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These
notes are from:
| School of Clinical Medicine |
Dr H Earl
Cancer is a major health problem
worldwide and the morbidity and mortality from cancer give rise to
much suffering. The risk of developing cancer in an individual's
lifetime is about 33%, and the risk of dying of cancer is 25%.
Cancer is not only a disease of the elderly although for many
cancers the incidence increases with age. Breast cancer in the US
and Western Europe is the commonest female cancer, and accounts for
the most cancer deaths in women. Eighteen percent of women who
develop breast cancer will be under 50 years of age and with an
average 50% mortality this will produce a significant number of
deaths in a population of wives and mothers who are making major
contributions to the nurture of future generations and the economy.
Loss of life in this age group has very serious consequences both
for society in general and for the individual families involved.
There are now major health programmes throughout the world involved
in research and development into prevention, early detection, and
new treatments with the aim of reducing the morbidity and mortality
from breast cancer. It is of some considerable interest that the
East in general has amongst the lowest rates of breast cancer in the
world. This is assumed to be a combination of environmental and
genetic factors and their interaction
The causes of breast cancer are
fundamentally unknown although we do know that there are some
important predisposing factors. Most of these are in some way
related to hormonal factors, particularly the effects of oestrogens
on the breast. An early menarche and a late menopause are both
predisposing factors for the subsequent development of breast
cancer. This would suggest that the longer the breast epithelium is
exposed to the effects of oestrogens in a woman's lifetime the more
likely is breast cancer to develop. Pregnancy seems to be a relative
protective factor. The age of a woman at her first full term
pregnancy is also an important factor, with women who are young
(under 20 years) being relatively protected from the subsequent
development of breast cancer. We know from epidemiological studies
that the risk of developing breast cancer slowly increases as the
age of first full term pregnancy gets later and later, but after the
age of 35 years from the point of view of breast cancer risk it is
better to remain nulliparous. What effect first full term pregnancy
has on the breast is essentially unknown, although in animal models
it is clear that the breast epithelium undergoes "terminal
differentiation" and it is likely that the cells retain some
heritable characteristics which have some protective effect against
the carcinogens and promoters of breast cancer. Positive family
history is an important risk factor for breast cancer. The breast
cancer families with dominantly inherited BRCA1 and 2 genes are
clearly important, but account for only about 5% of the total breast
cancer problem. Much has been done in the field of genetic breast
cancers to detect faulty BRCA1 and 2 genes, and advise affected
families on the best management in prevention, prophylaxis and
treatment. Many more women however will have some increase in risk
because of family history, which does not follow the pattern of
dominantly inherited genes. It is likely that these women have a
multifactorial genetic predisposition involving a number of genes,
together with hormonal and environmental interactions. There is much
research going forward in this area at present, and the first
genetic epidemiology unit in the UK has been established in
Cambridge to look at these particular aspects.
Long term use of oral contraceptives
(OC) and hormone replacement therapy (HRT) have also been found to
increase the risk of breast cancer, although these effects are small
compared with the definite advantages of both treatments in societal
and personal terms for women. Obesity seems to play some role as a
risk factor and this probably is related to the peripheral
aromatisation of androgens to oestrogens in the postmenopausal
woman. Environmental and dietary risk factors are being studied
extensively worldwide at present. Factors, which are emerging,
include the insecticide lindane, and the possible protective effects
of diets rich in soya products, fresh fruit and vegetables, and
fish. The significantly lower incidence of breast cancer in the East
has been linked by many investigators to diet, and in particular the
high soya and phyto-oestrogen content of Eastern diets. That the
majority of this effect is environmental rather than genetic is
supported by the western levels of breast cancer risk acquired by
Eastern peoples moving to the US and Western Europe.
In the UK 30,000 new cases of breast
cancer are diagnosed each year making this the commonest malignancy
in women and causing nearly 15,000 deaths per year. Randomised
studies of prevention strategies particularly with the anti-oestrogens
Tamoxifen and more recently raloxifene, and retinoids have either
been completed or are on-going. The final analysis is awaited but it
is likely that effective preventive measures will be available in
the not too distant future.
A national population-based
breast-screening programme was commenced 6 years ago on the evidence
from randomised trials, which demonstrate a reduction in breast
cancer mortality from screening. This remains an area of
considerable medical debate, which centres on the question of
cost-effectiveness. In the not too distant future it should be
possible to better define women who are at increased risk of breast
cancer, to discover the reasons for their increase in risk, and then
to target both specific preventive and early detection strategies at
this "at risk" population.
The diagnosis of breast cancer is
made either through the National Breast Screening Programme or by
the presentation of women to their doctors with a lump in the
breast. The diagnosis is made by a combination of mammography,
breast ultra-sound and increasingly core biopsy and histopathologyof
the breast lesion rather than the previously used fine needle
aspiration and cytological analysis. The National Breast Screening
Programme uses mammography. There is increasing interest in Magnetic
Resonance Imaging (MRI) of the breast and there are a number of
on-going studies to establish its place in breast cancer diagnosis.
This technique may play an important role in screening high-risk
women form a young age because of the avoidance of ionising
radiation. In the UK there is a National Study looking at MRI use in
families at high risk.
Histopathology demonstrates that the
majority of breast cancers are invasive ductal carcinomas, graded
using an Internationally recognised system into grade I, II or III;
well- moderately- or poorly differentiated tumours. These account
for approximately 85% of all invasive breast cancers, the remaining
15% being mostly lobular carcinomas, which arise from the alveoli of
the breast. Other unusual cancers include medullary, tubular,
mucinous and small cell carcinomas. The breast-screening programme
has incresingy brought to medical attention a large number of women
with ductal carcinoma in situ, widely believed to be the precursor
to invasive breast cancer. Treatment of this condition follows a
scoring system of risk factors devised by Van Neuys.
Breast cancers will invade locally
and spread systemically and management consists of a combination of
local and systemic treatments, to reduce the risks of local
recurrence and distant metastases. Breast cancer spreads to local
lymph nodes both in the axilla and the internal mammary chain, and
then via the blood stream to produce distant metastases. A
combination of genetic changes within the tumour allows for
increased and chaotic cellular division, a reduction in apoptosis
(regulated cell death), invasion of local tissues and the
angiogenesis to support the tumour's continued growth. The ability
to invade blood and lymphatic vessels allows tumour cells to leave
the primary site and spread widely in the body. Other important
genetic changes allow the tumour cells to leave the vascular and
lymphatic system and for those tumour cells to grow into metastatic
lesions. As we learn more about the basic processes that occur in
the development and spread of breast cancer, more specific therapies
will be developed to counteract each of these steps. At present our
therapeutic tools include surgery to the breast (either conservation
surgery or mastectomy) and axilla, cosmetic breast reconstruction,
radiotherapy to the breast or chest wall, systemic treatments with
hormonal manipulation and chemotherapy.
SURGERY and RADIOTHERAPY
Fisher in the US demonstrated in a
randomised clinical trial 15 years ago that if breast conservation
therapy was surgically possible then the survival following breast
conservation and radiotherapy were the same as following more
radical surgery (mastectomy). This has a major impact on surgical
practice in the US and Europe. Axillary clearance is at present
accepted as standard treatment for the axilla, and this approach has
reduced local recurrence rates and allowed for important prognostic
information about the involvement of axillary node s tobe obtained.
Sentinel node biopsy is an interesting development I this area that
at resent is the subject of several randomised clinical trials.
Radiotherapy is delivered either to the breast following breast
conservation, or chest wall following mastectomy. Recent results
from the Scandanvian breast cancer group have demonstrated that this
approach not only decreases the risk of local recurrence but also
improves rates of cure.
SYSTEMIC HORMONAL THERAPY
Two thirds of all breast cancers
contain nuclear oestrogen-receptors (ER), which on reaction with
oestrogens bind to DNA at specific sites to promote cellular
division. This is one of the most important mechanisms by which
breast cancer cells divide, and one of our most successful ways we
have of interfering with breast cancer progression. Beatson in 1896
removed the uterus and ovaries of several women with metastatic
breast cancer, who responded well, and this was the first
demonstration of the effectiveness of hormonal manipulation in
breast cancer. Tamoxifen is an anti-oestrogen which competitively
inhibits the effect of oestrogen on the ER and since its development
in the early 1960s has been the most effective hormonal treatment
for breast cancer. In pre-menopausal women ovarian ablation, whether
by radiotherapy, oophorectomy, or more recently by GnRH-analogues,
is a highly effective treatment for ER positive breast cancer. In
post-menopausal women tamoxifen, aromatase inhibitors (anastrozole,
letrazole, exemestane), and progestogens are all effective
treatments in the metastatic setting. There is much research and
development into the group of drugs known as the selective estrogen
receptor modulators (SERMs), which will hopefully provide us with
increasingly effective anti-oestrogens with a reduced number of side
effects.
CHEMOTHERAPY
Breast cancer is a relatively
chemo-sensitive disease and chemotherapy in both the adjuvant and
metastatic setting is used very widely. As a result of the Early
Breast Cancer Trialists Collaborative Group (EBCTCG) Overviews the
benefit of both hormonal and chemotherapy in the adjuvant setting
has been exactly defined. The combination of cyclophosphamide,
methotrexate and 5 fluorouracil (CMF) is the most commonly used
combination of chemotherapeutic drugs and has been used over the
past 25 years. The role of CMF in both the adjuvant and metastatic
setting is well established. Over the past 20 years the
anthracyclines have had increasing use in the treatment of breast
cancer most commonly doxorubicin and epirubicin. The work of Dr
Gianni Bonadonna in Milan Italy has been groundbreaking in
establishing protocols of chemotherapy treatment in breast cancer.
Newer chemotherapeutic agents include the taxanes first developed
from the bark of the Pacific yew tree and subsequently from
semi-synthetic compounds. The effect of these in the adjuvant and
metastatic treatment of breast cancer are beginning to be seen. The
monoclonal anti-body herceptin to the membrane growth factor
receptor Her2-neu that is up-regulated in 30% of breast cancers has
also been shown in clinical trials to an effective adjunct to
chemotherapy. The development of signal transduction inhibitors,
novel anti-metabolites, novel chemotherapeutic agents, anti-sense
oligonucleotides, specifically designed inhibitors of the downstream
effects of mutated genes, the development of immunological therapies
and the increasing potential for "gene therapy", will have a major
impact on the prevention and successful treatment of breast cancer
in the next two decades.
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