The research of the Academic Department of Biochemistry
consists almost entirely of biochemical and molecular studies of
breast cancer, particularly in relation to hormonal and biomarker
aspects. We aim to use molecular/hormonal analyses to understand
better the dependence of breast cancer on oestrogens and to apply
new treatment approaches. These objectives are delivered by close
collaboration with clinical members of the Breast Unit and also
by collaboration with other prominent groups worldwide. Our studies
range from the epidemiological, involving hormonal analyses in many
thousands of apparently healthy women, to detailed trials of small
numbers of patients with advanced breast cancer. These clinical
studies are complemented by tissue culture work in areas of particular
interest. Part of our work also involves close collaboration with
the Breakthrough Toby Robins
Breast Cancer Research Centre.
Relevance
to the NHS Research and Development Programme
The Department aims to use its resources to
address clinically relevant questions. Of particular relevance
to the NHS nationally is our work on predicting those patients
with primary breast cancer (about 35,000 new cases each year in
the UK) who will benefit from tamoxifen treatment. About 80% of
these patients will receive this drug immediately after surgery,
often for more than 5 years, although only a minority will benefit
(see Apoptosis and Immunohistochemistry
Studies). In addition, our work on the development of aromatase
inhibitors over a 15-year period has helped to identify drugs
(anastrozole and letrozole), which are now being tested in international
clinical trials involving over 15,000 women. All these studies
are rated of high or very high relevance to the NHS research and
development programme.
Highlights of 2003
We
reported the outcome of the IMPACT neoadjuvant trial of the aromatase
inhibitor anastrozole versus tamoxifen versus the combination
of both drugs – a multicentre, international trial coordinated
by The Royal Marsden Hospital. Overall, anastrozole and tamoxifen
had similar clinical efficacy and therefore did not predict the
outcome of the ATAC adjuvant trial of the same drugs in nearly
10,000 patients. However, we made the important finding that changes
in the proliferation marker, Ki67, after only 2 weeks predicted
the outcome in the very large ATAC adjuvant trial. This points
the way to the possible use of this marker to markedly speed the
development of new drugs.
We reported
that in tumours that recur on tamoxifen adjuvant therapy, loss
of the oestrogen receptor and/or gain of HER2 occurred in 24%
of patients. This indicates that for accurate evaluation of the
status of these two markers that direct the use of appropriate
therapy, biopsy of secondary tumour deposits should be made whenever
feasible. This is important for both the use of currently available
treatments as well as the development of new, targeted agents.
Professor
Dowsett reported on behalf of the ATAC Trialists that the increased
benefit from anastrozole compared with tamoxifen in early breast
cancer was substantially greater in tumours positive for oestrogen
receptor but negative for progesterone receptor compared with
tumours positive for both receptors. If confirmed this result
would influence the choice of treatment of many thousands of patients.
Future aims
Each of the following
involves collaboration with the Breast Unit:
- To conduct clinical–molecular studies
which will determine whether the residual oestrogen levels in
patients on aromatase inhibitors are biologically and clinically
important;
- To conduct preclinical research to determine whether a combination
of an aromatase inhibitor with anti-growth factor receptor tyrosine
kinase inhibitors has advantages over the two agents individually.
To integrate these studies with parallel clinical studies;
- To conduct comprehensive molecular and biochemical characterisation
of cells from the circulation of metastatic breast cancer patients
and relate the characteristics to the response of the patients
to therapy;
- To determine expression profiles of responders and non-responders
to chemo- and/or endocrine therapy as judged by cDNA microarray;
- To develop a risk algorithm based on endocrine factors to
apply in trials of breast cancer prevention;
- To create comprehensive tissue microarrays from large breast
cancer trials (eg ATAC, HERA) for identification of responsive
and resistant subgroups.
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Molecular
Biology Group
Endocrine
Pharmacology & Epidemiology
Immunohistochemistry & Apoptosis
Studies
HER-2
Reference Testing Centre
In Partnership with The Royal Marsden NHS Trust
Last
Modified 23/06/04
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