http://bmj.bmjjournals.com/cgi/content/full/330/7485/205
BMJ  2005;330:205-206 (29 January), doi:10.1136/bmj.330.7485.205

Reduction in mortality from breast cancer
Screening and increased use of adjuvants are responsible—adjuvants more so

The survival of women who will be diagnosed with breast cancer in the
United Kingdom and Europe in 2005 is significantly better than that for
their counterparts diagnosed in the 1970s and '80s, although five year
survival remains lower in Europe than in the United States (79% v 89%).1
What is known about the reasons for these differences, and what could
increase survival still more?

Any improvement in survival is unlikely to be attributable to a change in
the biological behaviour of breast cancer. It must reflect improvement,
therefore, in diagnosing and managing breast cancer, leading to fewer
distant relapses and deaths. This could be a consequence of early
detection through screening or improved systemic treatment with adjuvants
after surgery to eliminate micrometastases and prevent recurrence.
However, screening amounts to secondary prevention rather than primary
prevention. Delay in diagnosing symptomatic breast cancer is associated
with inferior survival,2 but as no absolute correlation exists between the
chronology and biological behaviour of breast cancer, the term early can
be misleading. Even patients with small tumours which are node negative
may have a poor outlook despite apparently favourable prognostic factors
at diagnosis.

The two papers in this issue look at the impact of screening and adjuvant
chemotherapy on survival after breast cancer, with follow up of 10 years
and 30 years respectively.3 4 Both approaches have been studied and
integrated into service at the same time; we cannot evaluate one without
the other.

Olsen and colleagues report a 25% reduction (relative risk 0.7, 95%
confidence interval 0.63 to 0.89) in mortality due to breast cancer in the
population invited for screening in Copenhagen.3 The study covered the 10
years after the introduction of mammographic screening in 1991 and
compared the population during screening with historical, national, and
national historical controls. Significant results were found after six
years of follow up. The improvement in mortality was not related to change
in systemic treatment. Diagnostic and treatment strategies across the
whole of Denmark had been coordinated and standardised by the Danish
Breast Cancer Cooperative Group since 1977 and the study data were
controlled for time trends and regional differences such as the
introduction of screening in other regions of the country.

The size of the benefit attributed to screening in this study is broadly
in keeping with reported trials from other northern European screening
programmes where screening had been in place for 10 years or more.5 While
showing a reduction in mortality in the screened population, the UK
programme acknowledges that most of the benefit could be due to both
earlier presentation of symptomatic breast cancer and the uptake of
systemic treatment with adjuvant.5 Although better breast cancer survival
between 1990 and 1992 in the United States than in Europe can be
attributed to differences in stage,1 screening has no influence on
survival once stage has been taken into account. Furthermore, for both the
screened and non-screened populations, adjuvant systemic therapy (both
cytotoxic and hormonal) is likely to have an important role in improved
survival.

The 30 year follow up of adjuvant chemotherapy with cyclophosphamide,
methotrexate, 5-fluorouracil also reported in this issue confirms that
relatively short term adjuvant after optimal locoregional treatment for
breast cancer is associated with improved survival.4 The overall 21%
reduction in relative risk of death from all causes at 30 years in the
Bonadonna study4 is in keeping with the overview analysis by the Early
Breast Cancer Trialists Collaborative Group.6 The paper's findings are
also consistent with improved population survival in Canada following the
introduction of systemic treatment according to consensus guidelines for
women with node negative breast cancer.7

The mainly postmenopausal population in the Bonadonna study benefited from
systemic treatment in steroid hormone receptor positive and negative
cancers, which is again consistent with the worldwide overview. The
introduction of more effective adjuvant endocrine treatment with aromatase
inhibitors may reduce the additional benefit that cytotoxic chemotherapy
can bring over and above steroid hormone treatment for women with receptor
positive cancer.8-10 This presupposes, however, at least in part, a common
mechanism for action. Most women who take part in screening programmes are
postmenopausal, and for these women, introducing increasingly effective
systemic endocrine therapy for small cancers detected on screening may
improve survival further. Similarly, while the paper by Bonadonna proves
the benefit of chemotherapy for women with operable breast cancer, the
regimen used in that study has been superseded largely by more effective
regimens including anthracyclines and more recently taxanes.6

Where next? Identifying more breast cancers at earlier stages with "good
prognosis" can make decisions about appropriate adjuvant treatment more
complex, bringing a real risk of relative overtreatment of some women.
This could be particularly important in lymph node negative and steroid
hormone receptor positive breast cancer. Better understanding of the gene
expression signatures of breast cancers may lead to new classifications
that may have both prognostic and predictive information.11 A trial is
already investigating this approach in premenopausal women, comparing
selection by microarray signature against conventional criteria.12

Finally, while the work discussed here highlights the improvements in
survival from breast cancer attributable to systemic therapy and diagnosis
of small, node negative tumours, neither approach affects incidence. The
diagnosis of breast cancer, even with a supposedly good prognosis, can be
devastating, and we should not lose sight of primary prevention as a real
goal.

Alison L Jones, consultant

Academic Department of Oncology, Royal Free and University College
Hospitals, London NW3 2QG (alison.jones@royalfree.nhs.uk)

Papers pp 217, 220

Competing interests: AJ conducts clinical trials sponsored by a number of
pharmaceutical companies and is on the advisory board of some companies
including AstraZeneca, Novartis, Bristol Myers Squib, and Sanofi-Aventis.