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Chemoprevention Options for BRCA1 and BRCA2 Mutation Carriers

From the Institute of Cancer Research, The Royal Marsden National Health Service (NHS) Trust, Sutton, Surrey, United Kingdom.

Address reprint requests to Rosalind A. Eeles, MA, FRCP, FRCR, PhD, Institute of Cancer Research and The Royal Marsden NHS Trust, Downs Rd, Sutton, Surrey SM2 5PT, United Kingdom; email ros{at}icr.ac.uk

ABSTRACT

BRCA1 and BRCA2 breast cancer predisposition gene mutation carriers are at markedly increased risk of breast and other cancers. The consideration of chemopreventative options will depend on the cancer site and age-specific penetrance curve. Most chemoprevention studies to date have investigated the role of endocrine intervention in women at increased risk of breast cancer, and study results are conflicting. At the present time, there is uncertainty regarding whether endocrine intervention, particularly with tamoxifen, is as effective in BRCA1 and BRCA2 mutation carriers as in other women who are at increased risk of breast cancer because of hormonal factors or genes with moderately conferred cancer risks. Furthermore, if chemoprevention were needed for at least 10 years to produce an effect, new chemoprevention agents will need to be developed for women in their 30s, as the breast cancer risk curves are steepest between 40 and 50 years of age. Consideration is now being given to types of chemoprevention in this younger age group. There is also an increased risk of other cancers (in particular ovarian cancer and, in men, prostate cancer), and considerations regarding chemoprevention will have to encompass cancer at these sites.

THE BRCA1 AND BRCA2 GENES AND CANCER RISKS

APPROXIMATELY 5% TO 10% of breast and ovarian cancers occur as a result of highly penetrant germline mutations in cancer-predisposition genes.^1,2 One half of these are due to mutations in BRCA1 or BRCA2.³ BRCA1 on chromosome 17q codes for a protein of 1,863 amino acids⁴ and BRCA2 on 13q is approximately twice the size of BRCA1.⁵ Although deleterious mutations in both genes predispose to earlier onset and an increased risk of female breast cancer, the risk of cancers at other sites and the risk profile differs for the two genes. Collaborative studies by the Breast Cancer Linkage Consortium (BCLC) have combined data from numerous families with germline mutations in BRCA1 and BRCA2 world-wide to determine penetrance estimates and risks of other cancers in BRCA1 and BRCA2 mutation carriers. These have shown that both genes confer an increased risk of female breast cancer of 80% to 85% by the age of 80 years,^6,7 although the penetrance curve for BRCA1 starts to increase slightly earlier than BRCA2 (Figs 1 and 2). Both genes confer an increased risk of ovarian cancer; however, the lifetime risks are higher for BRCA1 (60% by age 80 years) than for BRCA2 (27% by age 80 years; the population risk is just under 1%), and the penetrance curve starts to increase earlier (late 30s) for BRCA1 than for BRCA2 (mid 40s; Figs 1 and 2). ⁷ It is now thought that both genes confer an increased risk of prostate cancer; this is three-fold for BRCA1⁸ and three- to seven-fold for BRCA2,^9,10 equating to an absolute risk of 6% to 14% by age 74 years; the population risk by this age is 2%. BRCA1 may also increase the risk of colon cancer to approximately 6% by age 70 years⁸; however, this needs to be confirmed from more recent data, and it is not seen in the other cancers profile in BRCA2 carriers. A recent analysis of the risk of other cancers in BRCA2 carriers has also reported a significantly increased risk of cancer of the stomach, pancreas, male breast cancer, head and neck cancer, ocular melanoma, cutaneous melanoma, fallopian tube cancer, and cancer of the gall bladder and bile duct.¹⁰ Because many of these latter cancers are rare in the general population, the absolute risk is still low in BRCA2 carriers.

View larger version (8K): [in this window] [in a new window]   Fig 1. BRCA1 breast/ovarian cancer risks.

View larger version (7K): [in this window] [in a new window]   Fig 2. BRCA2 breast/ovarian cancer risks.

Some researchers report a genotype/phenotype correlation of mutation position and breast/ovarian cancer risk,¹³ with mutations at the 5' end of BRCA1 and the central part of BRCA2 conferring a higher ovarian risk. What is unclear is whether this is a higher risk of ovarian cancer or a relatively lower risk of breast cancer, and further studies within the BCLC data set are ongoing. Table 1 lists the risks of cancers in BRCA1 and BRCA2 carriers.

Population studies that have systematically and nonsystematically collected young onset cases of breast cancer have shown that deleterious mutations in BRCA1 and BRCA2 are detected at a lower frequency in single young cases of breast cancer than in familial clusters with numerous young cases. Penetrance estimates from these studies have shown that although the deleterious mutations in BRCA1 and BRCA2 may be similar to those seen in high-risk families with numerous cases, the penetrance is lower at approximately 37% to 40%.^18-20

The development of intervention strategies for carriers of mutations in the BRCA1 and BRCA2 genes is determined by several factors. The first is primary prevention and secondary prevention in unaffected carriers using medical/surgical or other lifestyle strategies to prevent cancer development or the use of screening methods to detect cancers at an earlier stage. The options available are determined by the magnitude and age-at-onset–risk profile of cancer in carriers (the penetrance function of the gene) and the different cancer sites involved. The management of affected individuals who are BRCA1 and BRCA2 carriers may be altered by their carrier status, because the tumor histology, efficacy of treatment, and risk of subsequent cancer development after treatment of the first cancer may be determined by the BRCA1 and BRCA2 germline status. Because carriers of BRCA1 and BRCA2 mutations are relatively rare, the strategies for management should be determined by international multicenter studies.

OPTIONS FOR CHEMOPREVENTION

Epidemiologic studies indicate that estrogens play a significant role in the development of breast cancer.²¹ In mouse models, oophorectomy prevents breast cancer development and dimethylbenzanthracene-induced breast cancer in mouse models is reduced by the use of tamoxifen and the degree of reduction is dependent on the duration of tamoxifen exposure.^22,23 In women, many of the epidemiologic risk factors associated with breast cancer development relate to duration of estrogen exposure (early menarche, nulliparity,^24,25 oral contraceptive use,²⁶ hormone replacement therapy [HRT]²⁷ use, and late menopause).

Oophorectomy can reduce the incidence of breast cancer by up to 75%,²⁵ and oophorectomy and tamoxifen improve survival after breast cancer in an adjuvant setting.^28,29 It is thought that estrogens act as a promotional agent, because epidemiologic studies of radiation-induced breast cancer in Japanese women after exposure to irradiation from atomic bomb explosions showed that only women who were between 10 and 49 years of age at radiation exposure developed breast cancer 14 years later. Women who were postmenopausal at the time of exposure did not show an increased incidence. The highest risk of cancer development was in girls who were prepubertal at the time of exposure.³⁰ Furthermore, oophorectomy in women with BRCA1 or BRCA2 mutations may reduce the incidence of breast cancer by 50% and, interestingly, this does not seem to be affected by HRT.³¹

Given these pieces of evidence, the first series of chemoprevention trials using the antiestrogen tamoxifen in women at increased risk of breast cancer have been conducted, and three main trials have been reported. These are discussed in detail here.

THE TAMOXIFEN PREVENTION TRIALS IN WOMEN AT INCREASED RISK OF BREAST CANCER

The Royal Marsden National Health Service Trust Tamoxifen Prevention Trial
After completion of a pilot feasibility study that started in 1986 at The Royal Marsden Hospital, The Royal Marsden Hospital Tamoxifen Prevention Trial identified 2,494 (2,471 were analyzed) women, aged 30 to 70 years, who were randomized to either tamoxifen 20 mg/d or placebo. The trial was double-blind. Eligible patients were unaffected healthy women who had at least one first-degree relative younger than 50 years with breast cancer, one first-degree relative with bilateral breast cancer, or one affected first-degree relative with breast cancer at any age plus another affected first-degree or second-degree relative. In summary, eligibility for the trial was therefore based primarily on family history (according to the model of Claus et al² ). The median follow-up period was 70 months, and 58% of individuals remain on tamoxifen or placebo. No difference was seen between the incidence of breast cancer in the tamoxifen or placebo arms (tamoxifen, 34 cases; placebo, 36 cases; P = .8).³² There was no evidence of any interaction between the use of HRT, which was used by 26% of women at some time during the trial, and the effect of tamoxifen on breast cancer occurrence. Tamoxifen compliance at 5 years was 79%. Based on the Claus model,² using the Cyrillic 2.1 risk-assessment package, (Cherwell Scientific, Oxford, United Kingdom) 44 of the 70 women had greater than 50% chance of having a breast cancer predisposition gene.

The National Surgical Adjuvant Breast and Bowel Project P1 Study (NSABP-P1)
In 1992, a randomized trial of tamoxifen 20 mg/d versus placebo was started in women at increased risk of breast cancer, as defined by their absolute age (60 years or older), or if they were 35 to 59 years of age and had a 5-year predicted breast cancer risk of at least 1.66% (the same risk as that of a 60-year-old woman free of any other risk factors), or if they had a history of lobular carcinoma-in-situ. The model was based on the Gail model.³³ The variables in this model are age of the unaffected woman, number of first-degree relatives with breast cancer (but not their age at diagnosis and no information is used from other relatives or of other cancers), nulliparity or age at live first birth, number of breast biopsies, history of a pathologic diagnosis of atypical ductal hyperplasia, and age at menarche. A total of 13,388 women were randomized to receive tamoxifen 20 mg/d or placebo for 5 years. Tamoxifen reduced the risk of invasive breast cancer by 49% (P = < .00001).³⁴ The effect was greater in women 60 years of age or older (55%) than women 49 years of age or younger (44%). Risk was also reduced in women with a history of lobular carcinoma-in-situ (56%) or atypical ductal hyperplasia (86%). Tamoxifen reduced the risk of carcinoma-in-situ by 50% (P = < .002) and the occurrence of estrogen receptor–positive tumors by 69%, but it had no effect on the reduction of incidence of estrogen receptor–negative tumors.

The Italian Randomized Trial of Tamoxifen Chemoprevention in Hysterectomized Women
From October 1992 until July 1997, women 35 to 70 years of age who had a hysterectomy for benign reasons were recruited into a double-blind randomized tamoxifen chemoprevention study. A confounding factor was the fact that 48.3% of women had previously undergone bilateral oophorectomy, which would be expected to reduce the risk of breast cancer in both groups by 50% to 75%. A total of 5,408 women were randomized and the median age was 51 years; only 18.2% had one first-degree relative or second-degree relative with breast cancer. The median time on study intervention was 30.5 months, and no difference was seen (tamoxifen, 19 cases; placebo, 22 cases; P = .64) in the incidence of breast cancer in either group.³⁵

DISCUSSION OF THE ADVERSE EFFECTS OF TAMOXIFEN CHEMOPREVENTION

Other Cancer Risks
The NSABP-P1 Study³⁴ showed that women who had been treated with tamoxifen had a three-fold greater risk of developing invasive endometrial cancer (95% confidence interval, 1.35 to 4.97). This risk predominantly occurred in women older than 50 years and was 1.21 in women 49 years of age or younger. In women older than 50 years, the rate of endometrial cancer development on tamoxifen equates to approximately 1% over 5 years. There was no increased risk of cancer at sites other than the endometrium in any of the three studies.^32,34,35

Thromboembolic Complications
The incidence of deep vein thrombosis, pulmonary embolism/superficial phlebitis, and stroke was higher in the tamoxifen arm. In the NSABP-P1 study, this equated to a relative risk of 1.59 (95% confidence interval, 0.93 to 2.77). In the NSABP-P1 study, the excess incidence of stroke in the tamoxifen arm was seen in women who were 50 years of age or older.³⁴

Quality of Life
The two significant quality-of-life issues are an increased incidence of hot flushes (46% in the United States) and vaginal discharge (29% in the United States study) in the participants on tamoxifen. An alternative way of presenting these data is to assess the excess number of hot flushes and incidences of vaginal discharge that occur because of the drug above the incidence that would have occurred normally in women of the same age group; in the American study, this was 12% and 20%, respectively.

WHY IS THERE AN APPARENT CONTRADICTION BETWEEN THE RESULTS OF THE THREE TRIALS AND HOW SHOULD WE MOVE FORWARD?

Why Is There a Difference Between the Three Trials?
A recent review³⁶ discusses all of the arguments for and against the use of tamoxifen as a chemoprevention agent in women at increased risk. Within this article, some of the possible reasons for differences between the three trials are discussed. There are several possible scenarios: (1) the differences are merely due to an issue of power, (2) compliance issues were present, (3) the use of HRT in the Italian and British trials may confound the tamoxifen effect, and (4) the study populations were different.

The issue of power. There was only approximately a 10% chance that the British study would have failed to show a reduction in the incidence of breast cancer in women receiving tamoxifen if the size of the effect in the NSABP-P1 study is correct. The chance that both the United Kingdom and Italian studies would have missed such an effect because they were underpowered is only 2%.

Compliance issues. In the United Kingdom study, compliance was checked using serum tamoxifen measurements that were confirmed in 96% of a subset of 390 participants. A surrogate marker of a drop in cholesterol levels in women taking tamoxifen was confirmed in 34 of the 36 participants who developed breast cancer.

The use of HRT. In the United Kingdom study, HRT was used concomitantly in tamoxifen in 26% of women. It was clearly shown that there was no evidence of any negative interaction between HRT and tamoxifen that could account for any reduction in the tamoxifen chemopreventative effect.³²

Study population differences. The NSABP-P1 study defined risk using the Gail model.³³ In this model, much of the risk is based on nongenetic factors, and some of the factors contributing to increased risk, such as ductal carcinoma-in-situ and atypical ductal hyperplasia, are very likely to be endocrine sensitive. Although the Gail model takes into account the number of first-degree relatives, it does not assess their age at diagnosis nor the impact of other cancers such as ovarian cancer, which is known to markedly increase the probability of the presence of a BRCA1 or BRCA2 mutation.³⁷ The proportion of study participants with no family history was 4% in the Royal Marsden Hospital trial and 24% in the NSABP-P1 trial. However, the Italian trial, which was also negative, had a very low proportion of women with a family history (only 18% had one first-degree affected relative and only 2.5% had two or more), but this trial may have been negative for other reasons (namely, the high rate of oophorectomy). A full pedigree analysis has been undertaken of the United Kingdom trial, and the interaction between tamoxifen chemoprevention and the probability of the presence of a breast cancer predisposition gene (BRCA1, BRCA2, or BRCAX) according to the Claus model² indicates a greater chemopreventative effect for tamoxifen in women who have a less than 50% chance of the presence of a breast cancer predisposition gene (P = .04). These data and the analysis of the tumor characteristics in the Royal Marsden Trial will be reported elsewhere. The high incidence of oophorectomy (which is known to reduce the incidence of breast cancer in BRCA1/BRCA2 carriers³¹ ) in the participants in the Italian trial may be providing a reduction in cancer incidence for both the control and treated arms. If this were the case, then this trial shows that tamoxifen does not reduce breast cancer incidence more than the preventative effect of oophorectomy. The cumulative incidence curve in the placebo arm in the Italian trial shows an incidence of 10 cases per 1,000 women per 4 years, which equates to a 0.25% risk per year. Women at a one in two risk of carrying a BRCA1/2 mutation would have a 1.5% incidence per year. Most women in the study did not have a family history of breast cancer and, therefore, are very unlikely to be in a BRCA1/2 mutation-positive family and their baseline cumulative breast cancer incidence would therefore be lower than this.

THE WAY FORWARD

Should the United Kingdom Trials of Tamoxifen Versus Placebo Continue?
The NSABP-P1 trial was terminated early on advice from their Data Monitoring Committee. Before starting the study, it had been agreed that one of the stopping rules would be a statistically significant reduction in the incidence of invasive breast cancer; this was achieved and therefore the trial was stopped and women on the placebo arm were offered tamoxifen. There was considerable controversy about stopping the trial because it was unclear whether the original stopping rules, devised before the start of the trial, were appropriate. The problem with stopping the trial at this time is that it will not be possible to detect the effect of tamoxifen on mortality from breast cancer. Although the diagnosis of breast cancer has quality-of-life issues, it is likely that the breast cancers that would have occurred in participants receiving tamoxifen are highly curable (ie, small, estrogen receptor–positive cancers with ductal carcinoma-in-situ). It is therefore possible that there may be no overall health benefit from taking tamoxifen. The differentially greater benefit was seen in estrogen receptor–positive tumors and those with carcinoma-in-situ, and tumors in BRCA1 and BRCA2 mutation carriers (in particular, those with BRCA1) are more likely to be high-grade estrogen receptor–negative and have less ductal carcinoma-in-situ.^28,38

The United States Food and Drug Administration has approved the use of tamoxifen for reduction in incidence (but not prevention) for women at increased breast cancer risk and has licensed the drug for possible use in unaffected BRCA1/2 mutation carriers in the United States. However, there is no evidence at this time that BRCA1/2 mutation carriers will gain benefit from tamoxifen. Furthermore, it would seem that most women who harbor a breast cancer predisposition gene in the Royal Marsden trial are unlikely to have BRCA1 or BRCA2. Tamoxifen is only used in healthy women in the United Kingdom within the context of a clinical trial because of the residual uncertainties regarding which group may benefit and whether there is truly an overall health benefit. For these reasons, the large multicenter British/Australian trial, the International Breast Intervention Study (IBIS), will continue.

Because tamoxifen has adverse effects on the endometrium, new-generation selective estrogen receptor modulators have been identified for use in trial. The main interest is in raloxifene, which is currently licensed for use in postmenopausal women for osteoporosis. In osteoporosis trials, raloxifene for this indication reduced the relative risk of early breast cancer incidence in postmenopausal women.³⁹ There is no reported experience of raloxifene in premenopausal women. A trial has now started (Study of Tamoxifen and Raloxifene [STAR]; NSABP-P2) comparing tamoxifen with raloxifene in postmenopausal women. Because tamoxifen has been licensed by the United States Food and Drug Administration as a breast cancer incidence–reducing agent, a raloxifene versus placebo arm is unacceptable in the United States.

In BRCA1 and BRCA2 mutation carriers, the penetrance curve for breast cancer risk starts to increase at 35 years of age and the steepest part of the curve is between 40 and 50 years. If chemoprevention would be expected to need a lead time of 10 years before the increase in incidence of breast cancer, then chemoprevention agents would need to be given from at least 35 years, if not younger. The United Kingdom and Australia are shortly starting a pilot study of raloxifene and Zoladex (goserelin; Zeneca Pharmaceuticals, Wilmington, DE), called the Raloxifene and Zoladex Research Study (RAZOR). This pilot will initially assess the acceptability, compliance, and quality-of-life issues in offering monthly Zoladex and daily raloxifene to women aged 35 to 45 years who are at very high risk of breast cancer because of a strong family history. The entry criteria will include a higher lifetime breast cancer risk threshold than those used for the tamoxifen studies. For women who are at lower risk, the Royal Marsden Hospital is investigating a daily supplement of isoflavonoid phytoestrogens as a possible breast cancer chemoprevention agent. Retinoids have previously been used but have a higher side-effect profile.

CHEMOPREVENTION OF OTHER CANCERS IN BRCA1/BRCA2 MUTATION CARRIERS

The risks of other cancers in BRCA1 and BRCA2 mutation carriers are listed in Table 1. These show that BRCA1/2 mutation carriers are also at increased risk of ovarian cancer in females and prostate cancer in males.

Ovarian Cancer Risk in Women
The oral contraceptive pill has been shown to reduce the risk of ovarian cancer in BRCA1 and BRCA2 carriers to the same degree as that in the general population.⁴⁰ However, there is concern about the effect of oral contraceptive use on the increased risk of breast cancer in such women, and there are no reported data to define this risk at the present time.

Prostate Cancer Risk in Men
The absolute risk of prostate cancer in male carriers of BRCA1/2 mutation is not as high as the ovarian and breast cancer risk in female carriers; the risk by the age of 74 years is 6% to 14% (population by this age is 2%).^8,10 Prostate cancer chemoprevention is being developed using trials of selenium and vitamin E (the SELECT trial), which will be open to men according to age or ethnic status; no special category has been included in the eligibility criteria for BRCA1 or BRCA2 male carriers. The rationale for using selenium was that it reduces the incidence of prostate cancer by two thirds in a study of selenium given to skin cancer patients.⁴¹ The rationale for using vitamin E is based on epidemiologic evidence that low vitamin E levels are associated with higher prostate cancer risk.⁴²

In conclusion, the conflicting results from the large trials of tamoxifen chemoprevention in women who are at increased risk of breast cancer using different populations of women at risk indicate that chemoprevention trials should include pedigree analysis and the storage of constitutional DNA samples so that as genes are characterized, possible differential chemopreventative effects can be elucidated in different genetic risk groups. A pedigree analysis and mutation detection data correlated with tamoxifen chemoprevention in the NSABP-P1 study are awaited with interest to see whether similar differential effects are seen as in the United Kingdom study. Because the number of BRCA1 and BRCA2 mutation carriers from all of the studies world-wide will be small, a meta-analysis of BRCA1 and BRCA2 mutation status and its interaction with tamoxifen chemoprevention effectiveness will be important.

ACKNOWLEDGMENTS

Supported by The Royal Marsden NHS Trust, The Cancer Research Campaign, and the Hugh Knowles/Tony Maxse fund in memory of Georgina Knowles.

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