BRCA 1 mutations were identified in 9/124 (7%) women where there
was a family history of breast cancer without ovarian cancer, 10/57 (18%) where
family members had bilateral breast cancer, 28/60 (47%) with family members with
both breast and ovarian cancer or a single member with both cancers.
This suggests that even when subjects are selected from families with a strong
history of breast cancer only about 7 in 100 will be found to have BRCA 1
mutations. So more than 9 out of 10 tests would be negative, with 10% or fewer
positive, if screening for BRCA1 mutations were instituted. The implication is
that BRCA1 mutations may account for fewer than half of hereditary cases of
breast cancer, not much higher figures suggested previously (see
Bandolier
18
). Routine screening, even where there is a family history, will be wasteful in
that it will require enormous back up, both scientific and medical, including
counselling, to undertake responsibly. Furthermore, women who do not have a
mutation have to be cautioned to prevent a false sense of security, because, in
the striking words of the article, "negative tests are not truly negative". That
is, women with negative results for BRCA1 mutation are still at risk of cancer.
Scientists have already identified more than 200 different mutations in the two
BRCA genes. But we do not know how these different mutations differ in their
relative contributions to breast, ovarian and other cancers. Clearly some
mutations are responsible for the very high risks identified in some families,
but others are likely to be within the normal variations found in many genes
(polymorphisms) and not be relevant to cancer. It is also likely that different
mutations will determine different types of cancers with different pathologies
and different outcomes. There are some very preliminary indications that
mutations towards one end of the BRCA1 gene are more likely to lead to breast
cancer while those towards the other end of the gene are more likely to give
ovarian cancer. It is also suggested that mutations in the BRCA2 gene are less
likely to be found in early onset breast cancer than are BRCA1 mutations.
Moreover the same mutations may behave differently in different populations of
women. This emphasises the importance of modifying factors in determining the
final outcome (eg, reproductive history, hormone therapy, diet, smoking and other
genes which, for example, control the metabolism of hormones). We must not forget
that all cancers are ultimately determined by a combination of genetic and
environmental factors and the interplay of these is one of our most urgent
subjects for research.
The problem of statistical prediction becomes especially worrying when
irreversible decisions are based on it. The question of whether to have
prophylactic mastectomies or oophorectomies for carriers of BRCA mutations is a
particularly difficult one. A theoretical model [3], based on a number of
statistical assumptions, estimated that prophylactic mastectomies would add 2.9
to 5.3 years of life expectancy for a 30 year old carrier of a mutation and an
oophorectomy would add 0.3 to 1.7 years. Estimated gains in life expectancy
decline with age, however. Gains would be minimal for a 60 year old, less than
one year on average, very little more than the estimated gain in life expectancy
of 8 months for a woman without a mutation.
But as correspondence suggests [4], even this reported gain in life expectancy
may overstate the benefit of prophylactic surgery to the patients for several
reasons:
- The effects of surgery on quality of life are ignored.
- Risks associated with surgery are immediate. Benefits (prevention of
cancer) accrue over time.
- The reported gain in life expectancy applies only to women who already know
they have the gene mutations. Screening to find the mutation would carry its
own demerits - not least those of false positive or false negative results in
circumstances where prevalence may not be high.
So this information should encourage a conservative approach to prophylactic
surgery. But patients are individuals rather than units of a statistical study
and each needs to be given individual consideration. Where this involves changes
in genes which predispose to breast cancer this means access to experts who
themselves are in possession of the latest information and are able to
communicate this in a digestible form to worried people who do not understand the
science or statistics.
References:
- B Healy. BRCA genes - Bookmaking, Fortunetelling, and Medical Care. New
England Journal of Medicine 1997 336: 1449-9.
- FJ Couch, ML DeShano, A Blackwood et al. BRCA1 mutations in women attending
clinics that evaluate the risk of breast cancer. New England Journal of
Medicine 1997 336: 1409-15.
- D Schrag, KM Kuntz, JE Garber, JC Weeks. Decision analysis - effects of
prophylactic mastectomy and oophorectomy on life expectancy among women with
BRCA1 or BRCA2 mutations. New England Journal of Medicine 1997 336:
1465-71.
- JD Birkmeyer, HG Welch. Risk of breast cancer in carriers of BRCA gene
mutations. New England Journal of Medicine 1997 337: 787.
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