Chemoprev_abs

Chemoprevention of Breast Cancer

Prepared by Mark Levine, MD, MSc, FRCP(C) Chair, Steering Committee; Jean-Marie Moutquin, MD, MSc, FRSC(C), Member, Canadian Task Force; Ruth Walton, MSc, Research Associate, Canadian Task Force; John Feightner, MD, MSc, FCFP, Chair, Canadian Task Force

These recommendations were finalized by the Task Force in June 2000

Objective

To assist women and their physicians in making decisions regarding preventing breast cancer with tamoxifen and raloxifene.

Burden of Suffering

Breast cancer is the most frequently diagnosed cancer among Canadian women and accounts for 30% of all new cancer cases each year. In Canada, 19,200 new diagnosed cases of breast cancer and 5,500 deaths from the disease were estimated for the year 2000. Incidence rates for breast cancer have increased slowly and steadily since 1984, rising most rapidly among women aged 50 to 79. The 1995 rate of 28.4 deaths per 100,000 is the lowest reported since 1950 and recent declines in mortality have been attributed to early detection through screening and improved treatment.

The most important risk factor for women is age, with most breast cancers occurring during the postmenopausal years. Evidence from epidemiological and experimental animal studies suggests that estrogen(s) play a significant role in the development of breast cancers. Many of the established risk factors such as early menarche, nulliparity, and late menopause relate to the timing of and the cumulative exposure of breast tissue to reproductive hormones. The inability to alter most risk factors means that individual women have limited options to reduce their risk appreciably.

Options

Interventions aimed at modulating risks through the use of pharmacologic agents were reviewed. The hypothesis that estrogen is an important promoter of human breast cancer raises the possibility that endocrine intervention can prevent or reduce the risk of the disease. Primary chemoprophylaxis for breast cancer has evolved from the research on tamoxifen and other anti-estrogenic drugs that are used as adjuvant breast cancer therapies or as treatments for osteoporosis. Other methods of reducing estrogenic activity that have been proposed, but are not considered in this review, include dietary control, progestin therapy, and ovarian ablation.

Outcomes

The following outcomes were reviewed: reduction of risk of breast cancer, mortality from breast cancer, the kinds and magnitude of adverse effects on other health outcomes.

Evidence

The electronic databases MEDLINE, PreMEDLINE CINAHL, HealthStar, Current Contents, and The Cochrane Library were searched for articles in English from 1966 to August 2000 using the key words “breast neoplasms”, and “chemoprevention” “tamoxifen”, “raloxifene”.

Abstracts of all articles retrieved were read, and the reference lists of key articles were hand-searched. Additional relevant papers were found by reference review. Experts in the field were also consulted to ensure that no significant studies (up to January 2001) were missed.

All evidence was systematically reviewed using the procedures of the CTFPHC and the Steering Committee. The primary authors collaborated in applying standardized evidence-based evaluation methods. Appendix 1 describes the definitions of the levels of evidence and recommendation grades.

Recommendations were graded as:

A Good evidence to support the recommendation that the condition be specifically considered in a PHE.

B Fair evidence to support the recommendation that the condition be specifically considered in a PHE.

C Poor evidence regarding inclusion or exclusion of the condition in a PHE, but recommendations may be made on other grounds.

D Fair evidence to support the recommendation that the condition be specifically excluded from consideration in a PHE.

E Good evidence to support the recommendation that the condition be specifically excluded from consideration in a PHE.

Quality of evidence was rated according to 5 levels:

I Evidence from at least 1 properly randomized controlled trial (RCT).

II-1 Evidence from well-designed controlled trials without randomization.

II-2 Evidence from well-designed cohort or case-control analytic studies, preferably from more than 1 centre or research group.

II-3 Evidence from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments could also be included here.

III Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees.

Values

This guideline is a joint project of the Canadian Task Force on Preventive Health Care (CTFPHC) and the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Members of these groups used an evidence-based method for evaluating the effectiveness of preventive health care interventions. Recommendations were not based on cost-effectiveness of options. Patient preferences were not discussed.

Background papers providing critical appraisal of the evidence and tentative recommendations prepared by the primary authors were pre-circulated to the members of each group. Evidence for this topic was presented and deliberated upon in meetings of both groups from October 1999 to June 2000. Consensus was reached on final recommendations.

Benefits, Harms, and Costs

Three randomised trials of tamoxifen reported inconsistent results. The largest randomised trial (NSABP-P1) reported that tamoxifen reduced by 49% (p<.00001) the incidence of invasive breast cancer in women who were at high risk. Two other trials did not report significant differences in risk reduction. There is statistically significant evidence from these trials that tamoxifen therapy increased the risk of thromboembolic disease, endometrial cancers and cataracts in women. No differences in mortality outcomes have been reported to date. The balance between benefits and harms varies by age, risk level and personal health factors.

The clinical trial of raloxifene therapy (MORE) was designed primarily to study the effects of raloxifene on osteoporosis. Results from a secondary analysis suggest that the risk of breast cancer was reduced in women taking raloxifene by 76% over the median 40 months of treatment. Raloxifene therapy increased the risk of thromboembolic disease significantly.

Recommendations

Recommendation grade [A, B, C, D, E] and level of evidence [I, II-1, II-2, II-3, III] are indicated after each recommendation. Citations in support of individual recommendations are identified in the guideline text.

Women at low or normal risk of breast cancer (Gail risk assessment index of <1.66% at 5 years): There is fair evidence to recommend against the use of tamoxifen to reduce the risk of breast cancer in women at low or normal risk of the disease [D, I].
Women at high risk for breast cancer (Gail risk assessment index of > 1.66% at 5 years): Evidence supports counselling women at high risk on the potential benefits and harms of breast cancer prevention with tamoxifen [B, I]. The cutoff for defining high risk is arbitrary, but the National Surgical Adjuvant Breast and Bowel Project P-1 study included women with a 5-year projected risk of at least 1.66% according to the Gail index, and the average risk of patients entered in the trial was 3.2%. Examples of high-risk clinical situations are: two first-degree relatives with breast cancer, a history of lobular carcinoma in situ, or a history of atypical hyperplasia. The duration of tamoxifen in such situations is 5 years based on the results of trials of tamoxifen in women with early stage breast cancer. If a woman raises concerns or has already been evaluated and is calculated to be at high risk, then individuals experienced and skilled in counselling may discuss the benefits of tamoxifen versus the harms.

Important additional issues

Prevention of breast cancer with raloxifene: Current evidence does not support recommending raloxifene therapy to lower risk of breast cancer outside of a clinical trial setting.

Screening using the Gail risk assessment index: This index was the major eligibility criterion for enrolling women in the one study that demonstrated potential benefit from chemoprevention. However, it has not been evaluated for use as a routine screening or case finding instrument; validation of the technology is required. Overall, current evidence does not support a shift to its routine use in physicians' offices for screening or case finding purposes. However, when a woman or her physician are concerned about her increased risk for breast cancer, the index can be a useful tool in deciding whether to pursue an in-depth discussion of the pros and cons of chemoprevention. Hence, the approach to identifying women at higher risk who warrant counselling and shared decision‑making will vary across practices. (The Gail risk assessment index can be obtained from http://bcra.nci.nih.gov/brc/).

Validation

The authors' original text was revised by both the Canadian Task Force on Preventive Health Care, and the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. The final document reflects a consensus of these contributors. External validation was through the CMAJ review process.

Selected References

Source Document:

Levine M, Moutquin JM, Walton R, Feightner J. Chemoprevention of Breast Cancer. CMAJ 2001; 164(12):1681-90.

A	Good evidence to support the recommendation that the condition be specifically considered in a PHE.
B	Fair evidence to support the recommendation that the condition be specifically considered in a PHE.
C	Poor evidence regarding inclusion or exclusion of the condition in a PHE, but recommendations may be made on other grounds.
D	Fair evidence to support the recommendation that the condition be specifically excluded from consideration in a PHE.
E	Good evidence to support the recommendation that the condition be specifically excluded from consideration in a PHE.

I	Evidence from at least 1 properly randomized controlled trial (RCT).
II-1	Evidence from well-designed controlled trials without randomization.
II-2	Evidence from well-designed cohort or case-control analytic studies, preferably from more than 1 centre or research group.
II-3	Evidence from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments could also be included here.
III	Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees.