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Project Title: Clinical Trials of Phytoestrogens for Breast Cancer

Contact:

Barbara Sorkin, Ph.D.
NCCAM, NIH
Phone: 301-496-8004
Fax: 301-480-3621

This project concept do***ent describes proposed research. Project
concepts are presented for review and comment to the National Advisory
Council for Complementary and Alternative Medicine during its open
session meeting. Therefore, this is a public do***ent. It is not a
solicitation for applications. Depending on the Council's
recommendations and other considerations, a solicitation may or may
not result. Any solicitation that does result may be different from
the proposed research described in this do***ent. The NCCAM project
officer is not at liberty to discuss the solicitation until after it
is released.
Background

Phytoestrogen (PE) supplementation is one of the most pressing issues
today for women's health in general, and specifically after a breast
cancer diagnosis. Treatment for chemotherapy-induced amenorrhea among
premenopausal women is controversial, and many women are seeking
over-the-counter PE products consisting of plant-derived nonsteroidal
compounds (isoflavones, lignans) with estrogen-like biologic activity.
The impact of PEs for these women deserves investigation in clinical
studies.1 Research is needed to inform the medical community and guide
women given the increasing incidence of breast cancer and the
subsequent risk of cardiovascular and bone degeneration without
hormone replacement.

Approximately 40 million women in the United States are menopausal or
postmenopausal, and their numbers will increase to 65 million over the
next 10 years.2 Despite the benefits associated with conventional
estrogen replacement therapy (ERT) including preservation of
cardiovascular, skeletal, genitourinary, and possibly cognitive
health3 as well as alleviation of menopausal symptoms, less than 20%
of women in the United States use ERT.4 Healthy women are fearful that
ERT will increase their risk of breast cancer. These concerns are
relevant since one in eight women will be diagnosed with breast cancer
in their lifetime, and a recent study found that ERT with progestin
(for endometrium protection) increased breast cancer risk.5 Women who
have had a breast cancer diagnosis fear that ERT will increase their
risk of a new breast primary tumor or a cancer recurrence.6 The
current number of breast cancer survivors in the United States may be
as high as 2.5 million women, and with earlier detection among younger
women and adjuvant chemotherapy that causes ovarian failure,
increasing numbers of women are postmenopausal after breast cancer
treatment.7

A critical review of the literature suggests that for healthy
postmenopausal women, the benefits of ERT outweigh the risks.8 For
women who develop breast cancer while taking ERT, their clinical
outcome is similar (if not better) than those not taking ERT at the
time of diagnosis.9,10 For women with a prior diagnosis of breast
cancer, the literature suggests ERT has no major detrimental effects,
although these studies are limited by small sample sizes.8 However,
millions of breast cancer survivors worldwide are currently advised
against ERT,7 and a recent consensus conference confirmed that only a
fraction of breast cancer survivors would accept ERT, even if studies
suggested relative safety.7

The debate whether or not to withhold ERT has been fueled recently by
data summarized from 10 randomized trials of approximately 1,800 women
under 50 years of age. The study showed that ovarian ablation reduced
the annual rates of recurrence and death by about 25%, a rate similar
to that from adjuvant chemotherapy.11 A second review of 13 randomized
trials with 16 groups of patients reported that drug-induced
amenorrhea (DIA) was associated with significant disease-free survival
in eight groups. In each of the five studies that assessed survival,
DIA was associated with longer survival.12

The risk of menopause with polyagent adjuvant chemotherapy is
estimated at 53% to 89%,12 and 78% of women receiving chemotherapy and
72% endocrine therapy (i.e., tamoxifen) experienced disruptive hot
flashes.13 The treatment of hot flashes is extremely limited
currently. Consequently, women are keenly interested in alternative,
natural approaches. A study of 113 breast cancer patients (85% who
were post menopausal and of those, only 24% were menopausal at
diagnosis), hot flashes were reported by 65%, and half of this group
rated their symptoms as severe. Of the 74 women reporting hot flashes,
50% were using vitamins and 6% had tried herbs; 33-37% would like to
learn more about herbs and vitamins.13 There is a growing interest in
PE approaches as evident in the rapid accrual of 182 breast cancer
patients within 2 months to a trial evaluating soy PE.1 Soybeans have
a high content of isflavones that bind estrogen receptors with an
affinity 100 times lower than estradiol. Endogenous levels, however,
may be 100 to 1000 times greater than endogenous estrogens.14 PE from
soy may be classified as a selective estrogen receptor modulator
(SERM), and their clinical impact on conventional therapy (i.e.,
tamoxifen) could be favorable, unfavorable, or neutral.1 A recent
study found that 150 mg of soy isoflavones taken orally did not
alleviate hot flashes in breast cancer survivors, 68% of whom were
receiving concurrent adjuvant endocrine therapy.15 Clinical studies
have found increased cell proliferation in breast tissue16 and nipple
aspirates17 for women consuming PE. Animal studies have found that PE
can either augment or antagonize estrogen-induced mammary epithelial
cell proliferation, depending on the dose of both agents18 whereas in
vitro studies have found a biphasic effect for PE in estrogen
receptive breast cell lines with proliferation at lower doses and
growth inhibition at higher doses.19
Purpose of Proposed Initiative

This initiative will support Phase II trials to assess the impact of
PE supplementation on the health of women after a breast cancer
diagnosis. Particular emphasis will be placed on dosing trials,
whether used as a single agent/modality or in combination. Preference
will be given to clinical trials that include laboratory studies to
validate mechanistic hypotheses or clinical correlates that can
meaningfully guide further clinical development. It is expected that
some of this work will lead to definitive Phase III trials to
determine the efficacy of PE supplementation.
Objectives

The primary objective of this initiative is to evaluate the role of PE
supplementation alone versus the following: diets rich in PE, standard
ERT, ERT with PE, and/or multifaceted CAM interventions with PE
acupuncture, TCM, etc.

Secondary objectives could include 2) assess the impact of PE on
estrogen-responsive tissues and clarify their role as estrogen
agonists and antagonists and 3) determine bioavailability (i.e.,
pharmacodynamics and pharmacokinetics), intermediate outcomes, and
toxicity of PE supplements.
Significance

The limited experimental data are contradictory and unclear whether PE
inhibits or enhances breast cancer proliferation and at what dose.
Similarly, epidemiologic data are mixed on the protective effects of
soy for breast cancer and unable to differentiate the effects of PE
supplementation from diets rich in PE. A recent workshop on
phytoestrogens concluded that a significant knowledge gap exists on
the role of phytoestrogens distinct from soy foods and that the
potential adverse effects for breast cancer and endometrial cancer
require monitoring. Studies funded through this initiative will
address the contradictory evidence and allow clinicians and patients
to make informed decisions.
Proposed Funding Mechanisms

R01s
Proposed Funding

In Year 1 $2,300,000. Total project costs for 4 years: $9,200,000