Breast cancer prevention: present and future

CANCER TREATMENT REVIEWS 2001; 27: 261±273 doi: 10.1053/ctrv.2001.0235, available online at http://www.idealibrary.com on

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CONTROVERSY

Breast cancer prevention: present and future A. K. Salih and I. S. Fentiman Department of Surgical Oncology, Guy's Hospital, London, UK Increased risk of breast cancer may result from modifiable factors such as endogenous hormone levels, obesity, HRT, and nonlactation, or non-modifiable factors such as genetic susceptibility or increasing age. Those factors that are easiest to modify may have a limited impact on the totality of breast cancer. The Gail model, based on known factors may be useful for estimating lifetime risk in some individuals. Tamoxifen prevention still remains contentious. In the NSABP-P1 study, there was a 49% reduction in risk of breast cancer in women given tamoxifen but in the Italian and Royal Marsden trials, no effect on breast cancer incidence was detected, possibly because of the different case-mix in these studies. Raloxifene, tested in the MORE trial reduced the incidence of breast cancer by 65%. The effect was restricted to ER positive tumours: no reduction in ER negative cancers was seen. Life-style factors such as diet, obesity, exercise, and age of first full term pregnancy and number of pregnancies have a mild to moderate impact on risk and so may have little effect on the incidence of breast cancer. Reduction of alcohol intake could lead to a modest reduction in the risk of breast cancer but possibly adversely affect other diseases. So far, studies of retinoids have not shown a benefit in terms of breast cancer risk reduction. Fat reduction and GnRH analogues reduce mammographic density but have not yet been shown to affect risk. & 2001 Harcourt Publishers Ltd Key words: Breast cancer; prevention; risk factors; genetic susceptibility tamoxifen; raloxifene.

INTRODUCTION Breast cancer remains one of the most common epithelial neoplasms with 170,000 new cases estimated annually in the US. Approximately one in ten women in the developed world will be affected by breast cancer during their lifetime (1) but only 5±10% have a mutation in a cancer susceptibility gene (1,2). Almost half of the genetic cases are due to mutations in BRCA 1 or BRCA 2 (3). The majority of cases are of unknown aetiology making targeted prevention unachievable. Significant breast cancer risk factors include age, early age at menarche, late age of menopause and late age at first pregnancy. These are not practically modifiable. Those factors that can be potentially modified, albeit with difficulty, are endogenous hormone levels, obesity, exercise, HRT, alcohol indulgence, lactation, oral contraception and diet. Unfortunately, those

Correspondence to: I. S. Fentiman, Department of Surgical Oncology, Guy's Hospital, London, SE1 9RT, UK. 0305-7372/01/027261 ‡ 13 $35.00/0

factors that are easiest to modify may have a limited impact on the totality of breast cancer (4). Increased risk of breast cancer has also been found to be associated with several reversible detectable biomarkers, including serum estrogen and testosterone (5), mammographic breast density (6), insulin growth factor-1 (7) and intraepithelial neoplasia (8). Based on known risk factors for the development of breast cancer, Gail et al. developed a model to estimate the 5-year or life-time probability of disease developing in an individual woman (9). This used multivariate logistic regression of risk factors including race, age, age at first pregnancy, age of menarche, nulliparity, first-degree relatives, and prior history of benign breast disease, in particular atypical ductal and lobular hyperplasia. Women with a previous history of ductal carcinoma in situ (DCIS) or invasive breast cancer were not considered in this model and so it cannot be used to measure their risk. The Gail model categorizes women into low, moderate and high-risk groups. In the US the model has been used to identify highrisk women for chemoprevention (10) but has not & 2001 HARCOURT PUBLISHERS LTD

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been popular in the UK. As another approach, Feigelson and Henderson suggested developing a multigenic model of breast cancer susceptibility and then to screen women to determine those who carry a combination of alleles that put them at significantly increased risk (4). This method is still experimental. The current available options for prevention of breast cancer include endocrine chemoprevention, life style modification and prophylactic mastectomy with and without oophorectomy. As yet, none of these approaches has been shown to reduce mortality from the disease.

CHEMOPREVENTION Tamoxifen In 1986 Cuzick, Wang, and Bulbrook outlined the theoretical basis for using tamoxifen in a prevention trial (11). They argued this was a logical extension of breast screening and that because of the evidence of the efficacy of tamoxifen in the established disease, without undue side-effects, the agent could block the effect of more biologically available estrogen in women at risk. This was backed up by observations showing a reduction in contralateral breast cancers in women given adjuvant tamoxifen for breast cancer (12,13).

NSABP-P1 breast cancer trial This trial started in April 1992 and closed in September 1997 recruiting 13,388 women aged 35 years, the largest prevention trial to date (14). Almost 96% of the participants were white and the median follow-up was 54.6 months. They were randomized either to tamoxifen 20 mg (6, 681 women) or to placebo (6,707 women) for five years. The trial was terminated prematurely because of evidence of a statistically significant reduction in risk of breast cancer risk in the tamoxifen group. All participants had an estimated 5-year risk of 1.66 according to a modified Gail model including race, age, age at first live birth, age at menarche, age at menopause, nulliparity, number of benign biopsies and atypical ductal hyperplasia (ADH) (9). Of the entrants, 31% were aged 60 with no other risk factor. The study also included women with a history of lobular carcinoma in situ (LCIS) treated with excision alone. Women with histories of deep vein thrombosis, pulmonary embolism and DCIS were excluded from the study. The result was a 49% reduction in invasive breast cancer (P < 0.0001, risk ratio 0.51, 95% confidence

A . K. SALIH AND I. S. FENTIMAN TABLE 1 Results of the NSABP P-1 prevention trial Feature

Breast cancer rate per 1000 women Placebo

Risk ratio (95% CI)

Tamoxifen

Overall invasive Overall DCIS

2.7 6.8

1.4 3.4

0.50 (0.33±0.77) 0.51 (0.39±0.66)

Age 49 50±59 60

6.7 6.3 7.3

3.8 3.1 3.3

0.56 (0.37±0.85) 0.49 (0.29±0.81) 0.45 (0.27±0.74)

ADH Yes No

10.1 6.4

1.4 3.6

0.14 (0.03±0.47) 0.56 (0.42±0.73)

LCIS Yes No

13.0 6.4

5.7 3.3

0.44 (0.16±1.06) 0.51 (0.39±1.09)

First degree FH 0 1 2 3

6.4 6.0 8.7 13.7

3.0 3.0 4.8 7.0

0.46 0.52 0.55 0.51

(0.24±0.84) (0.36±0.37) (0.30±0.97) (0.15±1.55)

TABLE 2 Annual morbidity rates in the NSABP-P1 trial Morbidity

Rate per 1000 women

Risk ratio (95% CI)

Placebo Tamoxifen Thrombo-embolism Deep vein thrombosis 0.8 Pulmonary embolism 0.2 Stroke 0.9

1.3 0.7 1.4

1.60 (0.91±2.86) 3.01 (1.15±9.27) 1.59 (0.93±2.77)

Endometrial cancer 49 years 50 years

1.1 0.8

1.3 3.0

1.21 (0.41±3.60) 4.01 (1.70±10.9)

Fractures Hip Hip/Spine

0.8 5.3

0.5 4.3

0.55 (0.25±1.15) 0.81 (0.63±1.05)

interval 0.39±0.66). The risk reduction was greater in women who had had a previous diagnosis of atypical hyperplasia or LCIS. There was a reduction in the annual incidence of invasive breast cancer from 6.8 per 1000 women in the placebo group to 3.4 per 1000 in the tamoxifen group. This result is similar to that which was expected from the adjuvant studies with regard to contralateral breast cancer (15). There were 175 cases of invasive breast cancer in the placebo group compared with 89 cases in the tamoxifen group. This reduction in the risk was seen within the first year and continued throughout the period of the study. Tamoxifen was effective in preventing breast cancer in all age subgroups (49, 50±59 and

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60 years) as well as in women with histories of atypical hyperplasia and LCIS. Tamoxifen however had an inhibitory effect on oestrogen receptor positive (ER‡) tumours only and showed no effect on ER-tumours. The incidence of ER‡ invasive breast cancer was reduced from 5 per 1000 in the placebo group to 1.6 per 1000 in the tamoxifen group. Estrogen receptor positive tumour was reduced by 69% (risk ratio 0.31, 95% CI 0.22±0.45). There was a slight increase in ER-negative tumours (OR 1.22, 95% CI 0.74±2.03). The result also showed a reduction of 50% in the incidence of non-invasive breast cancer including DCIS and LCIS (P ˆ 0.002, risk ratio 0.50, 95% confidence interval 0.33±0.77). There was also a significant reduction in the development of small tumours (2 cm) compared with large lesions. The reduction in the incidence of invasive breast cancer was equally marked in women both with and without a family history of breast cancer. In the tamoxifen group there was a 19% reduction in osteoporotic fractures compared with the placebo group. There was no significant difference in the incidence of fatal and non-fatal cardiovascular events despite the fact that tamoxifen by its estrogenic effect on lipids reduces low density lipoproteins (LDL) cholesterol by 10±20%. In postmenopausal women, two adjuvant trials have shown reductions in death from myocardial infarction and admission for cardiac disease (16,17). There was a 2.5-fold increase in risk of endometrial cancer in the tamoxifen group (OR 2.53 (95% CI 1.35±4.97), similar to that found in the tamoxifen adjuvant trial overview of the adjuvant trials (15). This effect was seen in women aged 50 and above, OR 4.01 (95% CI 1.70±10.90). Additionally, there was a significant increase in the incidence of vascular events in the tamoxifen group, mainly in women aged 50 years. There was a three-fold increase in the incidence of pulmonary embolism, a 60% increase in the incidence of deep vein thrombosis and a 59% increase in strokes. Hot flushes were reported by 78% of the tamoxifen group and 65% of the controls (P ˆ 0.001). Vaginal discharge occurred in 55% and 34% respectively (P ˆ 0.001). Menstrual irregularity and vaginal bleeding were slightly higher but not to a statistically significant degree. There was no difference between the two groups with regard to weight gain, and mood change. Because so few deaths occurred in either group (tamoxifen 3, placebo 6), there was no evidence that tamoxifen reduces mortality from breast cancer. A recent analysis of the risks and benefit concluded that tamoxifen is more beneficial for younger women (18). Health related quality of life (HRQL) for 11,064 women followed up for 36 months was evaluated (17). There was no significance difference between two

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groups with regard to the proportion of participants scoring above a clinical significant level on the Center for Epidemiological Studies-Depression scale (CES-D). No significant difference was noted in the Medical Outcome Study SF-36 of physical and mental status. However, this study showed a higher incidence of gynaecological symptoms and sexual dysfunction for the tamoxifen treated women but no change in overall sexual activities. Because of concerns over the side effects of tamoxifen particularly in women over 50, it is not clear which groups of women should receive it as a prevention therapy. It has been recommended that women should receive tamoxifen only when their risk approaches 1% per year for women with an intact uterus and 0.5% for hysterectomized women (18). There is some concern that HRT given simultaneously might increase the thromboembolic effect of the tamoxifen (19). The effectiveness of tamoxifen for prevention of primary breast cancer beyond 5 years is uncertain. The NSABP-14 adjuvant trial found that 5-years of tamoxifen treatment for estrogen receptor-positive breast cancer reduced the risk of new primary cancer in the contralateral breast and this was not further reduced by continuation for an additional 5 years.

European tamoxifen prevention trials Following the Internet announcement of the NSABP P-1 results in April 1998, two smaller Europe studies were published in the Lancet (20,21). Both studies randomized women to tamoxifen 20 mg daily versus placebo and preliminary results showed no reduction in breast cancer incidence. The four published chemoprevention trials are outlined in Table 3.

Italian tamoxifen chemoprevention trial To avoid endometrial stimulation, only hysterectomized women were recruited (20). The aim was to recruit 20,000 women but because of low compliance and participant dropout (>25%), only 5408 women aged 35±70 years with a normal or low risk of developing breast cancer were eventually studied. After a median follow-up of 46 months there was no difference in the incidence of breast cancer (placebo 22, tamoxifen 19). Although the result of this study contradicted the result of the NSABP P-1 study, there was some evidence of a reduction in the incidence of breast cancer (19 versus 11, OR 0.58) in the women who took tamoxifen for more than one year. This finding may not be significant because of the small number of cancers detected in this study. Interestingly, there was only one case of breast cancer in the women who were on tamoxifen and

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A . K. SALIH AND I. S. FENTIMAN TABLE 3

Outline of chemoprevention trials NSABP

ITALIAN

RMH

MORE

Total Median age Aged <50 y Agent versus placebo

13,388 50-59 37 Tamoxifen 20 mg

5,408 51 38 Tamoxifen 20 mg

2,471 47 62 Tamoxifen 20 mg

Median follow-up months HRT use Breast cancer risk

46 12% Normal/low

70 26% Family history

First degree family history

54.6 < 10% High 1.6% within 5 years 76%

7,705 67 Few Raloxifene 60 or 120 mg 40 10% Osteoporosis

12%

96%

12%

Compliance Agent Placebo

76% 80%

80% 75%

74% 86%

78% 75%

Breast cancers Agent Placebo OR

124 224 0.51

19 22 0.91

34 36 0.94

22/2 32 0.35

* Measured by Modified Gail model; OR, Odds ratio.

HRT compared with eight in the placebo and HRT group (0.02). This suggests that tamoxifen is more potent in preventing breast cancer when combined with exogenous estrogens. Tamoxifen increased thromboembolic disease. The majority of vascular events in this study were superficial phlebitis (33 cases in the tamoxifen treated group versus nine in the control group), followed by deep vein thrombosis (six cases versus three in the control group). There was no evidence for increased pulmonary embolism in this trial (one case in each group). The results should be interpreted with caution because of the low power and compliance of the study (20% of the required sample was achieved) and because it included mainly low and normal risk women.

The Royal Marsden tamoxifen pilot study In this study 2471 women with a family history of breast cancer were randomized to tamoxifen (20 mg/day) versus placebo (21). Median follow-up was 70 months and family history of breast cancer was the only risk factor requirement for entry. The women in this study were younger than those in the NSABP P-1 group (62% versus 40% aged <50 years) and the majority had a strong family history of breast cancer. It was estimated that approximately 36% of the participants in this study had at least an 80% chance of harbouring a genetic mutation gene for breast cancer. There were 36 breast cancers in the placebo group compared with 34 cases in the tamoxifen group. The study failed to show any effect for tamoxifen in reducing the risk of breast cancer in this group of women. However the sample size of the study was small and the women in this study

were allowed to continue with HRT and even to start it if that was indicated (26% of the subjects took estrogens during the trial). One possible explanation of why this result conflicts with NSABP-P1 trial is that approximately 70% of genetically transmitted cancers (BRCA1/2) are ER negative and unlikely to be affected by tamoxifen. Against this, oophorectomy early in life has been shown to reduce the risk of breast cancer among BRCA1 carriers significantly (see below). There was evidence of increased endometrial cancer (four cases in the tamoxifen group versus one in the control group) and a higher incidence of deep vein thrombosis and pulmonary embolism (seven cases versus four in the control group). Hot flushes and vaginal discharge were significantly higher in the tamoxifen group (P ˆ 0.001 for both). There was a higher incidence of menstrual irregularity and bleeding (P ˆ 0.002). Nausea was significantly higher (P ˆ 0.02) but no difference was observed in the incidence of weight gain, or mood change.

MORE (Multiple Outcomes of Raloxifene Evaluation) This study was designed primarily to evaluate the effect of the selective estrogen receptor modulator (SERM) raloxifene on osteoporosis (22). Only postmenopausal women under the age of 80 years were recruited for this study. The median age for entry was accordingly much higher than in the tamoxifen trials. No risk factor for breast cancer was needed for entry and indeed there are some data suggesting that

BREAST CANCER PREVENTION

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the hypoestrogenization associated with low bone density may be protective in terms of breast cancer (23,24). In this trial 2576 women were assigned to receive placebo and 5129 to receive raloxifene (2557 took 60 mg/day and 2572 took 120 mg/day). Accordingly, the number of women receiving raloxifene was twice that in the placebo group (5129 versus 2576). Their mean age was 66.5 years. Almost 96% of the women were white, and 12.3% reported a family history of breast cancer. The study showed the greatest reduction in breast cancer risk (relative risk 0.35, 95% CI 0.21±0.58). Twenty-two breast cancers were found in the raloxifene group (5129 women) and 32 cancers in the placebo group (2576 women). The reduction was particularly marked in the case of invasive breast cancer. During the three years of this study 27 cases of invasive breast cancer were detected among 2576 women in the placebo group compared with 13 among the 5129 women treated with raloxifene (relative risk [RR], 0.24; 95% CI, 0.13±0.44; P < 0.001). Raloxifene reduced the risk of newly diagnosed breast cancer by 76% during a median of 40 months of treating postmenopausal women for osteoporosis. Raloxifene, like tamoxifen, reduced estrogen receptor positive breast cancer by 90% but was not effective in reducing the incidence of estrogen negative tumours, supporting the concept that raloxifene acts by interacting with estrogen receptors in the breast to competitively inhibit estrogen-induced DNA transcription (26). In order to prevent one breast cancer, 126 women need to be treated. Side effects of raloxifene are shown in Table 4. There was no increase in risk of endometrial cancer but there was more thromboembolic disease in those taking raloxifene. No significant difference in the rate of thromboembolic disease was found in the 60 and 120 mg groups. The agent was well tolerated: 33 women (0.6%) assigned to the raloxifene group

and 2 (0.1%) assigned to the placebo group discontinued treatment because of hot flushes (P ˆ 0.001). Influenza-like syndromes, endometrial cavity fluid, peripheral oedema, and leg cramps were reported more frequently in the raloxifene group. In the MORE trial raloxifene reduced the risk of vertebral fractures but not of other fractures (28). It appears that raloxifene is more potent than tamoxifen in reducing breast cancer but it is difficult to compare the results of the studies. The women in NSABP-P1 were, on average, younger and at lower risk compared with those in the MORE study. Like tamoxifen, it is not clear how long this estrogen receptor modulator will be able to prevent the development of breast cancer. That is why, it is important to determine the long-term effects of raloxifene and other selective estrogen receptor modulators because metastatic breast cancer can develop resistance to tamoxifen after long-term exposure (29,30). Adjuvant tamoxifen treatment for primary breast cancer reduces the chances of contralateral breast cancer when used for five years, but this effect is not seen when it is used for more than five years. The MORE trial is continuing to assess the effectiveness and safety of the longer-term use of raloxifene. If the result of this study is confirmed by further follow-up, raloxifene might be preferred over tamoxifen for reduction in the risk of breast cancer and fractures in women with an intact uterus (24).

STAR trial This trial, initiated by NSABP, is a secondgeneration breast cancer prevention trial. It is a randomized double-blind trial that evaluates 22,000 postmenopausal women with an increased risk of breast cancer. Women will be randomized to receive

TABLE 4 Rate of side effects among women assigned to 60 or 120 mg of raloxifene hydrochloride or placebo Side effect

Placebo

Raloxifene 60 mg

Raloxifene 120 mg

P value

Influenza syndrome Hot flushes Leg cramps Peripheral oedema Diabetes Thromboembolism Endometrial cancer Vaginal bleeding Endometrial cavity fluid Hypercholesterolemia Hypertension

293 165 96 114 14 8 4 62 43 121 231

346 249 178 134 31 25 4 67 60 55 177

345 299 178 168 28 24 2 56 66 50 194

0.01 <0.001 <0.001 0.01 0.01 0.002 0.67 0.99 0.02 <0.001 0.01

(11.4) (6.4) (3.7) (4.4) (0.5) (0.3) (0.2) (3.1) (5.7) (4.7) (9.0)

(13.5) (9.7) (7.0) (5.2) (1.2) (1.0) (0.2) (3.4) (8.1) (2.2) (6.9)

(13.4) (11.6) (6.9) (6.5) (1.1) (0.90) (<0.1) (2.8) (8.7) (1.9) (7.5)

P value for combined raloxifene hydrochloride treatment groups versus placebo. All data are presented as numbers (percentages).

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tamoxifen 20 mg daily or raloxifene 60 mg daily for five years. It is based on the positive results of tamoxifen in the prevention of breast cancer (NSABP P-1) trial and the possibility that raloxifene is as effective as tamoxifen with fewer side effects (MORE trial).

IBIS (International Breast Cancer Intervention Study) This is an ongoing study of 6037 women randomized to tamoxifen (20 mg) versus placebo (31). The intended duration of the trial is 5 years. Although pathological and endocrine factors like nulliparity and benign breast disease have been considered, the main criteria for entry were based on family history of breast cancer (for detail see 31). The estimated risk of breast cancer for entry was ten-fold for women aged 35±39 years, four-fold for women aged 40±44 years, and two-fold for women aged 45±70 years compared to the normal population. In this study 91% of the women had at least one first-degree relative with breast cancer and 20% had two or more first-degree relatives with breast cancer. Like the RMH study, the women in this study were generally younger than in other chemoprevention studies (NSABP-P1 and MORE). The median age for entry was 50 years. No results are yet available from this study. Several questions remain unanswered.     

Which groups of women bene®t from tamoxifen chemoprevention? What is the optimal duration of the treatment? How long the effect of tamoxifen will last in preventing breast cancer? Can tamoxifen be replaced an agent with fewer side effects? Is tamoxifen is actually preventing the cancer or simply delaying it?

Some of these questions may be answered by the ongoing IBIS trial in which the Steering Committee has agreed that the study will not be terminated prematurely so that the impact of stopping tamoxifen on subsequent breast cancer risk can be determined.

CHANGE OF LIFE STYLE There is some conflicting epidemiological evidence about life style effects on the incidence of the breast cancer. The marked increase in the incidence of breast cancer among Asian-American women within a decade of their immigration to the US, is an obvious evidence of the influence of western life style, in particular diet, on the incidence of breast cancer (32).

There are several factors that have been reported to be associated with breast cancer. These factors for example include diet, obesity, exercise, and age of first full term pregnancy and number of pregnancies. Although these factors are reported to have mild to moderate risk relationships with breast cancer, it is uncertain that modification of these factors will alter the incidence of breast cancer. It is difficult to test the hypothesis that the reduction in dietary fat will result in reduction in the incidence of breast cancer in the view of the conflicting evidence. While there are arguments to support the role of fat in the promotion of breast cancer (33), there are other studies that failed to show that relation (34). Experimental studies suggested that highfat diet acts as promoter for carcinogenesis (35,36). Significant reduction in the level of serum oestradiol has been shown in a meta-analysis of dietary fat intervention studies (37). Although increased serum estrogen level is considered as a breast cancer risk factor, it is uncertain whether a reduction in the level of oestradiol will ultimately reduce breast cancer significantly (38). The results of the ongoing randomized controlled study (the American Women Health Initiative Study), that examines the effects of low-fat diet on the reduction of breast cancer and other chronic diseases among postmenopausal women are awaited (39). Meta-analysis of case control but not cohort studies suggest a possible weak association of fat with breast cancer. That association has been found particularly for saturated fats in older women (40,42). Hunter et al. (1996) presented a pooled analysis of seven cohort studies of fat intake in relation to the risk of breast cancer. The conclusion from this analysis, showed that a reduction in fat consumption in midlife, in western countries, is unlikely to produce significant reduction in the incidence of breast cancer (40). Holmes et al. reported no association between the amount or types of fat with breast cancer risk after a long follow up of 88, 795 women in a cohort study (43). In an overview of 12 case-control studies presented by Howe et al., a significant association between fat and breast cancer was reported among postmenopausal women (P ˆ 0.0002), but the effect among premenopausalwomenwasnotsignificant(41).However, regression analysis from 21 countries, looking at fat consumption per capita and its relation to the incidence of breast cancer suggested that, among postmenopausal women, a 50% reduction in dietary fat results in a 2.5-fold reduction in breast cancer risk. This effect was less consistent in the premenopausal women. Non-fat calorie supply and gross national product per capita added no further explanation of the variation in the incidence of cancer among those countries (44).

BREAST CANCER PREVENTION

This inconsistency of the results might reflect either lack of association between breast cancer and dietary fat or difficulty in measuring actual fat intake or both. With the current data, the role of fat reduction as a mean of achieving reduction in the risk of breast cancer is undefined. Obesity in postmenopausal women increases the risk of breast cancer, but in premenopausal women is associated with reduced risk. Regular exercise and reduction of weight can reduce the risk of breast cancer in postmenopausal women (45,46,47). In these women, the possible mechanism of risk reduction may be mediated through decreases in the serum level of estrogen, insulin and insulin like growth factor 1, IGF-1 (47). Lean premenopausal women have higher serum levels of insulin and IGF (48). Possibly exercise reduces the risk of breast cancer by preventing obesity especially among postmenopausal women (49). There is compelling evidence that alcohol increases the risk of breast cancer (50). For every 10 g/day of alcohol there is a 9% increase in the risk of breast cancer. It has been shown that alcohol raises the level of estrogen in both urine and serum. It is possible that the reduction of alcohol consumption could lead to a modest reduction in the risk of breast cancer (54) but might have an adverse effect in terms of heart disease. Smoking is not among the risk factors for breast cancer. It causes reduction in urinary estrogen in premenopausal women (55), elevation of androgen in postmenopausal women (56), and early menopause (57). All these changes are associated with reduced risk of breast cancer but no reduction in incidence has been found in smokers. The anti-oestrogenic effect of smoking might lead to a reduction in hormonedependent breast cancers but obviously it increases the risk of lung cancer and heart diseases (58). In one study, smokers of more than 40 cigarettes per day had a significantly higher chance of dying from breast cancer compared with non-smokers (59). It seems that consumption of vegetables rich in anti-oxidant carotenoids is associated with decreased incidence of breast cancer among premenopausal women (60). It has been shown that Vitamin D derivative and retinoids enhance apoptosis and reduce the level of insulin growth factor level (61,62). There is increasing evidence that raised insulin growth factor (IGF-1) is associated with increased risk of breast cancer (63). In an Italian randomized trial of 3000 women with small node negative breast cancer they were given the synthetic retinoid (vitamin A analogue) fenretinide, or placebo for 5 years (64). There was a significant reduction in the risk of contralateral breast cancer in premenopausal women but an increased risk in postmenopausal women. Overall there was no

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effect on the prevention of a second cancer. A phase II trial examining the effect of fenretinide in postmenopausal women on HRT is ongoing (65). Retinoid, rexinoid and Vitamin D analogues currently are under investigation as candidates for a prevention trial. Postmenopausal women on hormone replacement therapy (HRT) for five years or more have their risk of breast cancer increased by 35% (66). The risk reverts to normal after 5 years of HRT cessation (66). HRT that consists of estrogen and progesterone may carry a higher risk of breast cancer than HRT containing estrogen alone (67). As a result, it would be sensible to avoid the progesterone in hysterectomized women. There is some evidence of a better survival rate for women diagnosed with breast cancer while taking HRT compared with those of the same age not on HRT (68). There is a small but significant risk of breast cancer among oral contraceptive pill (OCP) users but generally cancers diagnosed in women on OCP are less advanced compared with women not taking OCP (69). The increased risk is reverts to normal after ten years of cessation. Taking into consideration the advantages of both HRT and OCP, these usually outweigh the potential breast cancer risks. Nulliparity or first full-term pregnancies after age 30 are associated with a mildly increased risk of breast cancer but current career demands mean that many women are unable to modify this reproductive risk. Ionizing radiation may be carcinogenic at relatively low dosage in the developing breast. Low-dose scalp irradiation for treatment of ringworm in Israeli children led to an excess of breast cancers (relative risk: 2.9) after a follow-up of more than 30 years (70). Among women who had radiation for acute postpartum mastitis there was a four-fold increase in breast cancers after 25 years of follow-up (71). Other than protecting the developing breast from ionizing radiation and avoidance of excessive radiation from mammography this is not applicable for prevention but may provide clues about the likely time scale from induction to presentation of breast cancer.

PREVENTION THERAPY FOR BRCA1/2 GENE MUTATION CARRIER Highly penetrative germline mutations in cancer predisposition genes are the cause of 5±10% of breast cancers and ovarian cancers (72). Of these genetic susceptibility cases, about half are due to BRCA1/2 mutation (3). Further mutations in other genes await discovery. The cumulative life risk of invasive breast cancer in the women with BRCA1 or BRCA2 mutation is about 70±85% and for ovarian epithelial cancer

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about 25±65% (1,73±75). Non-carriers of the mutated genes, in families with a known mutation, have the same risk as the general population. It has been shown that up to 90% of healthy firstdegree female relatives of patients with breast and ovarian cancers are potentially interested in BRCA1/2 testing, (76,77). In terms of DNA testing for BRCA1/2 mutation among the unaffected members of the families with BRCA mutation, Lerman (76) reported that 66% of the unaffected females and 48% of males were ready to undergo testing, while Meijers-Heijboer et al. (78) reported that 57% of females and 22% of males were eventually ready for testing. This difference might be due to differences in the counselling process, characteristics of the studied groups and mode of enrolment of these families. The important factors that influence the decision for BRCA testing in both male and female are parenthood (having children), whether the subject specially women have chosen surveillance or prophylactic treatment and the age of the subject (78,79). The current options that are available for the women with BRCA1/2 mutation are regular surveillance, chemoprevention, prophylactic mastectomy and oophorectomy. There is little evidence to suggest that changes of life styles have any effect on reducing the risk of breast cancer in this group of women. Brunet et al. reported that smoking reduces the risk of breast cancer in BRCA1/2 mutation carriers (80). Interestingly, the age at first pregnancy seems to have no protective effect on breast cancer in mutation carrier (82). In counselling this group of patients these facts need to be made clear.

relatives with breast cancer had a similar reduction in the incidence of invasive and non-invasive breast cancers compared to those without a family history of breast cancer. No effect was seen however in the RMH study (23), in which 96% of the women had at least one first-degree relative with breast cancer. This suggests that probably tamoxifen is not an ideal chemoprevention agent in this group of patients. In the MORE study, it is unlikely that there were any BRCA1/2 mutation carriers in this group of women so the preventive role of raloxifene in high-risk cases is unknown. Only 30% of breast cancers among BRCA1 carriers are ER positive (83). In the carriers of the BRCA2 mutation there are higher percentages of ER positive tumours (84). For this reason current chemoprevention therapy is likely to be less effective in mutation carriers. It is possible that chemoprevention and oophorectomy have more effect on BRCA2 mutation carriers where a higher percentage of tumours are ER‡. This may partly explain the reduction in breast cancer risk among women with family history of breast cancer, in the NSABP-P1. Interestingly prophylactic oophorectomy has been shown to reduce breast cancer risk among BRCA1 carriers significantly (RR ˆ 0.53, 95% CI 0.33±0.84). The results of the NSABP-P1 and oophorectomy in reducing the risk of breast cancer indicate that more studies are needed to evaluate the effects of antiestrogen therapy in reducing the risk of breast cancer among the carriers of gene mutations.

Surveillance

In carriers of BRCA1/2 mutations who have the entire field of mammary epithelium at risk of neoplasia, bilateral prophylactic mastectomy would appear to be a drastic but effective treatment. Although it is likely that this would be beneficial the efficacy and risk of relapse in residual tissue remain unquantified. There are no randomized trials, nor any comprehensive national registers from which the necessary data can be collected which can be used to advise patients at risk (83). There are two types of prophylactic mastectomy subcutaneous and total both of which can be performed with and without immediate reconstruction. In subcutaneous mastectomy, the overlying skin is spared together with the nipple-areolar complex. With either type of mastectomy, it is not possible to eradicate the chance of developing breast cancer completely because cancer can develop even in a microscopic amount of breast tissue. As it might be expected the amount of retained breast tissue will be higher in cases of subcutaneous mastectomy (84).

Women with a family history of breast cancer are at increased risk of breast cancer at a younger age but their breast tissue is denser and mammographic screening is less sensitive. There is uncertainty regarding the efficacy of screening in women with a family history of breast cancer. Because the risk is present at an early age, it has become common practice to initiate screening at an early age in the absence of clear benefit. Despite early diagnosis of breast cancer among high-risk young women under regular surveillance, it is likely that at least a quarter of those contracting breast cancers will ultimately die of distant metastasis (82).

Chemoprevention In the NSABP-P1 trial (13), women of all age groups, on the tamoxifen arm, with one or more first-degree

Prophylactic mastectomy

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269

TABLE 5 Follow-up of patients treated by bilateral prophylactic mastectomy Author

Number Risk

Pennisi (85) 1500 Ziegler (87) 510 Hartmann (86) 425 214

Follow-up Cancers

Low/moderate 9 years High 9 years Moderate 14 years High 14 years

0.6% 1.18% 4 (0.94%) 3 (1.4%)

The two major series are summarized in Table 5 (85,86). Pennisi reported the results of prophylactic subcutaneous bilateral mastectomies in 1500 women of whom 30% were lost to follow-up and only 20% had a first-degree relative with breast cancer (85). After nine years follow-up, nine breast cancers developed (0.6%). Ziegler and Kroll re-analysed the data for 510 high-risk women in whom 6 (1.18%) developed subsequent breast cancer (87). Hartmann et al. reported 14-year follow-up after prophylactic mastectomies in 639 women with a family history of breast cancer (86). Of these 90% were subcutaneous and >90% had immediate reconstruction. The incidence of breast cancer for the highrisk group (214 women) was 1.4%. The estimated risk reduction in this review was at least 90%. All 7 cancers occurred among women who had subcutaneous mastectomy. The majority of cancers developed in the axilla and upper outer quadrant after both total and subcutaneous prophylactic mastectomies (88,89,90,91). This reflects the fact that excision of the axillary tail of the breast is technically difficult in subcutaneous mastectomy. Additionally, when performing total mastectomy it may be difficult to know exactly where to stop dissecting in the axilla. These series of mastectomies were performed before the diagnosis of genetic mutation become available. Schrag et al. constructed a model to evaluate the impact of bilateral prophylactic mastectomy (BPM) on the carriers of BRCA mutations (92). In this model BPM was found to reduce the risk of breast cancer by 85% resulting in a gain of 2.9±5.3 years of life span if the procedure was performed at the age of 30 years, but no significant gain if performed at the age of 60 years. The combination of BPM and oophorectomy was predicted to gain 3.2±7.6 years. In a separate analysis, Grann et al. predicted that BPM would reduce the risk of breast cancer by up to 90% (93). The gain in life span was 2.8±3.4 years for BPM, and 3.3±6.0 years for the combination of BMD with prophylactic oophorectomy. However there is only preliminary evidence to suggest that BPM is effective in reducing the risk of breast cancer. After 16 years follow-up Hartmann et al. reported no breast cancer among 18 women with BRCA1/2 mutations

who underwent BPM (94). In another retrospective study, Meijers-Heijboer et al. reported no breast cancer in 76 carriers of BRCA1/2 when they were followedup for a median of 27 months following their mastectomies (95). There are large variations in the acceptability of the BPM option among unaffected women with BRCA mutation. Lynch et al. reported in two separate studies an uptake of 11/31 (35%) and 2/12 (17%) (96,97). Meijers-Heijboer reported that among Dutch women 35/68 (51%) opted for BPM (78). The predictive factors for prophylactic mastectomy were parenthood and age of the women. No woman older than 55 years opted for prophylactic mastectomy (78). Although prophylactic mastectomy is a mutilating and irreversible procedure, affecting body image and inhibiting sexual relations, women who have had adequate counselling rarely express regret. Instead they are relieved from the fear of cancer (78,98,99). The group that accepted PBM had reduction of their psychological morbidity (P < 0.001) and anxiety (P ˆ 0.001). There was higher anxiety among those declining the procedure (99). In this study, where the majority of the women had reconstructive surgery following their mastectomies there was no difference in the sexual activity or body image compared with women who declined the procedure (98). It is important that the women being considered for BPM should be managed by a multidisciplinary team including a clinical geneticist, a clinical specialist breast care nurse, a breast surgeon and sometimes a plastic surgeon. They should also be offered a protocol of cancer genetic risk assessment and a clinical psychological assessment. As reconstruction has to be offered to every woman considered for BPM, the breast surgeon needs to have good experience in breast reconstruction, or work closely with a plastic surgeon will be required. Patients should be shown photographs of good, satisfactory and poor cosmetic results. When BRCA mutation carriers develop breast cancer their annual risk of contralateral breast cancer is 5.6% (100) and this has led some to consider prophylactic contralateral mastectomy in this group of patients. This may not affect survival: the first primary clinically detected breast cancer determines the survival of breast cancer patient (101,102). Because of the increased risk of ovarian cancers in women with the BRCA1 mutation women bilateral oophorectomymay also be of benefit (103). There is evidence that oophorectomy early in life leads to reduced breast cancer risk (104). In a case-control study Rebbeck et al. compared 43 BRCA1 mutation carriers who had prophylactic oophorectomies with 79 carriers that had no surgery with an average follow-up of 8 years (53). Bilateral oophorectomy resulted in a 50% reduction in the incidence of breast cancer. This

270

result was not affected by the use of hormone replacement therapy.

FUTURE PREVENTION TRIALS Further chemoprevention trials with aromatase inhibitors, for example, anastrazole, letrazole and others, in combination with bone preserving agents such as oral biphosphonates are in an active stage of planning (105). These agents do not increase the chance of uterine cancer and cause less thromboembolic disease (106). It is possible that the new generation of estrogen receptor modulators (107), for example, LY 353381 (Arzoxifene), are an attractive subjects for future trials, as preliminary data indicate that they lack uterine agonistic effect and probably have fewer adverse effects than the traditional SERMs. Aiming at the reduction of the exposure to the ovarian hormones which has been shown to be a risk factor for breast cancer, Spicer et al. in a pilot study, have shown the feasibility of suppressing the ovarian functions with gonadotrophin releasing hormone agonist (LHRH) regimens combined with low-dose hormone replacement (to avoid the side effect of hypoestrogenization) (108). This approach resulted in a reduction of mammographic density which may be a surrogate measure of breast cancer risk. Targeting nulliparity as a risk factor for breast cancers: short-course hormonal combinations that mimic pregnancy for nulliparous women in their early twenties might reduce the risk of breast cancer (109). Reduction in the level of estrogen or estrogen metabolites can be achieved by soy/isoflavones. In vitro, Genistein (a phyto-estrogen) decreased cell growth and enhanced differentiation of human breast cancer cells (110). However, when Key et al. reported an interventional prospective study, there was no reduction in breast cancer risk in women taking phyto-estrogen (111). There are several potentially reversible risk markers that are associated with breast cancer. These include aberrant methylation and histone deacetylation of the promoter region of many tumour suppressor genes (112±115). The combination of histone deacetylase inhibitors combined and demethylating agents provides a new approach to prevention that might work for both ER‡ve and ERÿve tumours (116,117). Other observed changes are increased expression of cyclo-oxygenase-2 (COX-2), tissue polyamines, angiogenesis and protease activity (118±121). Harris et al. have reported that the women regularly taking non-selective COX inhibitors (non-steroidal anti-inflammatory drugs, NSAIDS), have a 50% reduction in breast cancer risk (P<0.01) (122). These

A . K. SALIH AND I. S. FENTIMAN

inexpensive relatively non-toxic agents are suitable for chemoprevention trials and a COX-2 (celecoxib), Tyrosine kinase inhibitor (ZD 1839) and polyamine synthesis inhibitor (difluoromethylornithine), are in an active planning stage for prevention testing. These agents might be used lor both pre- and postmenopausal women without altering the menstrual cycle or inducing hot flushes. It is possible that pairing tyrosine kinase inhibitors to SERMs like tamoxifen can decrease the chance of tamoxifen resistance in ER‡ precancerous lesion (122). Another group of agents that act by increasing apoptosis is currently under investigation for prevention trials and they include perillyl alcohol (a monoterpene) (123) and sulfone metabolite of sulindac (124). Prevention of breast cancer has come a long way since the idea of using tamoxifen was first proposed (125). Knowledge of what can and cannot be achieved with endocrine intervention is now leading to a new generation of trials examining modulation of other non-endocrine biochemical pathways. ldentification of new risk factors and novel biochemical agents should lead in time to a significant chance of population prevention of breast cancer.

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