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Nelson HD, Huffman LH, Fu R, et al. Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2005 Sep. (Evidence Syntheses, No. 37.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility

Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility [Internet].

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Appendix O. Evidence Table of Chemoprevention Trials

StudyNPopulation / SettingDemographicsInclusion / Exclusion criteriaAssignment and attritionMonitoringResultsAdverse effects
Tamoxifen (20 mg per day)
International Breast Cancer Intervention Study (IBIS-I) (IBIS, 2002)59 7,152Women with increased risk for breast cancer recruited through family history clinics, relatives of women with breast cancer, breast screening centers, general practitioners, and media in UK, Australia, New ZealandMean age 50.8 years 54.7% between ages 45–54Included if age 35–70 with risk factors (2-fold relative risk for ages 45–70, 4-fold relative risk for ages 40–44, 10-fold relative risk for ages 35–39 based on family history and other criteria).*3,574 placebo, 3,578 tamoxifen 3,528 (98.9%) placebo began treatment (8 excluded due to breast cancer at entry)All had baseline mammograms at time of randomization to exclude pre-existing cancer and a blood sample for cholesterol assays and marker studies. Mammograms were done every 12–18 months and blood samples at 1 year and 5 years. Follow-up was performed every 6 months during the 5 years of active treatment and by annual questionnaire or clinical visit thereafter for up to 5 years. Details of side-effects were collected at every visit. Concomitant medications were recorded.170 cases of breast cancer. All cases: 69 tamoxifen vs 101 placebo, RR=0.68, 0.50–0.92; Invasive: 64 tamoxifen vs 85 placebo, RR=0.75, 0.54–1.04; Non-invasive: 5 tamoxifen vs 16 placebo, RR=0.31; 0.12–0.82; Breast cancer deaths: 2 in each group. Highest risk among women with two or more 1st- or 2nd-degree relatives with breast cancer (62%). Yearly frequency of breast cancer for placebo group was 6.74 per 1,000 (projected 7.5 per 1,000).Endometrial cancer (11 tamoxifen vs 5 placebo; RR=2.2, 0.8–6.06); most in women >50 years old at randomization (10 tamoxifen, 3 placebo); all postmenopausal at diagnosis; no deaths from endometrial cancer.
60% from UK, 37% from Australia or New Zealand 49% postmenopausal and 41% had previously used HRTExcluded if any previous invasive cancer (except non-melanoma skin cancer), previous DVT or pulmonary embolism, current use of anticoagulants, life expectancy <10 years, pregnant or planning pregnancy.959 (26.9%) completed 5 years 3,523 (98.6%) tamoxifen began treatment (5 excluded due to breast cancer at entry)Venous thromboembolic events (43 tamoxifen vs 17 placebo; RR=2.5, 1.5–4.4). Most risk and all deaths from thromboembolic events on tamoxifen occurred after surgery.
837 (23.4%) completed 5 years Total of 7,139 included in analysis; median follow-up 50 monthsAll cause death rate (25 tamoxifen vs 11 placebo, p=0.028). Vasomotor/gynecological problems 21% higher on tamoxifen than placebo, breast complaints 22% lower. Increased hot flushes, vaginal discharge, abnormal vaginal bleeding on tamoxifen. Hysterectomy rate 2.7% on placebo, 4.2% on tamoxifen (p=0.002). Ovarian cysts and amenorrhea more than 2 times as common on tamoxifen in premenopausal women.
National Surgical Adjuvant Breast and Bowel Project P-1 Study (Fisher et al, 1998)60 13,388Women with increased breast cancer risk by age, Gail model risk, or history; recruited from multiple clinical centers in the USOf 13,175 with follow-up: 2.6% 35–39 years old 39.3% 35–49 30.7% 50–59 30% 60 years or older 6% 70 years or older 96.4% whiteIncluded if at increased risk for breast cancer due to 1) 60 years or older, 2) 35–59 years with 5-year predicted risk of at least 1.66% by Gail model, 3) history of lobular carcinoma in situ. Also must have 10 years life expectancy, no clinical evidence of cancer, not pregnant, normal white blood cell and platelet counts, normal hepatic and renal function, available for follow-up, have undergone endometrial sampling, taken no HRT oral contraception or androgens at least 3 months before, and no history of DVT or pulmonary embolism.57,641 considered, 14,453 agreed to be medically evaluated for eligibility, 13,954 met eligibility requirements, 13,388 randomized (6,707 placebo, 6,681 tamoxifen). 13,175 had follow-up and were included in final analysis; median follow-up 55 months; 73.9% exceeded 36 months follow-up, 67% 48 months, and 36.8% 60 months.Blood was obtained at entry for BRCA1/BRCA2 mutation testing (see King et al, 2001189).175 invasive breast cancer cases in placebo vs 89 in tamoxifen groups (RR=0.51, 0.39–0.66). 69 non-invasive cases in placebo vs 35 in tamoxifen (RR=0.50, 0.33–0.77). Decreased risk occurred in women 49 years and younger (44%), 50–59 years (51%), and 60 years or older (55%). Tamoxifen reduced ER positive tumors but not ER negative.Rate of endometrial cancer was increased in tamoxifen group (RR=2.2, 0.8–6.06), predominantly in women 50 years or older, no deaths. Rates of venous thromboembolic events were elevated in tamoxifen group (RR=2.5, 1.5–4.4) occurring more frequently in women age 50 and older.
Tamoxifen (20 mg per day)
Royal Marsden Hospital Trial (Powles et al, 1998)61 2,508Women with a family history of breast cancer; Royal Marsden Hospital, UKMedian age: 47 years <50: 774 tamoxifen, 749 placeboIncluded if healthy aged 30–70 years with increased risk due to family history of breast cancer, no evidence of breast cancer at entry to trial. Postmenopausal HRT allowed. Excluded if any history of cancer, DVT, or pulmonary embolism. Premenopausal women considering pregnancy or taking oral contraception were also excluded.14 withdrew before randomization, 2,494 randomized: 1,250 tamoxifen (12 excluded from analysis), 1,244 placebo (11 excluded from analysis)Follow-up every 6 months included clinical examination and assessment of toxicity and compliance; mammography annually. Compliance assessed by direct questioning and checked against random blood testing. Serum cholesterol measured before treatment and every 6 months thereafter.Breast cancer incidence was the same for tamoxifen and placebo (34 tamoxifen, 36 placebo, NS); of these, 8 were non-invasive (4 each group). No interaction between use of HRT and effect of tamoxifen on breast cancer occurrence (12/523 HRT on tamoxifen, 13/507 HRT on placebo, p=0.6) Those who started HRT while in study had significantly reduced risk. Nulliparous women had 2-fold increase in risk of breast cancer compared with women with children.Occurrence of adverse events was low. For endometrial cancer: 4 cases tamoxifen, 1 placebo, NS. 156 completed 8 years medication; 877 stopped prematurely for non-toxic reasons or side-effects (320 tamoxifen, 176 placebo, p<0.0005). 336 tamoxifen and 305 placebo required HRT during study. 280 (11%) lost to follow-up for over 18 months.
Pre/perimenopausal: 822 tamoxifen, 812 placebo2,471 used in analysis: 1,238 tamoxifen, 1,233 placebo; median follow-up 70 monthsBlood samples collected from 1992 for future genetic testing.
Postmenopausal: 416 tamoxifen, 421 placebo
On HRT at start: 187 tamoxifen, 202 placebo
Italian Tamoxifen Prevention Study (Veronesi et al, 1998)62 5,408Women with hysterectomies from 55 participating centers, of which 51 were in Italy (5,230 patients, 97%), 3 in South America, and 1 in GreeceMedian age: 51Included if healthy aged 35–70 years without breast cancer and had a hysterectomy. Excluded if severe concurrent illness or history of cardiac disease, endometriosis, and suspected or certain previous DVT.4,989 refused, 1,499 ineligible, 527 not contactable, 996 missingFollow-up during treatment included minimum of twice-yearly assessment of side-effects and compliance; mammograms annually.No difference in breast cancer occurrence between placebo (22) and tamoxifen (19); no breast cancer deaths. Statistically significant reduction among women taking tamoxifen and HRT during trial: among 390 women on HRT assigned to placebo, 8 cases of breast cancer vs 1 case in 362 on tamoxifen. No difference in effects of tamoxifen between women <50 years (p=0.72) and women >50 years (p=0.77). No difference in frequency of ER positive breast cancer between tamoxifen (10) and placebo (8).Significantly increased risk of vascular events and hypertriglyceridemia among women on tamoxifen. 56 women experienced vascular events, 18 placebo, 38 tamoxifen (p=0.0053); 42 were superficial phlebitis, and 9 diagnosed with DVT (6 tamoxifen, 3 placebo).
5,287 (98.3%) total hysterectomy; 1,412 (26.3%) ovary conservation; 2,595 (48.3%) bilateral oopherectomy; 998 (18.6%) unilateral oophorectomy; 282 (5.2%) no information available5,408 randomized (2,708 placebo, 2,700 tamoxifen)
3,837 took assigned medication (1,966 placebo, 1871 tamoxifen)
149 completed 5 years treatment; median follow-up 46 months
Raloxifene (60 or 120 mg per day)
Multiple Outcomes of Raloxifene Evaluation (Cummings et al, 1999)64 7,705Postmenopausal women with osteoporosis recruited from 180 clinical centers in 25 countries, including US and Europe.Mean ageIncluded if at least 2 years postmenopausal, 80 years or younger, with osteoporosis, not on HRT.7,705 randomizedAll provided with daily supplements: 500 mg calcium and 400–600 IU of cholecalciferol. Mammograms were optional after 1st year, but required after 2 and 3 years of treatment. Women who refused mammograms were offered breast ultrasound. Annual transvaginal ultrasonography was performed in 17 designated centers for all women with an intact uterus. Subsets of patients received this exam at other centers. Endometrial biopsies were recommended for women with symptoms of vaginal bleeding, endometrial thickness >8 mm on ultrasound, or with increases in endometrial thickness of at least 5 mm.56 cases of breast cancer were reported, 54 confirmed; 12 classified as in situ, 40 classified as invasive, insufficient information to classify 2 cases. 13 cases of invasive breast cancer on raloxifene and 27 on placebo occurred by the end of the trial (RR=0.24, 0.13–0.44). Raloxifene was associated with a decrease in ER positive but not ER negative cancers. Approximately 126 women would need to be treated for a median of 40 months to prevent 1 case of invasive cancer.By 40 months, higher rates of DVT (38 cases, 0.7%) and pulmonary embolus (17 cases, 0.3%) on raloxifene than placebo (5 cases, 0.2%; 3 cases, 0.1% respectively). Risk of venous thromboembolic disease higher on raloxifene than placebo (RR=3.1, 1.5–6.2). Among 5,957 women who had not had a hysterectomy, endometrial cancer occurred in 4 (0.20%) on placebo and 6 (0.25%) on raloxifene.
 66.6 placeboExcluded if had known, suspected, or history of breast cancer, invasive endometrial cancer, abnormal uterine bleeding, history of stroke or venous thromboembolic disease during past 10 years, any type of cancer (other than superficial skin cancer in previous 5 years), secondary causes of osteoporosis, or other bone diseases. 2,576 placebo
 66.4 raloxifene 5,129 raloxifene
95.7% white for both groups  2,557 took 60 mg
Current smoker  2,572 took 120 mg
 16.5% placebo6,932 (90%) continued past first annual visit (6,333 [91%] had mammogram and 177 [3%] had breast sonography)
 16.9% raloxifene6,381 (83%) continued past second annual visit (5,642 [88%] had mammogram and 176 [3%] had breast sonography)
Family history of breast cancerContinued past 36 months
 12.1% placebo 1,924 (75%) placebo
 12.4% raloxifene 3,977 (78%) raloxifene; median follow-up 40 months.
*

Family history criteria for IBIS-1: All criteria permit entry from age 45 years

1.

First-degree relative who developed breast cancer at or before age 50

2.

First-degree relative with bilateral breast cancer (permits entry from age 40; if relative diagnosed before age 40, permits entry at age 35)

3.

Two or more first-degree or second-degree relatives with breast cancer (permits entry from age 40 if both developed breast cancer before age 50, permits entry at age 35 if both relatives are first-degree and both developed breast cancer before age 50)

4.

Benign breast biopsy and first-degree relative with breast cancer

5.

Lobular carcinoma in situ (permits entry from age 35)

6.

Atypical hyperplasia (permits entry from age 40)

7.

Nulliparous and a first-degree relative who developed breast cancer

8.

Risk equivalent (strong family history, not fitting specific categories, but judged to be at higher risk than eligibility category by the study chairman)

Family history criteria for Royal Marsden Hospital Trial

1.

One first-degree relative under 50 years old with breast cancer, or

2.

One first-degree relative with bilateral breast cancer, or

3.

One affected first-degree of any age plus another affected first-degree or second-degree relative

4.

Benign breast biopsy and a first-degree relative with breast cancer

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