Response to letter from Professor Lubinski regarding "Common susceptibility genes for cancer: search for the end of the rainbow"
We thank Professor Lubinski for the letter.
(1) We commend Professor Lubinski for collecting and maintaining a
large biobank relatively inexpensively. There is a still a cost for the
genetic tests, which may be high. We disagree with the claim the costs of
clinical trials for late-stage cancer drugs are an order of magnitude
greater than for detection and prevention studies. Early detection and
prevention studies require tens of thousands of subjects followed for many
years, while clinical trials for late-stage cancer drugs are much smaller
and shorter in duration.
(2) We commend Professor Lubinski for obtaining large sample sizes
for the studies of association between common genes and cancer. (Because
it was not clear from the letter, we want to point out that the sample
size for each particular cancer investigated needs to be large.) However
some of the genes listed in Table 1, such as BRCA1, are not the common
susceptibility genes that we had discussed. The high relative risk of 4
for one CHEK2 variant also makes us wonder if this gene runs in families.
Considering the most recent paper cited, Debniak et al, International
Journal of Cancer, 2006 118, 3180-2, the smallest p-value in their Table 1
was .0004 which is about eight times larger than the type I error we had
computed in our paper of 0.0000474 (with a prior probability of an
association of .001 and a false positive reporting probability of .05). In
any event, large confirmatory studies will be necessary to determine if
these preliminary estimates of associations between common genes and
cancer represent true or false positives.
(3) Detection of premalingnant lesions or early cancers does not
necessarily save lives, as some of these may never cause medical problems
in a person’s lifetime if undetected and untreated or simply because early
treatment may not be effective. Furthermore there are harms associated
with early detection programs such as unnecessary biopsies and sometimes
application of toxic therapy when treatment is not necessary. Based on
results from randomized trials, mammography at age 50 is generally
recommended for women regardless of the results of a genetic test.
Without data from a randomized trial, it is not possible to clearly know
if benefits outweigh harms in breast cancer screening among younger women
with a particular genetic variant.
Competing interests: No competing interests