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Early Reproductive Events
and Breast Cancer:
A Minority Report
March 10, 2003
Introduction:
As an invited participant in the recently concluded
NCI workshop "Early Reproductive Events and Breast
Cancer", held Feb. 24-26, I file these public
comments in the form of a minority report, inasmuch
as I am in partial disagreement with the findings
of the workshop submitted to the Board of Scientific
Advisors and the Board of Scientific Counselors, and
subsequently with the unanimous approval of these
Boards, to the NCI Director, Dr. Andrew von Eschenbach.
The need for such a report as this is underscored
by the fact that, although my dissent was made, in
part, on the public record during the final session
on Feb. 26, there was no mention of any dissent in
the Summary Report which constituted the final submission
of the workshop. Such an omission might indeed be
misinterpreted as signifying the unanimous agreement
of all the expert participants. Moreover, the fact
that the workshop was abruptly concluded without prior
notice at the end of what was scheduled to be the
penultimate public session, there was no opportunity
for anyone to make a full and formal statement enumerating
and justifying any points of disagreement. Hence I
take this opportunity to do so now.
II. General Comment: Scope of the workshop and opportunity
for scientific scrutiny and review of the data:
1) Overall Time Constraint: The scope of the research
which was presented and discussed during such a brief
workshop was enormous by any measure, and thus there
was little time for extensive discussion or analysis
of any data. Indeed, the large number of findings
that emerged testifies to the fact that, going in
to the workshop, there was little if any disagreement
on the vast majority of findings. For example, the
breast cancer risk-lowering effect of full-term pregnancy
has been so well established for so long, that in
his opening address on Feb 24th, Dr. Hoover declared:
"We're here to focus on the protective effect
of pregnancy."
As Dr. von Eschenbach himself made clear in his opening
remarks, however, the workshop was in fact prompted
by controversy surrounding the question of an association
between induced abortion and breast cancer incidence.
Thus, while such an association has been frequently
reported, the NCI had concluded-and posted on its
website a year ago-that "it appears that there
is no overall association
". With the workshop's
having so much ground to cover, any sort of "comprehensive
review", of the abortion-breast cancer data,
which is what Dr. von Eschenbach envisioned, according
to his opening remarks, would have been a difficult
task. Nevertheless, I came to the workshop prepared
to participate actively in just such an exercise.
2) Yet more troubling than the difficult time constraints
for accomplishing a thorough vetting of the scientific
data concerning induced abortion and breast cancer
was the fact that the very design of the workshop
rendered such a task impossible, to wit:
a) There were presentations only by scientists advancing
the hypothesis previously advanced by the NCI, i.e.,
that there is no such association. The formal presentation
in the Feb. 25th public session was made by Dr. Leslie
Bernstein, whose area of specialization has been mostly
in other areas, namely, the effects of exercise and
obesity and breast cancer risk, with no opportunity
whatsoever for a balanced presentation by other authors
who have published in this area. For example, I was
the principal author of a comprehensive review and
meta-analysis on abortion and breast cancer (Brind
et al., 1996). The only other presentations on the
issue were by Drs. Polly Newcomb and Mads Melbye,
during the closed session of five-minute "Late-Breaking
Results". It is inconceivable that a genuine
and fair review of any controversial issue could ever
be conducted without providing the opportunity for
scientists with differing views to present and discuss
their findings.
b) Abortion-breast cancer presentations included the
presentation of new data (from Drs. Bernstein, Newcomb
and Melbye), with no time for examination or scrutiny
of such data, and,
c) Such "late-breaking" data was not made
available for examination at all during the workshop.
During the question and answer session following Dr.
Bernstein's lecture, I specifically requested that
the new data be made available for review at the workshop.
However, Dr. Bernstein replied that she would not
release the data until its publication. (This exchange
was made on camera during a public session, the record
of which will presumably be made available on the
NCI website.) All new data should have been made available
to workshop participants well in advance of the meeting,
were there to be an opportunity for any real review.
III. Specific Dissent:
1) Contrary to the workshop finding: "Induced
abortion is not associated with an increase in breast
cancer risk (1)", I remain convinced that the
weight of available evidence suggests a real, independent
positive association between induced abortion and
breast cancer risk. This conclusion is based upon:
a) The fact that of 38 epidemiological studies published
through 2002, 29 have reported relative risks greater
than 1.0, with 17 of these achieving at least borderline
statistical significance (Among studies on US women,
13 of 15 have reported a positive overall association,
8 of them achieving at least borderline statistical
significance.)
b) Cohort studies or case-control studies nested in
prospective databases which do not report a positive
association, are seriously flawed by massive misclassification
(Melbye, et al., 1997; Goldacre et al., 2001) and/or
the use of inappropriate comparison groups (Lindefors
Harris et al., 1989; Melbye et al., 1997). Indeed,
from what I could gather from Dr. Melbye's update
of his Danish data (during the question and answer
session), his stratification of relative risk by age
in 1973 (date of inception of his abortion registry)
was not accomplished by restricting the initial analysis
to different sub-cohorts. For example, he did not
reanalyze the data from scratch using only women born
since 1950 (instead of 1935), thus eliminating most
of the misclassified women from the analysis. Rather,
he applied a statistical adjustment to the initial
analysis of the entire cohort. Consequently, the large
distortion of the relative risk estimate in the direction
of underestimation, which we have pointed out (Brind
and Chinchilli, 1997), still applies. In contrast,
the only study nested in a prospective database (Howe
et al., 1989) utilized a pair-matched case-control
design, free of mismatching or misclassification.
c) While there remain inconsistencies in the causal
hypothesis of "total estrogen exposure"
as the mechanism for most risk factors (as pointed
out by Dr. Hoover in his Feb. 24th address), the role
of estrogen as a stimulator of cellular proliferation,
as well as the known genotoxic effects of certain
estrogen metabolites, still provide a biologically
plausible basis for most risk factors, including induced
abortion. Bioavailable estrogen achieves its highest
levels during the first two trimesters of a normal
human pregnancy, inducing maximal rates of cellular
proliferation.
d) Even if, for the sake of argument, one were to
ignore any effect of induced abortion as an independent
risk factor (i.e., as an exposure that increases risk
beyond the risk level attributable to the non-pregnant
state) it is grossly misleading to suggest that induced
abortion has no effect on future breast cancer risk.
Induced abortion has no meaning except in the case
where a pregnancy is already under way. Since aborting
a pregnancy denies a woman the long-term protective
effect of a full-term pregnancy, it is unarguable
that a woman's long-term risk of breast cancer will
be greater if she chooses abortion over childbirth.
Therefore, information provided to the public by the
NCI, including on its website, should state this unequivocally,
in order to provide meaningful guidance to women considering
abortion.
2) The workshop finding: "Breast cancer risk
is transiently increased after a term pregnancy.(1)"
is misleading, in that it suggests that risk will
be elevated beyond the level attributable to the non-pregnant
state. On the contrary, although there is a transient
increase, in which breast cancer risk reaches a peak
approximately 5 years postpartum, this peak risk level
does not exceed the risk attributable to the non-pregnant
state for women under age 25 at delivery. This was
acknowledged by Dr. Hsieh in the breakout session
in which I participated, in agreement with what his
group has reported in the literature (Lambe et al.,
1994).
3) The workshop finding that the effect of preterm delivery
on breast cancer risk constitutes an "epidemiologic
gap"-not even suggested by level 1,2,3 or 4 evidence
is not warranted, due to the presence of high quality
data in the literature. Indeed, as I pointed out in
my comments during the final session, the workshop paradoxically
based the conclusion that induced abortion does not
increase breast cancer risk largely on the work of Dr.
Melbye. Yet Dr. Melbye's own group has provided excellent
evidence of the risk-increasing effect of early pre-term
births (before 32 weeks) using the same population database
and the same statistical methodology (without the flaws
in the abortion study; see Brind and Chinchilli, 2000),
in agreement with the work of others (Hsieh et al.,
1999). This would indicate that early premature birth
has been supported by research with at least level 2
evidence. The discrepancy in the conclusions by the
workshop vis-à-vis these two variables is glaring.
Moreover, when I raised this concern at the final session,
no one addressed it at all, notably including Dr. Melbye,
who was present at the time.
Respectfully submitted,
Joel Brind, Ph.D., Professor,
Human Biology and Endocrinology,
Baruch College-CUNY, NY, NY, and President, Breast
Cancer
Prevention Institute,
Poughkeepsie, NY
References:
Brind J, Chinchilli VM, Severs WB, Summy-Long J.
Induced abortion as an independent risk factor for
breast cancer: a comprehensive review and meta-analysis.
J Epidemiol Community Health 1996;50:481-496
Brind J, Chinchilli VM. Letter re: Induced abortion
and the risk of breast cancer. N Engl J Med 1997;336:1834-5
Brind J, Chinchilli VM. Letter re: Induced abortion
and risk of breast cancer. Epidemiol 2000;11:234-5
Goldacre MJ, Kurina LM, Seagroatt V, Yeates. Abortion
and breast cancer: a case-control record linkage study.
J Epidemol Community Health 2001;55:336-7
Howe HL, Senie RT, Bzduch H, Herzfeld P. Early abortion
and breast cancer risk among women under age 40. Int
J Epidemiol 1989;18:300-4
Hsieh C-c, Wuu J, Lambe M, Trichopoulos D, Adami
H-O, Ekbom A. Delivery of premature newborns and maternal
breast-cancer risk. Lancet 1999;353:1239
Lambe M, Hsieh C-c, Trichopoulos D, Ekbom A, Pavia
M, Adami H-O. Transient increase in the risk of breast
cancer after giving birth. N Engl J Med 1994:331;5-9
Lindefors Harris B-M, Eklund G, Meirik O, Rutqvist
LE, Wiklund K. Risk of cancer of the breast after
legal abortion during first trimester: a Swedish register
study. BMJ 1989;299:1430-2
Melbye M, Wohlfahrt J, Olsen JH, Frisch M, Westergaard
T, Helweg-Larsen K, Ander-sen PK. Induced abortion
and the risk of breast cancer. N Engl J Med 1997;336:81-5
Melbye M, Wohlfahrt J, Andersen A-MN, Westergaard
T, Andersen PK. Preterm delivery and risk of breast
cancer. Br J Cancer 1999;80:609-13
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