Dietary Seaweed and Breast Cancer: A Randomized Trial

Abstract

Brown seaweeds are popular foods in Japan, where the incidence of breast cancer is about 1/6 the rate of that reported for American women. Seaweed is an excellent source of fiber, contains iodine, carotenoids, and both mammalian lignans and isoflavones. Seaweed may help to prevent breast cancer by several different mechanisms involving these and other constituents. In a preliminary study of toxicity and efficacy using 5 g/day of seaweed, we found seaweed was well tolerated and was associated with some biological changes in the variables measured. In this study, we will examine the effects of escalating doses I of seaweed supplementation in a group of healthy postmenopausal women with and without breast cancer. In our cross-over design, women will be randomized to either seaweed or placebo first. We will then give doses of seaweed or placebo (3 g/day for 3 weeks, then 6 g/day for 3 weeks), followed by 1 week of 6 g/day seaweed/placebo plus soy (2 mg isoflavone per kg bodyweight). Our primary outcome variables are changes in circulating estrogen levels, thyroid hormones, and urinary excretion of phytoestrogens. Adherence to our program will be measured by monitoring urinary excretion of iodine.

Full text

AD
GRANT
NUMBER
DAMD17-98-1-8207
TITLE:
Dietary
Seaweed
and
Breast
Cancer:
A
Randomized
Trial
PRINCIPAL
INVESTIGATOR:
Jane
Teas,
Ph.D.
CONTRACTING
ORGANIZATION:
University
of
Massachusetts
Medical
Center
Worcester,
Massachusetts
01655
REPORT
DATE:
May
1999
TYPE
OF
REPORT:
Annual
PREPARED
FOR:
U.S.
Army
Medical
Research
and
Materiel
Command
Fort
Detrick,
Maryland
21702-5012
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are
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of
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author(s)
and
should
not
be
construed
as
an
official
Department
of
the
Army
position,
policy
or
decision
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designated
by
other
documentation.
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QUALITY
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19991027
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98
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99)
4.
TITLE
AND
SUBTITLE
.
.
Dietary
Seaweed
and
Early
Breast
Cancer:
A
Randomized
Trial
6.
AUTHOR(S)
Jane
Teas,
Ph.D.
5.
FUNDING
NUMBERS
DAMD17-98-1-8207
7
PERFORMING
ORGANIZATION
NAME(S)
AND
ADDRESS(ES)
University
of
Massachusetts
Medical
Center
Worcester,
Massachusetts
01655
8.
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ORGANIZATION
REPORT
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9
SPONSORING
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ADDRESS(ES)
U
S
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Matenel
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Fort
Derrick,
Maryland
21702-5012
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/
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12b.
DISTRIBUTION
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13.
ABSTRACT
(Maximum
200
words!
.
Brown
seaweeds
are
popular
foods
in
Japan,
where
the
incidence
of
breast
cancer
is
about
1/6
the
rate
of
thaT^ported
for
American
women.
Seaweed
is
an
excellent
source
of
fiber,
contains
iodine,
carot
noxds,
and
botii
mammalian
lignans
and
isoflavones.
Seaweed
may
help
to
prevent
breast^cance,:
by^everal
different
mechanisms
involving
these
and
other
constituents.
In
a
preliminary
study
*}**%*&
efficacv
using
5
g/day
of
seaweed,
we
found
seaweed
was
well
tolerated
and
was
associated
wrih
some
SSSdSiS
ta
t£
variable
measured.
In
this
study,
we
will
examine
the
effects
of
escalating
doses
rfÄl^lion
in
a
group
of
healthy
postmenopausal
women
^LTT^TZ
Tn
n
,,r
cm^-over
design
women
will
be
randomized
to
either
seaweed
or
placebo
first.
We
will
then
give
to"o£
aweed
or
plcebo?3
g/day
for
3
weeks,
then
6
g/day
for
3
weeks),
followed
by
1
week
of
6
Xy
SSo
plus
soy
(2
mg
isoflavone
per
kg
bodyweight).
^/^^Z^
""
changes
in
circulating
estrogen
levels,
thyroid
hormones,
and
urinary
excretion
of
phytoestrogens.
Adherence
to
our
program
will
be
measured
by
monitoring
urinary
excretion
of
lodme.
14
SUBJECT
TERMS
Breast
Cancer,
Seaweed,
Soy,
Cross-Over
Design,
Randomized
Trial
17.
SECURITY
CLASSIFICATION
I
OF
REPORT
Unclas
sified
NSN
7540-01-280-5500
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SECURITY
CLASSIFICATION
OF
THIS
PAGE
Unclassified
19.
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OF
ABSTRACT
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15.
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OF
PAGES
J.-S:
PRICE
CODE
20.
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OF
ABSTRACT
Unlimited
Standard
Form
298
(Rev.
2-89)
Prescribed
by
ANSI
Std.
Z39-18
298-102
USAPPCV1.00

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using
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for
the
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and
Use
of
Laboratory
Animals,"
prepared
by
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on
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and
use
of
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Animals
of
the
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of
Laboratory
Resources,
national
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(NIH
Publication
No.
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Revised
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protection
of
human
subjects,
the
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to
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research
utilizing
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DNA
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the
investigator(s)
adhered
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promulgated by
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Institutes
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Health.
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of
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utilizing
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the
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Guidelines
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Involving
Recombinant
DNA
Molecules.
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of
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involving
hazardous
organisms,
the
investigator(s)
adhered
to
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Microbiological
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ytn

Table
of
Contents
Front
Cover
.
1
Standard
Form
(SF)
298
.
:
_
Foreword
.
2.
Table
of
Contents.
_
Introduction,
Body
6-9
Key
Research
Accomplishments
10
Reportable
Outcomes
.
li
Conclusions
.
.
12
References
12.
Appendices
:
!_
List
of
Personnel
;
I_

Dietary
Seaweed
and
Early
Breast
Cancer:
a
Randomized
Trial
Introduction
Brown
seaweeds
are
popular
foods
in
Japan,
where
the
incidence
of
breast
cancer
is
about
1/6
the
rate
ofthat
reported
for
American
women.
Seaweed
is
an
excellent
source
of
fiber,
contains
iodine,
carotenoids,
and
both
mammalian
lignans
and
isoflavones.
Seaweed
may
help
to
prevent
breast
cancer
by
several
different
mechanisms
involving
these
and
other
constituents.
In
a
prelimary
study
of
toxicity
and
efficacy
using
5
g/day
of
seaweed,
we
found
seaweed
was
well
tolerated
and
was
associated
with
some
biological
changes
in
the
variables
measured.
In
this
study,
we
will
examine
the
effects
of
escalating
doses
of
seaweed
supplementation
in
a
group
of
healthy
postmenopausal
women
with
and
without
breast
cancer.
In
our
cross-over
design,
women
will
be
randomized
to
either
seaweed
or
placebo
first.
We
will
then
give
doses
of
seaweed
or
placebo
(3
g/day
for
3
weeks,
then
6
g/day
for
3
weeks),
followed
by
1
week
of
6
g/day
seaweed/placebo
plus
soy
(2
mg
isoflavone
per
kg
bodyweight).
Our
primary
outcome
variables
are
changes
in
circulating
estrogen
levels,
thyroid
hormones,
and
urinary
excretion
of
phytoestrogens.
Adherence
to
our
program
will
be
measured
by
monitoring
urinary
excretion
of
iodine.

Body
Task
1.
Develop
Plan
for
Study
Computer
Database,
Months
1-3
a.
Normal
study
values
will
be
entered
for
each
outcome
variable,
so
out-of
range
values
will
immediately
alert
investigators
to
potential
problems.
Since
all
analyses
are
being
performed
at
the
end
of
the
study,
rather
than
concurrent
with
the
study,
and
normal
values
may
not
be
relevant,
we
are
plotting
the
values
longitudinally
for
each
patient
to
see
where
an
individual's
values
might
have
varied.
b.
Tracking
system
will
be
developed
to
monitor
each
volunteer,
and
to
record
data
from
laboratory
analyses,
medical
histories,
interviews
and
diaries.
The
tracking
system
has
been
developed
and
is
being
used.
c.
Train
project
coordinator
in
patient-centered
counseling
to
be
used
in
this
study.
Project
coordinator
was
trained
in
patient-centered
counseling.
d.
Orient
the
staff
to
the
study,
all
of
whom
work
in
the
Division
of
Preventive
and
Behavioral
Medicine.
Staff
was
oriented
to
the
study,
and
understood
the
overall
purpose
and
how
it
was
to
be
run.
Task
2.
Seaweed,
Months
1-3
a.
Identify
exact
location
of
seaweed
to
be
used,
visiting
the
collection
site,
overseeing
drying,
grinding,
and
encapsulation
processes.
Three
seaweed
harvesters
were
identified,
and
each
was
visited
(1
site
in
British
Columbia,
Canada;
1
site
in
the
San
Juan
Islands
(WA);
and
2
sites
in
Maine)
to
evaluate
harvesting
techniques,
reliability
of
location
identification,
age
of
plants
harvested,
transportation
methods,
drying
methods,
and
grinding
facilities.
Two
harvesters
(Larch
Hansen
of
Maine
Seaweed
Company,
located
in
Stuben,
Maine)
and
Ryan
Drum
of
Island
Herbs,
located
on
Waldron
Island,
Washington)
were
chosen,
and
seaweed
ordered.
About
10
encapsulators
were
interviewed.
Of
these,
two
were
chosen
for
possible
use.
Beehive
Botanicals
was
chosen
as
the
encapsulator
of
choice
based
on
a
site
visit
to
their
plant,
located
in
Hayward
Wisconsin.
That
facility
was
found
to
adhere
to
good
practices
of
quality
control
and
hygiene
and
the
method
of
encapsulating
was
highly
reliable.
b.
Overseeing
grinding
and
encapsulation
of
oatmeal
for
the
control
supplement.
Because
of
its
mucopolysaccharide
properties,
oatmeal
was
replaced
by
Maltodextrin,
a
more
biochemically
neutral
placebo.
The
Maltodextrin
was
encapsulated
by
Beehive
Botanicals,
under
the
same
conditions
as
the
seaweed
encapsulation.
Both
the
seaweed
and
the
placebo
capsules
are
made
of
white
gelatin.
The
capsules
were
analyzed
for
iodine
content,
and
found
to
have
none,
and
samples
of
the
final
seaweed
capsules
were

analyzed
for
iodine
content,
and
found
to
be
approximately
100
mcg/g
for
the
Alaria
used
in
the
pilot
study.
c.
Analysis
of
seaweed
for
iodine
and
seaweed
and
oatmeal
for
percentage
of
soluble
and
insoluble
fiber.
We
decided
to
rely
on
existing
fiber
content
analysis
done
by
Maine
Coast
Sea
Vegetables
on
the
Alaria,
and
the
company
analysis
of
Maltodextrin.
In
the
second
part
of
the
study,
using
two
different
seaweeds,
we
will
analyze
each
for
fiber
content.
Task
3.
Pilot
Test,
(proposed
for
Month
4)
actually
completed
by
month
7.
a.
Pilot
test
and
refine
data
collection
instruments.
1.
Twenty-two
commercially
available
seaweeds
were
analyzed
for
iodine
content.
The
iodine
content
varied
from
30
mcg/g
to
over
8,000
mcg/g.
Since
iodine
supplementation
of
more
than
1,000
mcg/d
was
considered
by
Dr.
Lewis
Braverman
of
Harvard
Medical
School
(and
collaborator
on
this
study)
to
be
potentially
toxic,
the
original
choice
of
Laminaria
was
changed
to
two
other
commonly
eaten
brown
seaweeds,
Sargassum
and
Alaria.
The
iodine
content
of
Laminaria
ranged
from
2,000
mcg/g
to
over
8,000
mcg/g.
Our
target
dose
is
5
grams/day.
The
iodine
content
of
Sargassum
is
30
mcg/g,
(we
would
be
providing
150
mcg/d
in
our
study),
and
the
iodine
content
of
Alaria
is
100
mcg/g
(we
would
be
providing
500
mcg/d
in
our
study).
There
is
some
evidence
that
supplementary
iodine
may
be
helpful
in
preventing
fibrocystic
breast
disease,
and
possibly
breast
cancer,
so
we
chose
Alaria
for
our
initial
pilot
study,
and
will
use
Sargassum
and
Alaria
in
the
escalating
dose
study.
2.
We
did
a
priliminary
study
of
2
volunteers
who
took
seaweed
capsules
with
and
without
soy
powder,
to
see
if
seaweed
was
likely
to
influence
urinary
phytoestrogen
excretion.
We
found
that
seaweed
alone
made
only
minor
differences,
but
seaweed
plus
soy
made
a
100-fold
difference
in
the
excretion
of
equol.
Equol
is
thought
to
be
the
phytoestrogen
of
particular
importance
in
breast
cancer,
and
only
about
1/3
to
Vz
of
all
Americans
is
an
equol
producer.
The
synergism
of
seaweed
(a
fiber
source)
and
soy
seemed
to
make
one
of
the
volunteers
become
an
equol
producer.
The
other
woman
was
already
an
equol
producer,
and
the
addition
of
seaweed
made
no
difference
in
her
rate
of
equol
excretion.
3.
Based
on
this
finding,
we
modified
the
pilot
study
to
include
6
weeks
of
seaweed/placebo
followed
by
a
week
of
seaweed/placebo
plus
soy.
We
wrote
a
small
grant
to
Protein
Technologies
and
obtained
high
isoflavone
soy
powder
for
use
in
the
study.
4.
In
order
to
account
for
important
food
sources
of
phytoestrogens,
questions
on
high
phytoestrogen-containing
vegetables
were
added
to
The
Seven
Day
Dietary
Recall
Questionnaire.
5.
Health
diaries
were
designed
for
use
by
the
participants
to
record
vegetables,
alcohol,
and
any
medication
changes
that
occurred.

6.
Fabric
bags
were
designed
and
sewn,
for
carrying
the
6
liters
of
urine
from
home
to
the
lab,
and
for
storing
at
home
during
the
collection
periods.
7.
Labeling
system
of
color-coded
and
numbered
sample
collection
vials
were
devised,
and
vials
were
labeled.
8.
Randomized
ID
numbering
system
was
devised,
so
that
at
each
visit,
the
patients
received
new
ID
numbers.
This
was
done
to
increase
blindedness
of
sample
analysis
by
laboratory
personnel.
Task
4.
Subject
Recruitment
and
Study,
Months
5-10
a.
Recruitment
of
healthy
volunteers
and
selection
of
eligible
subjects
is
estimated
to
take
2
months.
1.
Recruitment
into
the
study
has
been
delayed
for
two
reasons:
1)
the
fact
that
the
work
in
the
early
phases
was
very
labor-
intensive
and
seasonally
dependent;
and
2)
we
wished
to
use
information
from
another
study
to
inform
the
dosing
regiment
of
this
study.
Originally,
we
had
described
a
study
in
which
there
would
be
6
clinic
visits,
but
actually
there
would
be
13
(including
the
crossover
from
seaweed/placebo
to
placebo/seaweed).
The
first
year
of
this
study
would
have
been
to
look
at
the
effects
of
escalating
doses
of
seaweed
on
healthy
women.
In
the
other
grant,
funded
by
the
Susan
G.
Komen
Foundation,
we
planned
to
look
at
the
effect
of
a
single
dose
of
seaweed
on
the
same
variables,
and
to
monitor
for
any
side
effects.
So,
we
decided
to
wait
until
the
results
of
Komen
study
were
known
before
starting
this
study
of
the
effects
of
escalating
doses.
This
would
enable
us
to
utilize
the
budget
of
this
study
most
efficiently
by
tailoring
the
analyses
to
be
only
those
that
showed
the
most
variation
with
seaweed.
2.
Our
initial
recruiting
strategies
were
cumbersome.
In
May,
I
was
interviewed
on
a
Worcester
radio
talk
show
and
by
a
Boston-based
TV
news
station.
Because
we
didn't
recruit
enough
subjects
in
May
to
begin
the
study,
we
used
other
strategies.
We
mailed
a
letter
of
invitation
to
every
current
and
past
breast
cancer
patient
in
the
U
Mass
hospital
system,
made
visits
to
breast
cancer
support
groups,
and
recruited
via
word
of
mouth
referrals
from
people
who
had
been
in
previous
studies.
For
healthy
women,
we
used
lists
of
women
who
had
had
negative
mammograms,
and
mailed
letters
of
invitation.
On
average,
we
recruited
1/100
letters
sent
out.
Finally,
after
several
months
of
effort,
the
local
newspaper
(Worcester
Telegram
and
Gazette)
to
write
a
story
about
the
difficulties
of
recruiting
women
for
breast
cancer
prevention
studies,
and
to
use
our
study
as
an
example.
We
easily
got
enough
healthy
volunteers,
but
finally
had
to
accept
that
16
women
with
early
breast
cancer
was
the
most
we
could
recruit.
Since
we
wanted
to
start
everyone
together,
and
women
lost
interest
after
a
few
weeks
or
months
or
waiting
to
begin,
we
ran
our

preliminary
study
with
36
women,
(20
healthy
women,
and
16
women
who
had
been
treated
for
early
breast
cancer).
3.
In
our
preliminary
study
(Komen
funded),
we
wanted
to
start
everyone
at
the
same
time
point
in
order
to
ensure
that
the
effect
seasonal
variations
would
be
minimized.
This
created
tremendous
problems
for
potential
volunteers.
Most
of
the
volunteers
recruited
in
June
were
no
longer
interested/available
in
October.
Based
on
our
preliminary
data,
season
was
not
an
important
variable.
In
this
study,
volunteers
will
begin
our
study
within
2
weeks
of
initial
contact.
b.
Study
will
last
14
weeks
for
each
of
the
20
subjects.
1
.
There
is
no
change
of
plan
for
this.
The
study
will
last
20
weeks
for
each
subject.
There
will
be
two
doses
of
seaweed,
3
g/d
and
5
g/d,
and
the
subjects
will
come
in
for
clinic
visits
at
baseline,
at
3
weeks
(after
3
weeks
on
3
g/d),
at
6
weeks
(after
3
weeks
of
5
g/d),
at
7
weeks
(after
5
g/d
seaweed
and
2
mg
isoflavone/kg
body
weight),
at
10
weeks
(after
3
weeks
washout
period),
at
13
weeks
(after
3
weeks
on
3
g/d)
at
16
weeks
(after
3
weeks
of
5
g/d),
at
17
weeks
(after
1
week
of
5
g/d
and
2
mg
isoflavone/kg
body
weight)
and
at
20
weeks
(after
3
weeks
washout
period).
2.
The
number
of
subjects
will
depend
on
the
cost
of
the
analyses
to
be
done.
This
will
be
based
on
which
of
the
variables
who
significant
variation
as
a
result
of
seaweed
supplementation
in
the
pilot
study.
Task
5.
Data
Analysis
of
Results
from
Healthy
Volunteers,
Months
11-12
a.
Meetings
with
oncologists
to
present
preliminary
data.
1.
Meetings
will
take
place
as
soon
as
the
data
are
available.
b.
Final
meeting
with
volunteers
to
explain
study
results
and
to
answer
any
questions.
1.
Meeting
is
scheduled
for
September,
by
which
time
all
the
analyses
should
be
completed.
c.
Annual
report
to
USARMC
1.
This
is
the
annual
report
to
USARMC.

Key
Research
Accomplishments
1
.
Expanded
the
scope
of
the
research
to
include
soy
plus
seaweed
synergism.
2.
Widened
range
of
scientific
questions
to
be
asked
from
the
data,
and
increased
the
number
of
collaborators.
3.
Several
additional
analyses
were
added
to
the
pilot
study,
in
order
to
pinpoint
areas
where
seaweed
might
be
biologically
active.
These
include:
melatonin,
arsenic,
insulin-like
growth
factor
1
and
insulin-like
growth
factor
binding
protein
3,
a
range
of
carotenoids
including
fucoxanthin,
a
carotenoid
specific
to
brown
seaweeds,
estrogen
metabolites,
cancer
cell
inhibition
studies,
and
neurotensin.
Additional
funding
for
these
studies
has
been
obtained
from
Our
Danny
Fund
(a
University
of
Massachusetts
Cancer
Center
granting
fund)
and
the
LINK
laboratory
at
the
University
of
Massachusetts.
Individual
researchers
have
contributed
their
time
and
resources
to
pursue
these
interests,
and
we
have
been
able
to
contribute
some
money
by
not
having
a
secretary
and
by
doing
the
laboratory
processing
ourselves.
Results
are
pending.
4.
Visited
four
seaweed
harvesters
to
learn
how
seaweed
is
collected,
and
identified
potential
areas
of
contamination.
5.
Assayed
over
30
kinds
of
seaweed
to
find
the
lowest
iodine-containing
brown
seaweed
which
would
be
safe
for
human
consumption.
6.
Identified
and
visited
an
encapsulator
to
make
sure
seaweed
and
placebo
capsules
would
be
of
the
highest
quality.
7.
Identified
a
recruitment
strategy
that
was
effective.
Devised
patient
incentives
that
kept
drop
out
(due
to
lack
of
interest)
to
1
of
the
36
volunteers.
10

Reportable
Outcomes
None
yet.
The
first
analyses
were
available
June
1,
and
analyses
are
not
yet
complete.
11

Conclusions
1.
At
this
point,
we
know
that
taking
10
capsules
of
a
brown
seaweed,
Alaria
esculenta,
did
affect
thyroid
function
and
does
not
appear
to
affect
melatonin
function.
2.
Preliminary
work
suggests
that
fucoxanthin,
a
carotenoid
specific
to
brown
seaweeds,
appears
to
have
been
absorbed
by
the
women
in
our
study.
3.
Specific
results
of
most
of
the
analyses
are
not
yet
available.
12

References
No
published
papers
yet.
13

Appendices
None.
14

List
of
Personnel
P.I.
Jane
Teas,
Ph.D.
Co-P.I.
James
Hebert,
Sc.D.
Kathryn
Edmiston,
M.D.
Michael
Wertheimer,
M.D.
Project
Directors
Sue
Druker,
M.A.
Cara
Ebbeling,
Ph.D.
Research
Nurse
Bernadette
White
R.N.
Statistician
Yunsheng
Ma,
M.D.,
M.A.
15