watch piece of Pharmaceutical Medicine 26(6):411-420,
December 1, 2012
Adverse drug reactions (ADRs) associated with anti-tuberculosis (anti-TB)
drug regimens have considerable impact on anti-TB treatment, potentially
leading to unsuccessful outcomes. Nevertheless, the risk factors that
play a role in anti-TB drug-induced ADRs are not well established. It is
well documented that genetic polymorphisms in drug-metabolizing
enzymes (DMEs) result in considerably complex variability in anti-TB
drug disposition. In addition, the impact of pharmacogenetic variation on
the metabolism of anti-TB drugs may be modifiable by environmental
exposure. This study investigated the impact of the interaction between
environmental risk factors and pharmacogenetic polymorphisms in four
common DMEs – N-acetyltransferase 2 (arylamine N-acetyltransferase).
[NAT2], glutathione S-transferase theta 1 [GSTT1], glutathione
S-transferase mu 1 [GSTM1], and cytochrome P450 2E1 [CYP2E1] – on
commonly reported ADRs to first-line anti-TB drugs in 129 patients
receiving homogeneous TB treatment.

The patients monitored during drug treatment were divided into subgroups
according to the presence or absence of ADRs. Additionally, the patients’
clinical and demographic characteristics were collected in order to identify
the environmental factors that are potential triggers for ADRs induced
by anti-TB drug treatment. Pharmacogenetic variability was determined
by gene sequencing, TaqMan® assays, or polymerase chain reaction.
The study findings suggest that the NAT2 slow acetylator haplotype,
female sex, and smoking are important determinants of susceptibility
to ADRs induced by anti-TB drugs. Patients carrying multiple, but not
single, polymorphisms in the NAT2, GSTM1, GSTT1, and CYP2E1 genes
were found to have an increased risk of ADRs, as revealed by gene-gene
interaction analysis. Moreover, meaningful gene-environment interaction
models that resulted in the highest levels of ADR risk were identified. The
study findings provide evidence of the clinical impact of the interaction
between pharmacogenetic variability and environmental factors on ADRs
induced by anti-TB drug therapy. Predictive pharmacogenetic testing and a
comprehensive clinical history would therefore be helpful for identification
and careful monitoring of patients at high risk of this complication.
Costa GNO, Magno LAV, Santana CVN, et al. Genetic interaction between NAT2, GSTM1,
GSTT1, CYP2E1, and environmental factors is associated with adverse reactions to anti-
tuberculosis drugs Mol Diagn Ther 2012; 16 (4): 241-250
Personalized Medicine News - continued
Genetic Interaction between NAT2, GSTM1, GSTT1, CYP2E1, and Environmental Factors is Associated with
Adverse Reactions to Anti-Tuberculosis Drugs
17
Dallaspezia, S., Poletti, S., Lorenzi, C., Pirovano, A., Colombo, C. and Benedetti, F.; Molecular
Diagnosis & Therapy. 16(5):285-302, October 1, 2012.
Bipolar disorder (BD) is a recurrent and disabling illness, characterized by
periods of depression and mania. The history of the illness differs widely
between patients, with episode frequency emerging as a strong predictor

of poor illness outcome. Lithium salts are the first-choice long-term mood-
stabilizing therapy, but not all patients respond equally to the treatment.
Evidence suggests that alterations in glutamatergic systems may
contribute to the pathophysiology of depression. Moreover, glutamate
signaling is involved in brain development and synaptic plasticity, both of
which are modified in individuals affected by BD, and has been implicated
in the etiology of the disorder. The inactivation of glutamate is handled
by a series of molecular glutamate transporters (excitatory amino acid
transporters [EAATs]), among which EAAT2/SLC1A2 is responsible for up to
95% of extracellular glutamate clearance. A functional single-nucleotide
polymorphism at −181 bp from the transcription start site of the SLC1A2
gene has been described. This T-to-G (DNA forward strand) polymorphism,
commonly known as SLC1A2 −181A>C, affects transporter expression,
with the variant G allele inducing a 30% reduction in promoter activity
compared with the T allele.
This study investigated if factors affecting glutamate function, such as
SLC1A2 −181A>C (rs4354668), could affect recurrence of illness in
BD, and if they interact with lithium salt treatment. The observational
study, conducted in a university hospital in Milan, enrolled 110 subjects
(76 females, 34 males) affected by BD type I. Fifty-four patients had
been treated with lithium salts for more than 6 months. Patients were
genotyped for SLC1A2 −181A>C by PCR-restriction fragment length
polymorphism, and the influence of genotype on BD episode recurrence
rates, and the interaction between the single nucleotide polymorphism
and lithium treatment, were analyzed.
The SLC1A2 −181A>C genotype significantly influenced the total
recurrence of episodes, with T/T homozygotes showing a significantly
lower frequency of episodes (F = 3.26; p = 0.042), and an interaction
between lithium treatment and genotype (F = 3.77; p = 0.026) was found
to influence the history of the illness. The glutamatergic system could be

hypothesized to exert some influence on the history of illness in BD. The
SLC1A2 functional polymorphism was shown to significantly influence the
total episode recurrence rate, with wild-type T homozygotes presenting
the lowest number of episodes, G homozygotes reporting the highest
number, and heterozygotes showing an intermediate phenotype. The study
confirmed the efficacy of lithium treatment in reducing the recurrence of
illness in BD, and found an interaction between lithium treatment and
the SLC1A2 −181A>C genotype, confirming previous studies reporting an
interaction between lithium salts and the glutamatergic system.
Personalized Medicine News - continued
Influence of an Interaction between Lithium Salts and a Functional Polymorphism in SLC1A2 on the History
of Illness in Bipolar Disorder
18
Panattoni, L., Brown P. M., Te Ao, B., Webster, M. and Gladding P.; PharmacoEconomics.
30(11):1067-1084, November 1, 2012.
Use of genetic testing for CYP2C19 variants to guide thienopyridine
treatment is potentially cost effective for patients with acute coronary
syndromes (ACS) in New Zealand, especially in specific ethinic groups,
according to the results of an analysis published recently.
The researchers developed a decision-analytic model for patients aged
45−80 years hospitalised with ACS. Adverse cardiac event rates for the
NZ population were calculated based on data from TRITON-TIMI 38
substudies or national hospital data. The analysis was conducted from a
health funder perspective and costs were reported in 2009 New Zealand
(NZ) dollars.
Clopidogrel was the dominant strategy compared with prasugrel only, and
prasugrel was also dominated by a genetically-guided strategy (clinical
trial data). The incremental cost-utility ratio values for a genetically-
guided strategy versus clopidogrel were $NZ24·617 per QALY (clinical trial
data) and $8702 per QALY (hospital data). There was a 90% probability

that the genetically-guided strategy was cost effective at a threshold of
<·$10·000 using NZ hospital rates. The genetically-guided strategy was
particularly cost effective in patients of Maori, Pacific Island or Asian
ethnicity, primarily due to their increased risk of adverse cardiac events.
The authors commented that the results of their study “should give
clinicians who have decided to perform routine genotyping in their
patients confidence that their approach is justified until further evidence
is available”.
Personalized Medicine News - continued
Cost Effectiveness of Genetic Testing for CYP2C19 Variants to Guide Thienopyridine Treatment in Patients
with Acute Coronary Syndromes
n
Optimal Management of Brain Metastases from Breast Cancer
n
Molecular-based Classification of AML and its Role in Directing Rational
Therapy
n
New Insights into the genetics of Neuroblastoma: Implications for
Diagnosis and Therapy
n
Pharmacogenetics in Kidney Transplantation: Recent Updates and
Potential Clinical Applications
n
Assays for Prostate Cancer: Changing the Screening Paradigm?
19
Articles coming soon in Adis journals:
Molecular Biotechnology and Bioinformatics Workshop
November 19 – 23, 2012
Pune, India
Pathogen Safety Summit 2012

November 26 – 28, 2012
Munich, Germany
Diabetes, Cardiovascular & Renal Complications
November 28 – 29, 2012
London, UK
8th Annual Personalized Medicine Conference
November 28 – 29, 2012
Boston, MA, USA
IDIBELL Cancer Conference on Personalized Cancer Medicine
December 3 – 4, 2012
Barcelona, Spain
Biofest 2012
December 12 – 13, 2012
Hyderabad, India
3rd International Conference on Advances in Biotechnology
and Pharmaceutical Sciences
January 8 – 9, 2013
Kuala Lumpur, Malaysia
Biomarkers Summit
January 16 – 17, 2013
London, UK
Molecular Med Tri-Con 2013
February 11 – 15, 2013
San Francisco, CA, USA
Upcoming Events
20
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