Phase III, Randomized, Double Blind Trial Low Dose Tamoxifen Versus Placebo in Hormone Replacement Therapy (HRT) Users (HOT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01579734
Recruitment Status : Active, not recruiting
First Posted : April 18, 2012
Last Update Posted : January 31, 2018
Information provided by (Responsible Party):
European Institute of Oncology

Brief Summary:
The propose of this trial is to assess the effect of low dose tamoxifen for breast cancer prevention in HRT (Hormone Replacement Therapy)users.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Tamoxifen Drug: Placebo Phase 3

  Hide Detailed Description

Detailed Description:

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 placebo.

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).

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1884 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Official Title: 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.
Study Start Date : March 2002
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Placebo Comparator: Placebo
1 tablet day for 5 years
Drug: Placebo
1 tablet day for 5 years

Active Comparator: Tamoxifen
Tamoxifen 5 mg, (1 tablet) day for 5 years
Drug: Tamoxifen
1 tablet, 5 mg / day for 5 years
Other Name: Nolvadex, Istubal, Valodex

Primary Outcome Measures :
  1. breast cancer incidence [ Time Frame: 10 years ]
    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.

Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: 10 years ]

    Incidence of: other non-invasive breast disorders (i.e., LCIS, atypical hyperplasia) All other cancers (with special reference to endometrial cancer, colorectal cancer, ovarian cancer and melanoma).

    Bone fractures Cardiovascular events Venous thromboembolic events Clinically manifest cataract Overall mortality

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01579734

European Institute of Oncology
Milan, Italy, 20141
Sponsors and Collaborators
European Institute of Oncology
Study Chair: Umberto Veronesi, MD European Institute of Oncology

Responsible Party: European Institute of Oncology Identifier: NCT01579734     History of Changes
Other Study ID Numbers: IEO S51/200
First Posted: April 18, 2012    Key Record Dates
Last Update Posted: January 31, 2018
Last Verified: December 2017

Keywords provided by European Institute of Oncology:
breast cancer chemoprevention postmenopause

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Estrogen Antagonists
Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Bone Density Conservation Agents