BREAST CANCER MANAGEMENT 0039%6109/99 $8.00 + .OO CLINICAL OPTIONS FOR WOMEN AT HIGH RISK FOR BREAST CANCER Lynn C. Hartmann, MD, Thomas A. Sellers, PhD, Daniel J. Schaid, PhD, Susan Nayfield, MD, MSc, Clive S. Grant, MD, Julie A. Bjoraker, MD, John Woods, MD, and Fergus Couch, PhD For women at high genetic risk of breast cancer, three management options are generally considered: cancer surveillance, prophylactic surgery (mastectomy or oophorectomy), and chemoprevention. This article examines the available data for all three options with particular attention to a study of prophylactic mastectomy performed at the Mayo Clinic. A woman is considered to be at high genetic risk if her family history suggests an autosomal dominant predisposition to breast cancer. Features of such a family history include multiple relatives with breast cancer, early age at diagnosis and, in some families, ovarian cancer. At present, inherited mutations in several genes are known to manifest in hereditary patterns of breast cancer: BRCAI, BRCA2, p53 (Li-Fraumeni syndrome), PTEN (Cowden syndrome), and kMLHI and kMSH2 (Muir Torre syndrome). Mutations in these genes may account for 40% to 50% of hereditary breast cancer in this 14, 2o Clearly other susceptibility genes exist. Mutation-specific recommendations cannot be made based on the available scientific literature. In this review, women with high genetic risk include women with mutations in one of the known susceptibil- ity genes, women from families that are known to possess such a mutation although the woman has not undergone testing herself, and women from fami- lies with a hereditary pattern of breast cancer where testing was not performed or was inconclusive. An example of a woman at high risk can best illustrate the clinical chal- lenges. In the pedigree in Figure 1, individual 3:7 is 30 years old and has not From the Mayo Clinic, Rochester, Minnesota (LCH, TAS, DJS, CSG, JAB, JW, FC); and the National Cancer Institute, Bethesda, Maryland (SN) SURGICAL CLINICS OF NORTH AMERICA VOLUME 79 * NUMBER 5 - OCTOBER 1999 1189
Transcript
BREAST CANCER MANAGEMENT 0039%6109/99 $8.00 + .OO
CLINICAL OPTIONS FOR WOMEN AT HIGH RISK
FOR BREAST CANCER
Lynn C. Hartmann, MD, Thomas A. Sellers, PhD, Daniel J. Schaid, PhD, Susan Nayfield, MD, MSc,
Clive S. Grant, MD, Julie A. Bjoraker, MD, John Woods, MD, and Fergus Couch, PhD
For women at high genetic risk of breast cancer, three management options are generally considered: cancer surveillance, prophylactic surgery (mastectomy or oophorectomy), and chemoprevention. This article examines the available data for all three options with particular attention to a study of prophylactic mastectomy performed at the Mayo Clinic.
A woman is considered to be at high genetic risk if her family history suggests an autosomal dominant predisposition to breast cancer. Features of such a family history include multiple relatives with breast cancer, early age at diagnosis and, in some families, ovarian cancer. At present, inherited mutations in several genes are known to manifest in hereditary patterns of breast cancer: BRCAI, BRCA2, p53 (Li-Fraumeni syndrome), PTEN (Cowden syndrome), and kMLHI and kMSH2 (Muir Torre syndrome). Mutations in these genes may account for 40% to 50% of hereditary breast cancer in this 14, 2o Clearly other susceptibility genes exist. Mutation-specific recommendations cannot be made based on the available scientific literature. In this review, women with high genetic risk include women with mutations in one of the known susceptibil- ity genes, women from families that are known to possess such a mutation although the woman has not undergone testing herself, and women from fami- lies with a hereditary pattern of breast cancer where testing was not performed or was inconclusive.
An example of a woman at high risk can best illustrate the clinical chal- lenges. In the pedigree in Figure 1, individual 3:7 is 30 years old and has not
From the Mayo Clinic, Rochester, Minnesota (LCH, TAS, DJS, CSG, JAB, JW, FC); and the National Cancer Institute, Bethesda, Maryland (SN)
SURGICAL CLINICS OF NORTH AMERICA
VOLUME 79 * NUMBER 5 - OCTOBER 1999 1189
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CLINICAL OPTIONS FOR WOMEN AT HIGH RISK FOR BREAST CANCER 1191
had cancer. There are numerous cases of breast and ovarian cancer in this family. In fact, approximately one half the women in the family have developed either breast or ovarian cancer. This pattern of inheritance is autosomal dominant, in that the cancers appear in every generation, and there is maternal (2:5 + 3:6) and paternal (2:l + 3:l) transmission. In this family, the average age of diagnosis of breast cancer is 35. Patient 3:7 has very nodular breasts on examination and dense breast tissue on mammography. She has opted to pursue genetic testing and is found to be a carrier of the BRCAZ mutation present in this family. Her options for management include cancer surveillance, chemoprevention, and prophylactic surgery. What data support these options?
CANCER SURVEILLANCE
Cancer surveillance has been the management option preferred by most high-risk women.52 The intent of cancer surveillance, also referred to as "second- ary prevention," is to detect a cancer at the earliest stage possible. For breast cancer surveillance, the combination of breast self-examination, clinician breast examination, and mammography is currently recommended.
The Cancer Genetics Studies Consortium, organized by the National Human Genome Research Institute, convened a task force to review recommendations for the management of women with BRCAZ and BRCA2 mutations. The task force's recommendations were published in 1997." For breast cancer surveil- lance, the task force recommended monthly breast self-examination beginning at age 18 to 21, clinician breast examination every 6 to 12 months beginning at age 25 to 35, and annual mammography beginning at age 25 to 35. The task force stated that their recommendations were largely based on expert opinion. Clinician breast examinations are an important component of the surveillance strategy in these women at very high risk in whom the age of onset of breast cancer is early, because the sensitivity of mammography is reduced in younger women.
At present, little information is available by which to judge the efficacy of close monitoring for high-risk women.", 26 Unfortunately, data from the random- ized screening trials do not provide direct evidence regarding the effect of mammography on breast cancer mortality in high-risk women, because these trials generally lack risk factor data for their participants. The often mentioned false-negative rate of 10% for mammography is derived primarily from studies performed in women over the age of 50.48 Burhenne et al, however, cite a drop in the sensitivity of mammography in the Screening Mammography Program of British Columbia from 89% for patients older than 50, to 63% percent for women younger than 50.1° Similar findings have been reported in the Swedish Two- County Study of mammography, which found a false-negative rate for women aged 40 to 49 of 38%.53 Donegan cites a 29% false-negative rate with mammogra- phy for women under the age of 50.15 Kerlikowske et a1 studied a group of more than 30,000 women, aged 30 years and older, referred for mammography to the University of California-San Francisco Mobile Mammography Screening Pro- gram between 1985 and 1992.31 In this study, women were considered to have a positive family history if they had one affected first-degree relative. When stratified by age group, the positive predictive value for screening mammogra- phy was improved in women with a family history of breast cancer in the age groups 40 to 49 and 50 to 59. For women aged 30 to 39, 60 to 69, and 70 y or older with a family history of breast cancer, the positive predictive value for mammography was similar to that for women in those age groups without a
1192 HARTMANN et a1
family history. Thus, some data show a greater value of mammography in younger women with a family history of breast cancer, in whom breast cancer is more prevalent.
The possibility of false-positive mammograms must also be considered. Elmore et a1 performed a 10-year retrospective cohort study of breast cancer screening and diagnostic evaluations among 2400 women aged 40 to 69 at study entry who were unselected for family history.1s Of the women who were screened, 31.7% had at least one false-positive mammogram or breast examina- tion during the period of study. The false-positive rate with mammography was higher in younger women.
The issue of adherence to cancer surveillance guidelines is critical in the management of high-risk women. Studies of these women commonly demon- strate two findings. First, a substantial proportion of these women do not adhere to recommended breast cancer screening g~ ide l ines .~~ The percentage of women with a family history of breast cancer who have ever had a mammogram varies widely among different studies, from 35% to 84Y0.~. 36 Although some studies have suggested that women with a positive family history of breast cancer are more likely to comply with mammographic screening recommendation~,3~ this has not been consistently s h o ~ n . ~ ~ , ~ ~ The other finding seen commonly in studies of high-risk women is that they experience high levels of psychological distress, including persistent worry about developing breast cancer.%, 36, 38 It is thought that this concern may negatively affect their adherence to screening guide- lines.=, %
One source of prospectively ascertained data for close cancer screening in women at increased risk for breast cancer is the randomized chemoprevention trials reported to date. Stage-at-diagnosis data are available for the placebo group from the National Surgical Adjuvant Breast and Bowel Project P-1 study, which compared tamoxifen with placebo in high-risk women.I9 (The published chemoprevention trials are discussed in detail subsequently.) In the P-1 trial, clinician breast examination was performed every 6 months, and mammograms were performed annually. In the 6599 women who received placebo, 175 invasive breast cancers were diagnosed. Table 1 lists the distribution of nodal status and
Table 1. T AND N STATUS OF 175 INVASIVE BREAST CANCERS DIAGNOSED IN PLACEBO ARM OF NSABP P-1 TRIAL
Percentage No. of of
Nodal Status Patients Patients
Negative 116 1-3 positive nodes 36
Unknown 12 2 4 positive nodes 11
66 27
7
Tumor Size No. of Percentage of (cm) Patients Patients
5 1.0 1.1-2.0 2.1-3.0 2 3.1
Unknown
63 68 22 19 ‘ 3
36 39 13 11 1
NSABP = National Surgical Adjuvant Breast and Bowel Project
CLINICAL OPTIONS FOR WOMEN AT HIGH RISK FOR BREAST CANCER 1193
tumor size for these 175 cancers. Two thirds of these tumors were node negative, and 36% were 1.0 cm or less in size. The stage-at-diagnosis data were not stratified by the age group or risk level of study participants, however. Although the majority of cancers detected in this trial were early stage, many of these women would probably be advised to have adjuvant systemic therapy today.
Stage-at-diagnosis data have not yet been reported for the Royal Marsden tria1A5 In the Italian study of tamoxifen versus placebo, 41 breast cancers have been diagnosed in the 5408 women enrolled.5h The only data published thus far regarding their stage at diagnosis are that 11 of the cancers were nonpalpable and were detected mammographically; the other 30 were palpable.
Cancer surveillance has been the management option preferred by most high-risk women. Breast self-examination and clinician examination are vital adjuncts to mammography in this population. Improvements in breast imaging, especially for younger women with more dense breast tissue, should be a priority for research. Magnetic resonance (MR) imaging, in particular, is being evaluated as another imaging approach for high-risk women.23, 3y
PROPHYLACTIC SURGERY-MASTECTOMY
Historical Background
Prophylactic mastectomy is another option for reducing the risk of breast cancer. Either a total or a subcutaneous mastectomy can be performed with prophylactic intent.4, 57, 58 Both procedures remove most breast glandular tissue, but the subcutaneous mastectomy preserves the nipple-areolar complex. Al- though prophylactic mastectomy has been utilized for decades, until recently remarkably little information has been available regarding the long-term out- come of women who have elected this pr~cedure.~, 6, 1 1 , Zh One reported series of prophylactic mastectomy, by Pennisi et al, included 1500 women who had subcutaneous maste~tomy.~~ The data set was established in the mid-1970s by soliciting patients from members of the American Board of Plastic Surgery. One hundred sixty-five plastic surgeons contributed patients. Six women were known to have developed breast cancer following the procedure, and the authors concluded that the procedure provided effective prophylaxis. Concerns with this study include possible selection bias of patients with favorable outcome, a high lost-to-follow-up rate of 30%, the inclusion of women with cancer in the operated breast, the lack of definition of patients' underlying risk of breast cancer, and the absence of a central pathology review.
Despite prophylactic mastectomy, breast cancer can develop in residual breast glandular tissue. Surgeons have long recognized that breast tissue is widely distributed over the entire anterolateral chest wall and axilla, and that no mastectomy reliably removes all mammary tissue.z5 Because the subcutaneous mastectomy preserves the nipple-areolar complex and a small volume of retro- areolar supporting breast tissue to maintain vascular supply, there is theoretically a greater breast cancer risk than with total mastectomy. This comparison has not been studied, however, and case reports have detailed the occurrence of breast cancer following either total or subcutaneous prophylactic maste~tomy.'~, **, 5y
This concern is especially pertinent to genetically high-risk women, because each remaining cell contains a germline mutation.
In its position paper, the American Society of Plastic and Reconstructive Surgeons provides guidelines for prophylactic ma~tectomy.~ "Prophylactic mas- tectomy of the female breast may be total (simple) or subcutaneous. . . . Prophy-
1194 HARTMANN et a1
lactic mastectomy is recommended for either the treatment of breast symptoms or to prevent cancer from developing in the breast.” They list specific indications for prophylactic mastectomy: personal history of breast cancer, one first-degree relative with bilateral premenopausal breast cancer, two first-degree relatives with premenopausal breast cancer, lobular or ductal carcinoma in situ, prolifera- tive atypical hyperplasia, and severe dysplasia.
A combination of two or more of the following conditions are also cited in the position paper as possible indications for prophylactic mastectomy: one first- degree relative with premenopausal breast cancer, one first-degree relative with postmenopausal breast cancer, mammograms obscured by fibrosis, multiple prior breast biopsies, extreme fear of cancer, and refractory fibrocystic mastopa- thy or mastodynia.
These indications are very broad and describe women with widely divergent levels of risk. The level of risk suggested historically in the surgical literature as appropriate for prophylactic mastectomy has been a 15% to 25% lifetime risk.16J7 Of note, past studies suggesting this 15% to 25% threshold risk provide no method of calculating risk? 16, 50, 54
Mayo Clinic Study
The authors have performed a retrospective cohort analysis of women who had bilateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993 to determine the effect of the procedure on subsequent breast cancer incidence and mortality, surgical morbidities following prophylactic mastectomy, and various psychosocial parameters in women electing this procedure. A recent report detailed the identification and characteristics of women with a family history of breast cancer who had bilateral prophylactic mastectomy, their under- lying breast cancer risk, and subsequent breast cancer occurren~es.~~ To deter- mine the effect of prophylactic mastectomy on subsequent breast cancer inci- dence and mortality, the authors compared the total number of events observed among the study participants with the total number of events predicted by the Gail model and a nested sister control study.
Methods
Identification of Cohort. Six hundred thirty-nine women with a family history of breast cancer had prophylactic bilateral subcutaneous or total mastec- tomy at the Mayo Clinic between 1960 and 1993. The details regarding the identification of the study cohort have been p~blished.2~
Questionnaire. A study-specific questionnaire was sent to all women known to be alive or, if they were deceased, to their next of kin. For women known to be alive, the questionnaire requested the following information: age at menarche; nulliparity, or age at first childbirth; number of breast biopsies before prophylactic mastectomy; presence of worrisome findings on breast bi- opsy; family history of breast or ovarian cancer; personal occurrences of breast, ovarian, colon, uterine, or other cancer; post-prophylactic mastectomy complica- tions; reasons for prophylactic mastectomy; patient’s assessment of breast cancer risk before and after prophylactic mastectomy; effect of procedure on psychoso- cia1 parameters; and overall satisfaction with the prophylactic mastectomy and with reconstruction. The questionnaire for next of kin did not contain decision- making, subjective risk assessment or psychosocial questions.
High-Risk Versus Moderate-Risk Family History. The authors assigned
CLINICAL OPTIONS FOR WOMEN AT HIGH RISK FOR BREAST CANCER 1195
women to moderate-risk and high-risk categories based on their family history of breast cancer. A high-risk pedigree is consistent with a single-gene, autosomal dominant predisposition to breast cancer. Existing criteria for high-risk status include the number of relatives diagnosed with breast cancer, early age at cancer diagnosis, and presence of ovarian cancer, bilateral breast cancer, or male breast cancer in the family.', 26, 40, 41 The high-risk criteria utilized in this study are
two or more first-degree relatives with breast cancer one first-degree plus two or more non-first-degree relatives with breast
one first-degree relative younger than age 45 with breast cancer plus one
one first-degree relative with breast cancer plus one or more relatives with
two non-first-degree relatives with breast cancer plus one or more rela-
one non-first-degree relative with breast cancer plus two or more relatives
three or more non-first-degree relatives with breast cancer one first-degree relative with bilateral breast cancer
Women with a positive family history that did not meet any of these criteria were considered to be at moderate risk.
Gail Model. The Gail model is one way to predict the expected incidence of breast cancer in the cohort of women who elected bilateral prophylactic mastectomy. This model was based on 243,221 white women who were screened annually for breast cancer for 5 years.*' The Mayo bilateral prophylactic mastec- tomy cohort also represents a group of women who were followed regularly because of one or more high-risk characteristics, such as family history and multiple prior breast biopsies, and thus should be comparable with the group studied by Gail et al. The risk factors required to calculate the expected number of breast cancers with the Gail model include patient age, age at menarche, age at first live birth, number of previous breast biopsies, the presence of atypical hyperplasia, and the number of first-degree relatives with breast cancer. The details regarding the statistical calculations of predicted breast cancer events and mortality in the moderate-risk group have been published.24
Nested Sister Control Study. The Gail model may underestimate the risk of breast cancer in women with strongly positive family histories2 To estimate the number of breast cancers expected in the high-risk group, the authors performed a nested sister control study. The following data were collected for all biologic sisters of the high-risk probands: year of birth, breast cancer occur- rence and date of diagnosis, prophylactic mastectomy and year of procedure, vital status, and year and cause of death.
To determine the number of breast cancers expected among the prophylactic mastectomy probands had they not had the procedure, the authors used the age-specific breast cancer rates observed among the sisters. These rates were then applied to the follow-up ages for the probands, beginning at the age of surgery and ending at last follow-up (defined as breast cancer occurrence, death, or end of follow-up). Sisters with bilateral prophylactic mastectomy were excluded. The rate of breast cancer among the sisters was calculated in three ways. The authors first counted all breast cancers that occurred during the total years of observation, accounting for age-specific person-years of observation beginnirrg at age 18. Selection bias must be considered with this study design. For example, a woman may elect prophylactic mastectomy because her sister
cancer
other relative with breast cancer
ovarian cancer
tives with ovarian cancer
with ovarian cancers
1196 HARTMANN et a1
had breast cancer. Thus, this type of ascertainment could lead to oversampling of sisters with breast cancer and subsequent overestimates of expected breast cancers. Hence, the authors calculated a second rate for the sisters that included only those sisters’ breast cancers that occurred after their respective proband’s prophylactic mastectomy. Because some families are classified as high risk either partially or wholly because of breast cancer occurrences among sisters, creating a subset of high-risk families in this manner can still lead to oversampling of breast cancers among sisters and artificially inflate the rate of breast cancer among sisters. Therefore, the authors calculated a third rate that utilized Wein- berg’s method for correcting for multiple as~ertainment.~’, 51 The authors calcu- lated the breast cancer mortality rates for the biologic sisters with the same methods used to determine the sisters’ incidence rates.
Results
Patient Characteristics. A total of 639 women with a family history of breast cancer had bilateral prophylactic mastectomy between 1960 and 1993. Of these, 425 have a moderate-risk family history; 214 women from 203 families are high- risk, having met at least one of the criteria listed previously. Patient characteris- tics are listed in Table 2. Ninety-four percent of women elected breast reconstruc- tion following prophylactic mastectomy.
Vital Status and Follow-up. Of the 639 women, 609 (95%) are alive, and 30 (5%) are deceased. The authors have complete questionnaire and chart informa- tion regarding follow-up for 593 women; they were unable to locate 14 women (2%) with the questionnaire follow-up efforts. Thirty-two women or next of kin (5%) declined to fill out the questionnaire. Nevertheless, the authors have medi- cal record information, including cancer occurrences and some risk factor infor- mation, for all the 639 women and a minimum of 2 years follow-up for 99% of the cohort, with a median of 14 years of follow-up (9095 person-years).
Table 2. CHARACTERISTICS OF PATIENTS HAVING BILATERAL PROPHYLACTIC MASTECTOMY
Moderate-Ris k High-Risk Family History Family History
(n = 214) (n = 425)
Age at prophylactic mastectomy
Age at menarche
Nulliparous (%) Age at first live birth
Mean number of breast biopsies
median
median
median
befoie prophylactic mastectomy
Type of procedure (%) subcutaneous mastectomy total mastectomy
42
13 12
21 2.4
90 10
42
13 13
21 1.9
89 11
CLINICAL OPTIONS FOR WOMEN AT HIGH RISK FOR BREAST CANCER 1197
Expected Versus Observed Incidence of Breast Cancer
Moderate-Risk Group. The Gail model prediction of breast cancer events for the 425 moderate-risk women, with the current median follow-up of 14 years, is 37.4. Four of these women have developed breast cancer following prophylactic mastectomy (Table 3). This represents an 89.5% reduction (P < 0.00001) in breast cancer incidence following prophylactic mastectomy in women with a moderate-risk family history.
High-Risk Group. The 214 high-risk probands have a total of 403 biologic sisters. From age 18 to follow-up, these sisters have experienced 156 breast cancers (38.7%), 115 diagnosed before and 38 after their respective proband’s prophylactic mastectomy. Three women had breast cancer with an unknown date of diagnosis. The breast cancer incidence rates in the sisters were calculated in three ways: using all sister breast cancer events after age 18, using sister events following the proband’s prophylactic mastectomy, and using sister events from age 18 corrected for ascertainment. The number of breast cancers expected in the probands was then calculated (Table 4). Using all sister events, the number expected in the probands is 52.9. The number expected in the probands, after correction for ascertainment bias, is 30.0. Looking only at sister events that followed their proband’s prophylactic mastectomy, the expected number in the probands is 37.4. Three of the 214 high-risk probands have developed a post-prophylactic mastectomy breast cancer. Thus, prophylactic mastectomy re- sults in a 90% to 94% reduction in the risk of breast cancer in high-risk women, depending on the method used to calculate the expected rates.
Expected Versus Observed Breast Cancer Mortality
Moderate-Risk Group. The prediction of breast cancer deaths in the moder- ate-risk group, based on the Gail model prediction of expected cases, is 10.4. There have been no deaths from breast cancer in these 425 women. The reduction in mortality is 100% (95% confidence interval [CI] = 70% to 100%).
High-Risk Group. The breast cancer deaths expected in the probands are displayed in Table 5. Counting all sister breast cancer deaths, 30.6 are expected. After correction for ascertainment bias, the number expected is 19.4. Counting only deaths that followed the proband’s prophylactic mastectomy, 10.5 are ex- pected. Two of the 214 high-risk probands have died of breast cancer. Thus, there is an 81% to 94% reduction in mortality from breast cancer in high-risk women receiving prophylactic mastectomy, depending on the method used to calculate the expected rates.
Table 3. BREAST CANCERS AFTER BILATERAL PROPHYLACTIC SUBCUTANEOUS MASTECTOMY
Time After Risk Level Prophylactic Mastectomy from
Case No. Site of Cancer (years) Family History
1 Left breast 15 2 Chest wall 2 3 Left breast “above areola” 5 4 Chest wall 25 5 Bone marrow 12 6 Left lateral chest wall 3 7 Left nipple 6
Moderate Moderate Moderate Moderate High High High
1198 HARTMANN et al
Table 4. EXPECTED NUMBER OF BREAST CANCERS IN HIGH-RISK GROUP
Expected No. of Observed No. of Sister Events Used to Breast Cancers Breast Cancers
Breast Cancer Rates Sister Rates Probands in Risk (%) Confidence Interval Compute Expected Based on Among Reduction 95%
3
90 (70.g97.9)
All breast cancer events 52.9 3 94.3 (83.5-98.8) (pre- and postprophylactic mastectomy), from age 18 through follow-up
All breast cancer events 30.0 3 (pre- and postprophylactic mastectomy), from age 18 through follow-up (corrected for ascertainment)
mastectomy breast cancers from age at prophylactic mastectomy through
Only postprophylactic 37.4
follow-up
92 (76.6-98.3)
Breast Cancers After Prophylactic Mastectomy. Seven breast cancers have been documented following prophylactic mastectomy, three among the high-risk women and four among the moderate-risk women (see Table 3). Six were localized to the chest wall at diagnosis. One high-risk woman presented with bone metastases from an adenocarcinoma 12 years after her prophylactic mastec- tomy; immunostaining for estrogen receptor and progesterone receptor was negative, but was positive for gross cystic disease fluid protein 15. Her chest wall examination and mammogram of residual breast tissue were negative. In these seven women, the median time to development of breast cancer was 6 years, with a range of 2 to 25 years. All seven women had had bilateral subcutaneous mastectomy. In the 639 women in the Mayo study, 575 had subcu- taneous procedures, and 64 had total mastectomies. The difference between 7
Table 5. EXPECTED NUMBER OF BREAST CANCER DEATHS IN HIGH-RISK GROUP
Expected No. of Sister Deaths Used to Deaths Based on Observed No. of
Breast Cancer Rates Rates Probands in Deaths (%) Confidence Interval Compute Expected Sister Cohort Deaths Among Reduction 95%
All breast cancer deaths, 30.6 2 93.5 76.499.2 age 18+Follow-up
age 18-tFollow-up (corrected for ascertainment)
mastectomy breast cancer deaths, age at prophylactic mastectomy+ Follow- UP
All breast cancer deaths, 19.4 2 89.7 62.8-98.8
Only post-prophylactic 10.5 2 80.9 31.497.7
CLINICAL OPTIONS FOR WOMEN AT HIGH RISK FOR BREAST CANCER 1199
cancers in 575 subcutaneous procedures and no cancers following 64 total mastectomies is not statistically significant ( P = 0.38); so few events make the power for this comparison weak. The two women who have died of breast cancer survived a mean of 1.5 years after diagnosis of their post-prophylactic mastectomy cancer. Five women remain alive and free of disease following local treatment of their chest wall disease. These five women have survived a median of 8 years (mean 10 years) following their post-prophylactic mastectomy cancer.
Prophylactic Mastectomy-Conclusions
This retrospective cohort study demonstrates a reduction of approximately 90% in the risk of breast cancer, following prophylactic mastectomy, in women with a moderate- or high-risk family history of breast cancer. Mortality is also reduced significantly.
The use of a retrospective study to address prophylactic mastectomy has advantages and disadvantages. One advantage is that an intervention such as prophylactic mastectomy is not likely to be studied in a randomized, prospective trial. High-risk women would not be expected to consent to being randomly assigned to prophylactic mastectomy or chemoprevention, for example, because of the dramatic difference between the interventions being compared. Another advantage is that with a retrospective approach a reasonably long-term follow- up period, namely a median of 14 to 15 years, exists at the time of the study. Any nonrandomized design is subject to bias; in this study, possibilities for bias arise from the characteristics of women who select prophylactic surgery over other approaches. A prospective, nonrandomized trial would also be subject to these biases and would require years to accrue a sufficient number of partici- pants and follow them adequately.
A major limitation of a retrospective study is that it looks back at medical history. During the period for this particular study, namely 1960 to 1993, the ability to identify women who are at very high risk for breast cancer has become much more sophisticated. During the early part of this study, it was often thought that a woman was at high risk if she had one close relative with breast cancer. Today we know that this is not correct. Hence, the moderate-risk group in this study includes many women whose lifetime risk of breast cancer is not markedly elevated.
PROPHYLACTIC OOPHORECTOMY
Exposure to ovarian hormones is a known risk factor for the development of breast cancer.3z Bilateral oophorectomy before age 40 is associated with a decrease in breast cancer risk of approximately 50”/0, compared with women who have undergone a natural menopause.’, ’’, ’’ These observations have been made in women unselected for breast cancer risk. In a study of women with BRCAZ mutations, Rebbeck et a1 have observed a similar reduction in risk of breast cancer following prophylactic oophorectomy in premenopausal ~ o m e n . ~ ’
The advantages and disadvantages of hormone replacement therapy or the use of selective estrogen receptor modulators following prophylactic oophorec- tomy represent complex decisions and must be addressed on an individual basis.
1200 HARTMANN et a1
CHEMOPREVENTION
Tamoxifen
Three studies of tamoxifen as a breast cancer chemopreventive were pub- lished in 1998.19, 45, 56 The Breast Cancer Prevention Trial (BCPT) conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) compared tamoxifen with placebo and demonstrated a 49% reduction in the risk of invasive breast cancer with tamoxifen over the period of study (median follow-up 55 month^).'^ The 13,388 participants in the BCPT were considered at increased risk because they (1) were 60 years of age or older, (2) were between 35 and 59 years of age with a 5-year predicted risk for breast cancer of at least 1.66% using the Gail model, or (3) had lobular carcinoma in situ. Tamoxifen or placebo was given for 5 years. The patient characteristics and risk reduction data are summarized in Table 6.19 Thirty percent of participants were aged 60 or older. Twenty-four percent of the patients had no affected first-degree relatives; 57% had one affected first-degree relative; and 19% had two or more affected first-degree relatives. Overall, tamoxifen reduced the risk of invasive breast cancer by 49%. Risk reduction was seen in all age groups but was greater in older women.
Of note, two recently published interim reports of European breast cancer chemoprevention trials with tamoxifen showed no significant reduction in breast cancer incidence with the 56 One of these studies was limited to women with a family history of breast ~ancer.4~ The results of the BCPT and European trials are summarized in Table 7.&
What is the explanation for these disparate findings? The Italian study
Table 6. BREAST CANCER PREVENTION TRIAL: PATIENT CHARACTERISTICS AND REDUCTION IN INCIDENCE
~ ~~
Patient No. of Risk Ratio 95% Characteristics Patients (TamoxifenlPlacebo) Confidence Interval
enrolled healthy women aged 35 to 70 who had had a hysterectomy. The majority were not known to be at increased risk for breast cancer. The compliance of the study has been questioned, with 26% of women discontinuing participation. The Italian study enrolled fewer older women than did the BCPT (12% in the Italian study were aged 60 or older, compared with 30% in the BCPT). As mentioned previously, the BCPT showed a greater risk reduction with tamoxifen in older women (see Table 6). Tamoxifen did not reduce the incidence of estrogen receptor (ER)-negative tumors, which are more common in younger women.12 Regarding patient compliance and tolerance of the study drug, in the BCPT 23.7% of women taking tamoxifen stopped their therapy, compared with 19.7% of the women in the placebo group.19
The disparity between the BCPT findings and the Royal Marsden study is of more concern, because the Royal Marsden study was limited to women with a significant family history of breast cancer. This is the patient population most in need of effective risk reduction strategies. There are several possible explanations for the differing results in these two trials. First, the women in the Royal Marsden study had stronger family histories and tended to be younger than those in the BCPT. This suggests that tamoxifen may have less of a protective effect in women with an inherited risk of breast cancer. It has been shown that breast cancers occurring in BRCAZ- and BRCA2-mutation carriers are more likely to be high-grade and hormone-receptor negative.H, 2y, 42 Such tumors are less likely to respond to tamoxifen. As mentioned previously, the BCPT found no reduction in the incidence of ER-negative tumors with tamoxi- fen.I9 Although women participating in the Royal Marsden study could take hormone replacement therapy, similar numbers did so on both treatment arms, and outcomes were no different in hormone users and nonusers.
A strong family history of breast cancer was the sole criterion for entry to the British trial, but the BCPT enrolled women with a given risk level as determined by the Gail model. The Gail model incorporates both family history and nongenetic risk factors. Its handling of family history is limited to first- degree relatives only (zero versus one versus two or more affected relatives) and does not address their age at diagnosis. The Gail model places considerable emphasis on reproductive factors and prior breast biopsies. Women with a higher risk level, as calculated by the Gail model, may experience more risk reduction with tamoxifen.
The nonbreast effects of tamoxifen are summarized in Table 8. There was no effect on cardiac end-points. Bone fractures, considering all sites, occurred with the same frequency in the tamoxifen and placebo groups. There was a slight reduction with tamoxifen in fractures of the hip, spine, and wrist, but this was not statistically significant. The risk of endometrial cancer was elevated
1202 HARTMANN et a1
Table 8. BREAST CANCER PREVENTION TRIAL: SECONDARY END-POINTS
Number of Events Risk Ratio (9570 Confidence Interval) Tamoxifen Placebo
Ischemic heart disease
No difference
No difference 34
Bone fractures (all) 472 483 28 I myocardial infarctions 31
with tamoxifen, as was the risk of thromboembolic phenomena. These risks were primarily seen in women over the age of 50.
An unanswered and important question regarding tamoxifen as a chemo- preventive is the durability of its effect. As tamoxifen exerts its antineoplastic effect in a cytostatic manner, it is unclear how long the risk reduction will continue once the agent is stopped after its 5 years of use. In fact, concern about the time course of the tamoxifen effect led the recent Food and Drug Administration Oncologic Drugs Advisory Committee to eliminate the word "prevention" from the approval for tamoxifen. Rather, the Committee recom- mended that tamoxifen be indicated for "short-term risk reduction" of breast cancer.55 Additional unanswered questions include the effect of tamoxifen in BRCAZ- or BRCAZ-mutation carriers and its effect on mortality.
UNANSWERED QUESTIONS AND FUTURE DIRECTIONS
For women at high genetic risk for breast cancer, the use of oral contracep- tives for premenopausal women and hormone replacement therapy for post- menopausal women raises complex questions. The risks of breast or ovarian cancer must be balanced against the effects on other organs including bone, the cardiovascular system, and the genitourinary tract. The National Cancer Institute plans to initiate multisite clinical trials to address these complex issues in high- risk women.
The next generation NSABP chemoprevention trial, P-2, compares tamoxifen with raloxifene in women at increased risk for breast cancer. Postmenopausal women with a similar risk level as P-1 participants will be eligible.
SUMMARY
Women at hereditary risk of breast cancer face a difficult clinical decision. Each of the options available to them has unique advantages and disadvantages that are summarized in Table 9.
Many components enter a high-risk woman's decision: her objective risk of breast cancer; clinical features, such as the consistency of breast tissue and resultant ease of examination; breast density on mammography; personal charac- teristics, including her experience with cancer within her family; her role and
CLINICAL OPTIONS FOR WOMEN AT HIGH RISK FOR BREAST CANCER 1203
Table 9. COMPARISON OF MANAGEMENT MODALITIES FOR WOMEN AT HIGH RISK OF BREAST CANCER
Modality Advantages Disadvantages
Cancer Surveillance
Prophylactic Mastectomy
Prophylactic Oophorectomy
Tamoxifen
Preserves breast tissue Allows other options No intervention for those
who do not develop cancer
Reduces breast cancer risk significantly, apparently long-term
Tissue-specific intervention
Reduces breast cancer
Preserves breast tissue risk
Reduces risk, but results
Preserves breast tissue Allows other options
conflicting
Does not prevent disease Unknown effectiveness in
Adherence unknown early detection of disease
Loss of breast tissue Irreversible decision Major surgical intervention Treats women who would
not have developed cancer
Premature menopause with systemic effects
Replacement estrogen may affect breast cancer risk; selective estrogen receptor modulators have attendant side effects
not have developed cancer
effects
reduction in women with inherited risk unclear
unclear
not have developed cancer
Treats women who would
Undesirable systemic
Magnitude of risk
Duration of risk reduction
Treats women who would
responsibilities within her own nuclear family; her values and goals; her experi- ences with the medical system; and her subjective assessment of risk. It is generally believed that women significantly overestimate their risk of breast c a n ~ e r ? ~ , ~ ~ Thus, it is vital that a woman at risk have access to a genetic counselor who can provide accurate assessment of her risk. Women should be encouraged to take time to understand their risk level and the advantages and disadvantages of the options before them.
ACKNOWLEDGMENT
The authors are indebted to Gail Prechel for assistance with the preparation of the manuscript.
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