Screening for cancer: are biomarkers of value?

– February/March 2011 6 Tumour markers
Screening for cancer:
are biomarkers of value?
Intuitively, the measurement of biomarkers for cancer screening has
great appeal. This article reviews the current status of the biomarkers
most widely studied in cancer screening, but concludes that their use
to date has been disappointing in reducing mortality from cancer,
especially in asymptomatic populations. Their main utility in screening
is likely to be in high-risk populations, where the prevalence of cancer
is high. An example is the use of human chorionic gonadotropin
for screening for gestational trophoblastic neoplasia in patients
who have had a previous diagnosis of a hydatidiform mole.
by Prof. Michael J Duffy
Screening for cancer has great intuitive appeal,
since it is widely believed that the early detection
of malignancy followed by the initiation
of treatment results in improved outcome.
Consequently, population-based screening
for different types of cancer is now available
in many countries, including mammography
for breast cancer in women over 50 years of
age, the PAP smear for cervical cancer and
either colonoscopy or faecal occult blood
testing (FOBT) for colorectal cancer.
Compared to procedures such as mammography,
colonoscopy and smear testing, the
measurement of biomarkers is considerably
simpler and more convenient [1]. However,
as previously pointed out by Dr Sturgeon [3],
biomarkers generally have low sensitivities
and low specificities for early malignancy.
These disadvantages, when combined with
the low prevalence of cancers in a healthy
population, greatly limit the use of biomarkers
in screening programmes, especially
when used alone. Despite these disadvantages,
several biomarkers have either undergone
or are currently undergoing investigation
for cancer screening [Table 1]. The aim
of this article is to briefly review the current
status of the biomarkers most widely
studied for cancer screening.
PSA in screening for
prostate cancer
Although ad hoc or opportunistic screening
for prostate cancer is now common, the
benefit of this is unclear. Ideally, prior to
being used in general population screening,
a new screening modality should be shown
to reduce disease-specific mortality in a
large prospective randomised trial. In 2009,
preliminary results from two such trials on
prostate cancer screening were published.
One of these trials, the European Randomised
Study of prostate Cancer (ERSPC)
[4], was carried out in seven European
countries, while the second, known as the
Prostate, Lung, Colon and Ovary (PLCO)
trial [5] was performed in the USA. After
7-10 years of follow-up in this study, similar
rates of death from prostate cancer were
found in the screened and control arm. This
trial however, had several flaws including a
high frequency of PSA testing prior to the
start of the trial and substantial contamination
of the control group (i.e., subjects in the
control group had high rates of PSA testing).
Furthermore, there was a low rate of
diagnostic biopsies in subjects with elevated
PSA levels during the trial.
Compared to the PLCO trial, the European
study had a greater number of participating
subjects, longer follow-up and less contamination
of the control arm. Although
Marker or test
it showed that screening resulted in a 20%
reduction in mortality, the authors calculated
that 1410 men would have to be
screened and 48 additional cases of prostate
cancer would have to undergo treatment to
prevent one death from prostate cancer [4].
With these conflicting findings, it is not
surprising that published guidelines on
prostate cancer screening differ in their
recommendations as to whether or not
asymptomatic men should undergo PSA
testing for prostate cancer [6]. Although
expert panels differ in their recommendations
regarding PSA screening, most state
that prior to any testing, men should be
counselled regarding potential risks and
benefits of screening and that a shared
approach to decision making between
doctor and patient should occur.
Faecal Occult Blood Testing
in screening for colorectal cancer
In contrast to the role of PSA in prostate
cancer screening, four large randomised
prospective trials have all shown that
screening apparently healthy subjects over
50 years of age using FOBT reduces mortality
from CRC [7]. Combined results from
the four trials showed that the screening
resulted in a 16% reduction in the relative
risk of CRC mortality [7]. Following adjustment
for those subjects that failed to attend
screening, mortality reduction increased to
25%. Combined results from the four trials
however, failed to show a significant difference
in all-cause mortality between the
screened and control groups. This failure
Malignancy
Effect on reducing
mortality
FOBT Colorectal Yes
PSA Prostate Unclear
CA 125 Ovarian Unclear
AFP Hepatocellular* Yes**
VMA/HVA Neuroblastoma No
Pepsinogen Stomach* Unclear
HCG Trophoblastic*** Yes
Table 1. Biomarkers that have undergone or are currently undergoing evaluation in screening for
cancer. *Only in high-risk areas/high risk subjects. **Shown in a randomised trial to reduce mortality
in high-risk subjects in China (2). ***In patients who have had a previous hydatidiform mole.