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The HOT Study: Hormone Replacement Therapy Opposed by Low Dose Tamoxifen. A Phase III Trial of Breast Cancer Prevention With Low Dose Tamoxifen in HRT Users.

Phase 3
18 Years
80 Years
Open (Enrolling)
Breast Cancer

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Trial Information

The HOT Study: Hormone Replacement Therapy Opposed by Low Dose Tamoxifen. A Phase III Trial of Breast Cancer Prevention With Low Dose Tamoxifen in HRT Users.

While life expectancy has grown by approximately 30 years in the last century in western
countries, the age at menopause has increased by 2-3 years only. Thus, women are exposed to
postmenopausal symptoms and disorders related to estrogens drop for a considerable period of
their lifetime. The management of these frequent disorders is an important public health
issue. Although recent data from the WHI randomized trial have demonstrated that late
postmenopausal women (mean age 63.3 years) taking oral conjugated equine estrogens and
medroxyprogesterone acetate in a continuous combined regimen for prevention of coronary
heart disease have an increased risk of developing cardiovascular disease and breast cancer,
there is no question that treatment of menopausal symptoms with HRT (Hormone Replacement
Therapy) in younger women aged around 50 years is a clinically beneficial treatment. This is
even truer for women who enter menopause earlier than 45 years. It is prudent not to extend
the results of the WHI trial, as such, to other forms of HRT preparations, routes, dosages
and regimens or to early postmenopausal women with no apparent risk factors for CVD.
Recently data from a non-randomized study, the Million Women Study, have suggested that oral
combined regimens are associated with an increased and that transdermal estradiol does not
increase more than oral treatment, and in general may be less harmful: for instance,
transdermal estradiol has no effect on vascular inflammatory markers in contrast to the
increase observed with oral CEE (conjugated equine estrogens). Notably, more recent data on
the estrogens-alone group of the WHI trial show a lower breast cancer risk than the
combination, suggesting a important role of progestin in the risk, and a significant
reduction in colon cancer.

The increased risk of developing breast cancer, mostly estrogens receptor positive,
particularly with the combination of estrogens and progestin, has been associated with an
increased expression of estrogens receptors in the healthy breast tissue, thus leading to an
enhanced sensitivity to the estrogens signal. Moreover, reproductive factors such as early
menarche and delayed pregnancy are also associated with a higher risk of estrogens receptor
(ER) positive breast cancer. Thus, the addition of a SERM may reduce the hormone
growth-promoting effect on the breast gland. Tamoxifen has been investigated in four large
cooperative phase III trials for breast cancer prevention in at-risk women. While the
preliminary results of the Italian Tamoxifen Prevention Study in hysterectomized women
showed no difference between arms, a recent update after 7 years of follow-up suggests that
the combination of HRT and tamoxifen has a favorable effect and might even be synergistic.
At a mean observation time of 81 months, a 25% reduction of breast cancer was noted in the
tamoxifen arm compared with placebo (45 versus 34 events, Hazard Ratio, HR= 0.75, 95% CI,
0.48-1.18). While there is no difference in the subset of women who never took HRT before or
during the trial (HR=1.01, 95% CI, 0.60-1.70), women, who at some point before or during the
study, had ever taken HRT (n=1584) had fewer breast cancers in the tamoxifen arm (6 on
tamoxifen versus 17 on placebo, HR=0.35, 95% CI, 0.14-0.89). Among the women continuously on
HRT during the trial (n= 754), breast cancer events were 3 for women on tamoxifen versus 11
for those on placebo, respectively (HR=0.30, 95% CI, 0.08-1.06). Notably, 76.9% of HRT users
received transdermal unopposed ERT and further 6.5% took transdermal ERT combined with
progestins. Importantly, recent result from the IBIS I trial indicate that there is no
evidence that HRT use affects the tamoxifen benefit. Recent studies suggest that the
standard dose of tamoxifen may be reduced to one quarter (5 mg day) without significant loss
of its beneficial effects on circulating biomarkers, mostly reflecting cardiovascular risk.
Moreover, the efficacy of doses as low as one twentieth of the standard 20 mg/day dose on
breast cancer cell proliferation has been recently shown. Since the endometrial effect of
tamoxifen is dependent on treatment duration and dose, a dose reduction might reduce the
risk of endometrial malignancies, while retaining its preventive efficacy. On the other
hand, the addition of HRT containing progestins could further minimize the risk of
endometrial cancer associated with tamoxifen. Moreover, estrogen should reduce the incidence
of vasomotor and uro-genital symptoms, which are a major reason for tamoxifen withdrawal in
prevention studies. In the NSABP trial, women aged 50 or younger demonstrated no
significantly increased incidence of severe adverse events, including endometrial cancer
and, even more importantly, venous thromboembolic events (VTE). One possible explanation for
the lack of severe toxicity in premenopausal women is the concomitant presence of adequate
circulating estrogens levels which prevent tamoxifen from acting as an estrogens agonist on
these target tissues. Notably, in the IBIS I trial, no significant excess of endometrial
cancer and VTE was noted in the women on HRT who were allocated to tamoxifen compared to

The above background provides the rationale for a phase III chemoprevention trial in
postmenopausal healthy women HRT users and Tamoxifen: the HOT Study (Hormone replacement
therapy Opposed by low dose Tamoxifen).

Inclusion Criteria:

- Postmenopausal women candidates to HRT for control of menopausal symptoms or
prevention of postmenopausal disorders. women currently undergoing HRT for any
duration; (women off HRT for 1 year or longer are considered de novo users);

- negative bilateral mammography (within the last 6 months);

- written informed consent.

Exclusion Criteria:

Any type of malignancy, with the exclusion of CIN and non-melanoma skin cancer;

- active proliferative disorders of the endometrium such as atypical hyperplasia,
history of active endometriosis, unresected polyps, symptomatic myomata;

- alterations of metabolic, liver, renal and cardiac grade 2 function (NCI criteria
grade 2 or higher);

- any type of retinal disorders, severe cataract and glaucoma;

- presence of significant risk factors for venous events, including immobilization
within the last 3 months for longer than 2 weeks following surgery or trauma, history
of estrogen-associated and "sine causa" superficial phlebitis, deep venous
thrombophlebitis or other significant VTE (pulmonary embolism, stroke, etc.);

- use of tamoxifen, raloxifene or other SERMs within the last 4 weeks;

- anticoagulant therapy in progress (heparin or dicoumarol);

- active infections;

- severe psychiatric disorders or inability to comply to the protocol procedures; any
other factor that at the investigator's discretion contraindicates the use of either
tamoxifen or HRT.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention

Outcome Measure:

breast cancer incidence

Outcome Description:

The primary objective is to assess if tamoxifen at a low dose reduces the incidence of breast cancer in healthy postmenopausal women undergoing or willing to initiate hormone replacement therapy (HRT), including the women who will eventually withdraw HRT during the 5 year intervention period and additional 5 years of follow up.

Outcome Time Frame:

10 years

Safety Issue:


Principal Investigator

Umberto Veronesi, MD

Investigator Role:

Study Chair

Investigator Affiliation:

European Institute of Oncology


Italy: The Italian Medicines Agency

Study ID:

IEO S51/200



Start Date:

March 2002

Completion Date:

December 2012

Related Keywords:

  • Breast Cancer
  • breast cancer chemoprevention postmenopause
  • Breast Neoplasms