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Molecular Pathology
of these pathways could be used clinically, we conducted a
randomized phase II trial based on letrozole (LET arm) with or
Laboratory
without ‘metronomic’ oral cyclophosphamide. PI3K, AKT, and
mTOR were assessed on tumour specimens collected before
and after treatment in patients randomized in this trial. The
primary aim was to explore the changes of these molecular
targets before and after treatment. Secondary aims were to
Development and implementation of personalised
evaluate the relationship between these targets and conventional
medicine biomarkers into the clinic
clinical and biological prognostic variables and to correlate the
The era of personalised medicine has now spread from its
changes of these targets with clinical response and patient
beginnings in haematology (imatinib) and breast cancer
outcome. We observed that basal expression of the pathway
(tamoxifen) to encompass a wide number of tumour types and
was not significantly correlated with response or patient
targets. Personalised medicine involves the choice of drug
outcome. Both letrozole alone and letrozole with
treatment as a consequence the presence of a biomarker (often
cyclophosphamide resulted in a significant reduction of PI3K
a defined mutation) that indicates the susceptibility or resistance
expression (P = 0.02 and P < 0.005, respectively) and
of a patient to a specific drug. We have been working with a
phospho-mTOR expression (P = 0.0001 and P = 0.0001,
number of our medical oncology colleagues to develop and
respectively). pAKT showed no change in the letrozole arm,
implement appropriate methodology to detect these
whereas it was significantly decreased in the letrozole plus
predictive biomarkers using blood or tumour biopsies from
cyclophosphamide arm (P < 0.005). pAKT expression
patients. Our expertise in this area is now nationally and
reduction was associated with a greater response rate (P = 0.05)
internationally recognized with the result that our diagmostic lab
and greater reduction in Ki67 expression (P = 0.05).
has become the Australian centre of choice to offer statewide
Phospho-mTOR expression reduction was associated with
or national testing. Tests currently on offer include KRAS, BRAF,
a significantly longer disease-free survival in a multivariate
EGFR, NRAS, JAK2, NPM and TP53 together with S/FISH
assays for ALK, MET and HER2. In addition, we are also offering
a comprehensive portfolio of testing for familial cancer genes
We conclude that Letrozole inhibits key molecules in the PI3K
including BRCA1 and BRCA2 as well as clonality testing and
pathway. Changes in these molecules may have prognostic
translocation identification for haematological malignancies.
significance. These results should be taken into account when
planning prospective trials testing up-front aromatase inhibitor
Predicting the response of hormonal therapy on breast
with drugs targeting the PI3K/AKT/mTOR signalling pathway. cancer subsets Developing assays for personalised medicine
Endocrine therapies that interfere with estrogen receptor (ER)
function have contributed to a dramatic reduction in breast
The personalisation of medicine will depend on being able to
cancer mortality. To date, aromatase inhibitors have been shown
rapidly perform screening assays for markers that will predict
to be the most effective endocrine treatment in postmenopausal
response to therapy. High resolution melting (HRM) is a rapid
women with ER-positive breast cancer. The results obtained
and efficient method of screening that relies on the precise
with the third-generation aromatase inhibitor letrozole showed an monitoring of the melting of a DNA duplex. We have developed
improvement in patient outcome compared to results based on
sensitive HRM screening assays for multiple changes in cancer,
tamoxifen as an endocrine treatment. This benefit translates into
notably mutations in the KRAS, TP53, BRAF and KIT genes and
disease-free survival (DFS) improvement for adjuvant treatment
epigenetic changes in the MGMT and BRCA1 genes. Some of
and overall survival in patients with metastatic disease. However,
these assays are now being used diagnostically, particularly the
not all ER-positive breast cancers respond to endocrine
KRAS mutation assay that is being used to determine patients’
manipulation and many initially responding tumours develop
resistance to therapy with EGFR inhibitors. However, mutation
resistance. Currently we cannot identify patients likely to respond
detection in clinical tumour samples is challenging when the
to such therapies, which leads to overtreatment, exposure of
proportion of tumour cells, and thus mutant alleles, is low.
patients to potential drug toxicity and inefficient use of limited
Recently, a number of highly sensitive techniques have been
developed but cannot be validated by sequencing due to its
limited sensitivity. In addition, it is important to discriminate false
The growth factor family of epidermal growth factor (EGFR and
positives due to PCR errors or template degradation from true
HER2) are recognized to be implicated in such endocrine
mutations. We therefore have developed an adaptation of HRM,
resistance through activation of mitogen-activated protein
limited copy number HRM (LCN-HRM) which utilises the
kinase/extracellular signal-related kinase and/or the
ability of HRM to detect heteroduplexes when variant sequences
phosphatidylinositol 3’-kinase (PI3K)/AKT/molecular target of
are present. Multiple replicate reactions with a limited number of
rapamycin (mTOR) pathway. In vitro studies have shown that
target sequences per reaction readily allow low frequency
after long-term estrogen deprivation, i.e., during long-term
mutations to be detected by their aberrant melting patterns.
aromatase inhibitor administration, breast tumour cells exhibit
LCN-HRM is an effective and rapid single step method to
an activation of the PI3K/AKT/mTOR pathway as an adaptive
enable levels of sequence variation below the normal sensitivity
phenomenon of breast cancer cells to the low estrogen
of dideoxynucleotide sequencing to be detected in a way that
environment. To address whether measurement of members
then allows identification by sequencing. Molecular Pathology Laboratory: Created by Cancer Research, July 2013. The role of SNPs in the predisposition to somatic methylation Methylation of the CpG island in the MGMT promoter region
is a frequent event in several cancer types, including colorectal
cancer, lung cancer, lymphoma and glioblastoma. A correlation
between methylation and the T allele of the SNP rs16906252 in
colorectal carcinomas has previously been reported. As aberrant
MGMT methylation can be an early event in tumour
development, we tested the hypothesis that normal
individuals possessing the T allele may be predisposed to
somatic methylation at the MGMT promoter. Peripheral blood
monononuclear cell DNA from 89 healthy individuals was
genotyped at rs1690625 and assessed for the methylation
status of the MGMT promoter region using independent
quantitative methodologies capable of detecting low level
methylation. There was a strong association between presence
of the T allele and detectable methylation (p=0.00005) in the
peripheral blood DNA. Furthermore, when a MSP assay flanking
the SNP was used to amplify methylated sequences in
heterozygotes, only the T allele was methylated. Thus,
detectable somatic methylation of the MGMT promoter in
normal individuals is strongly associated with the T allele of the
rs16906252 MGMT promoter SNP. We are currently examining
the involvement of this SNP in cancer predisposition. Hypoxia in prostate cancer Hypoxia profoundly influences tumour behaviour conferring
a poor prognosis and resistance to chemo and radiotherapy.
BNIP3 is a hypoxia-induced protein involved in cell death and
survival but its role in human tumours is unclear. We investigated
the role of BNIP3 in prostate cancer. The expression of BNIP3,
the androgen receptor (AR), hypoxia inducible factor (HIF)-1a,
HIF-2a and another hypoxia regulated gene GLUT1 were
assessed in tissue microarrays constructed from 149 archival
radical prostatectomy specimens. Statistical analyses compared
expression of these factors between each other, conventional
clinicopathological parameters and PSA recurrence. Since an
association between BNIP3 and AR and the HIFs was
observed, the influence of hypoxia, dihydrotestosterone and
the AR blocker, Casodex, was also investigated in prostate cell
lines. BNIP3 was expressed in both the nucleus and cytoplasm.
There was a significant correlation between cytoplasmic BNIP3
expression and Gleason score, age, AR and GLUT1. There was
a significant correlation between nuclear BNIP3 expression and
HIF-1α expression and HIF-2α expression but no correlation
between BNIP3 and pre-operative PSA, tumour volume, margin
positivity or capsular invasion. There was an increase in BNIP3
expression under conditions of hypoxia (0.1% 02) but not with
dihydrotestosterone stimulation or with Casodex treatment. Our
findings suggest that BNIP3 is directly regulated by hypoxia but
that there may be a hormonal independent mechanism
coordinating the expression of BNIP3 in prostate tumours.
For more information contact: Professor Stephen Fox Phone: 03 9656 1529 Email: stephen.fox@petermac.org
Molecular Pathology Laboratory: Created by Cancer Research, July 2013.
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