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Decision Analysis of Prophylactic Surgery or Screening for BRCA1 Mutation Carriers: A More Prominent Role For Oophorectomy

From the Joint Center for Radiation Oncology Arnhem-Nijmegen (RADIAN) and Department of Human Genetics and Hereditary Cancer Clinic, University Medical Center Nijmegen; Nijmegen Institute for Cognition and Information, University of Nijmegen; and Department of Medical Psychology, Academic Medical Center, Amsterdam, the Netherlands.

Address reprint requests to Mariëlle van Roosmalen, MSc, Joint Center for Radiation Oncology Arnhem-Nijmegen (RADIAN), University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands; email: m.vanroosmalen{at}rther.azn.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: BRCA1 mutation carriers have a high risk of developing breast and ovarian cancer. Carriers may opt for prophylactic surgery and screening. Recent data suggesting that prophylactic oophorectomy reduces breast cancer risk have been incorporated in a decision analysis.

METHODS: A Markov model was developed to compare LE and QALE following four strategies: (1) prophylactic mastectomy and prophylactic oophorectomy (PMPO), (2) screening for breast cancer and prophylactic oophorectomy (BSPO), (3) prophylactic mastectomy and screening for ovarian cancer (PMOS), and (4) screening for breast and ovarian cancer (BSOS). The analysis was performed for a high (85% breast cancer, 63% ovarian cancer) and medium (56% breast cancer, 16% ovarian cancer) risk level. Utilities for the health states after prophylactic surgery were obtained from mutation carriers. Other model parameter values were obtained from the literature. Sensitivity analyses were performed.

RESULTS: When compared with BSOS, the average gain in LE for 30-year-old carriers in the high (medium) risk group was 11.7 (6.6) years for PMPO, 9.5 (5.3) years for BSPO, and 4.9 (4.4) years for PMOS. For 30-year-old carriers, BSPO had a QALE advantage when PO was performed before age 40. In the medium-risk group, there was a stronger advantage for BSPO when QALE was considered.

CONCLUSION: PMPO is the most effective strategy to prolong life. However, if patient preferences were taken into account, BSPO tends to be a better strategy in most women at medium risk or in young women at high risk when PO was performed before age 40.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
THE DISCOVERY OF the BRCA1 gene has created the possibility to test for inherited susceptibility for breast and ovarian cancer.¹ Between 5% and 10% of all breast and ovarian cancer cases in the general population are estimated to be carriers of a breast/ovarian cancer susceptibility gene.^2-4 Women with a BRCA1 mutation run a high risk of developing breast cancer (56% to 85%) and ovarian cancer (16% to 63%); these risk estimates vary depending on the population studied.^2,5-7

Options available to women with a BRCA1 mutation include intensive screening programs and prophylactic surgery of the breasts and/or ovaries.⁸ BRCA1 mutation carriers seem to be more interested in prophylactic oophorectomy than in prophylactic mastectomy.^9,10

Knowledge of the long-term efficacy of these strategies in women with a BRCA1 mutation is still evolving and the optimal strategy for management of these women remains to be established. Recent data suggest that prophylactic oophorectomy performed before the age of natural menopause is associated with a 43% reduction in breast cancer risk in BRCA1 mutation carriers, irrespective of the use of hormone replacement therapy.¹¹ In a follow-up study, Eisen et al¹² reported a breast cancer risk reduction of 76% if oophorectomy was performed before age 40. These findings are in line with the substantial breast cancer risk reduction after oophorectomy found in the general population.^13-15 If indeed oophorectomy performed before age 40 substantially reduces breast cancer risk in BRCA1 mutation carriers, the benefit of prophylactic mastectomy in addition to prophylactic oophorectomy will be smaller.

Prophylactic oophorectomy in BRCA1 mutation carriers is currently performed to reduce ovarian cancer risk. Oophorectomy is generally postponed up to age 35 to 40, after completion of childbearing, and can usually be done by laparoscopy, with minimal morbidity. If hormone replacement therapy is administered, long-term effects on the cardiovascular system and bone density will be limited and the effects on quality of life may be mitigated.^16-19

Decision analysis offers a method to balance benefits and drawbacks of screening and prophylactic surgery in a systematic and structured way.^20-24 An important aspect of decision analysis is the inclusion of measures of subjective well being (utilities) in the decision. For this specific decision, utilities were shown to be important.^21,22,24 Previous decision analyses did not include utilities assessed in BRCA1/2 mutation carriers but used utilities assessed in substitute subjects from various backgrounds.^21,22,24 We, however, assessed utilities of prophylactic surgery in 23 proven presymptomatic BRCA1/2 mutation carriers. The present decision analysis, therefore, improves on previous decision analyses on two major points: it takes the interaction between oophorectomy and breast cancer risk into account and it incorporates utilities assessed in BRCA1/2 mutation carriers.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Design of the Model
A Markov model employing tunnel states was constructed, using Data 3.0.18 software (TreeAge Software, Inc, Cambridge, MA).²⁵ The model compared four strategies, (1) prophylactic mastectomy and prophylactic oophorectomy (PMPO), (2) screening for breast cancer and prophylactic oophorectomy (BSPO), (3) prophylactic mastectomy and screening for ovarian cancer (PMOS), and (4) screening for breast and ovarian cancer (BSOS), with respect to their effect on life expectancy (LE) and quality-adjusted life expectancy (QALE) for women with a BRCA1 mutation.

Eleven possible health states were defined (Fig 1). A hypothetical cohort of BRCA1 mutation carriers moves yearly between health states according to the transition probabilities. We followed our cohort to age 90 years. Future life years were not discounted. Probability estimates for other model parameters were obtained from a review of the literature and are described in the next paragraph. Sensitivity analyses were performed to assess the effects of plausible parameter changes on the outcome.²⁶ The parameter value that brings about a change in preferred strategy is known as the threshold value. Baseline values and plausible ranges of model parameters are listed in Table 1. The age-specific annual risk of dying from all causes was taken from official statistics.²⁷

View larger version (18K): [in this window] [in a new window]   Fig 1. Representation of the Markov model. Health states are denoted by ovals. Each year, a hypothetical cohort of women with a BRCA1 mutation can move from one health state to another or stay in the same health state according to the arrows, with variable transition probabilities. The health state "well" includes four health states: well after each of the four strategies.

Protective effect of prophylactic surgery. Based on the data of a retrospective cohort study of women at high risk for breast cancer at the Mayo Clinic, we assumed that prophylactic mastectomy reduces the risk of breast cancer by 90%.²⁸ More recent data found that mastectomy was equally effective in BRCA1/2 mutation carriers.^29,30

On the basis of data from the Gilda Radner Familial Ovarian Cancer Registry, we estimated a 95% reduction in ovarian cancer risk after prophylactic oophorectomy.³¹ At the time of publication of the Gilda Radner data, the BRCA1/2 mutations were not yet cloned, so that the proportion of carriers in this database is unclear. However, Weber et al³² confirmed this estimate more recently in BRCA1/2 mutation carriers.³² We will refer to ovarian cancer developing after prophylactic oophorectomy as primary peritoneal carcinoma.

We assumed that oophorectomy performed before the age of 40, between ages 40 to 49, and after age 50 reduces breast cancer risk by 76%, 40%, and 6%, respectively.¹² This breast cancer risk reduction associated with oophorectomy at different ages was found in a follow-up of the study of Rebbeck et al,¹¹ who found a 43% risk reduction before age 50 in BRCA1 mutation carriers.

We assumed that prophylactic oophorectomy in premenopausal women is accompanied with hormone replacement therapy until the age of natural menopause. We assumed that hormone replacement therapy will not negate the reduction in breast cancer risk and reduces the risk of developing osteoporosis and cardiovascular diseases to the general population level.

The Early Breast Cancer Trialists’ Collaborative Group reported a risk reduction of breast cancer recurrence after oophorectomy of 26% among women aged under 50.³³ It is now recognized that adjuvant hormonal interventions are only of benefit in women with estrogen receptor–positive tumors. BRCA1-associated breast cancers have been associated repeatedly with estrogen receptor negativity.^34,35 The frequency of estrogen receptor positivity in BRCA1 mutation carriers was found to range between 32% and 36%, whereas the incidence in sporadic cases ranged between 63% and 65%. Because the incidence of estrogen-positive tumors in BRCA1 mutation carriers is about half of that in sporadic tumors, we assumed a risk reduction of 13% as a baseline value.^36,37 Among women aged over 50, we assumed no effect of oophorectomy on breast cancer recurrence.

Treatment of breast and ovarian cancer. The contralateral breast cancer risk for BRCA1 mutation carriers with a first primary breast cancer has been estimated to be as high as 60%.⁵ Although preliminary data suggested that breast conservation therapy is safe in BRCA1/2 mutation carriers, we assumed that bilateral mastectomy is performed if breast cancer is diagnosed. This is the treatment of choice in most European Family Cancer Clinics because of the high risk of multiple ipsilateral primaries and contralateral cancer.³⁸ Although contralateral prophylactic mastectomy has not been incorporated into standard practice in North America, there is a tendency towards more aggressive surgery in BRCA1 mutation carriers with breast cancer.³⁹ Surgical treatment of ovarian cancer includes at least bilateral salpingo-oophorectomy and hysterectomy.

Cancer survival data. Screening recommendations in BRCA1-positive women include biannual palpation and yearly mammography beginning at age 25 to 30 years. Brekelmans et al⁴⁰ found a lower sensitivity of screening in BRCA1/2 mutation carriers compared with population screening data. Nevertheless, they and others found no significant differences in survival between women with BRCA1-associated and sporadic breast cancer despite the biologic indicators of poor outcome among BRCA1-associated breast cancer.^36,41-46. Because it is still uncertain whether screening in BRCA1/2 mutation carriers contributes substantially to early detection of breast cancer, we based our survival on the United States National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) data for 1973 to 1998.⁴⁷

Data on the prognosis of BRCA1-associated ovarian cancer were obtained from Rubin et al⁴⁸ who found a better prognosis for BRCA1-associated ovarian cancer than for sporadic ovarian cancer. We did not adjust for ovarian cancer screening because there is no evidence that vaginal ultrasound or CA-125 measurement alters the prognosis of ovarian cancer. The prognosis of primary peritoneal carcinoma is reported to be worse than the prognosis of ovarian cancer.^49-51

Utilities. A utility is the subjective value given to a health state. We assessed utilities for prophylactic surgery with the time trade-off (TTO) method (Table 1), in which quality of life is traded against life duration in a better health state.²⁶ In our case, the better health state was BSOS, and its utility was set equal to 1. A utility of 0.92 for PMPO indicates that life after PMPO is subjectively equal to 92% of a life duration in the health state BSOS.

The utilities of prophylactic surgery were assessed in 23 proven carriers of a BRCA1 (n = 11) or BRCA2 mutation (n = 12) with a mean age of 38.5 years (range, 20 to 58 years). Presymptomatic carriers performed a choice-based TTO assessment in two interviews using a visual aid 2 months after they learned their carrier status (completion rate: 100%). Health state duration depended on the life expectancy of the carriers. These utilities were assessed within an ongoing randomized prospective study of the value of a formal shared decision-making program in the choice between screening and prophylactic surgery. We also incorporated the utility of breast cancer assessed in 12 symptomatic BRCA1/2 carriers 2 months after they received their test result. These women were diagnosed with breast cancer without distant metastases before blood sampling for genetic testing and had a mean age of 43.8 years (range, 35 to 55 years). The latter utilities were collected by converting a rating of own health, obtained by questionnaire, to a TTO-equivalent utility using a power function.⁵² For the utility of ovarian cancer and metastases, we calculated a weighted average of the TTO estimates from Grann et al^22,53 derived from various populations.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
The gains in LE and QALE after PMPO, BSPO, and PMOS, as compared with BSOS, are listed in Table 2 for two risk levels. For BRCA1 mutation carriers aged 30 years, we evaluated two additional strategies of delaying prophylactic oophorectomy until age 35 and age 40.

QALE
For 30-year-old BRCA1 mutation carriers in the high-risk group, QALE gains were largest after BSPO when prophylactic oophorectomy was performed before age 40. When prophylactic oophorectomy was delayed until age 40, PMPO led to the highest gain in QALE. For all other ages in the high-risk group, PMPO showed the largest gain. BSPO led to higher QALE gains than PMOS.

For 30-year-old BRCA1 mutation carriers in the medium-risk group, QALE gains were also largest after BSPO when prophylactic oophorectomy was performed before age 40. PMPO also led to the highest gain in QALE when prophylactic oophorectomy was delayed to age 40. Contrary to the high-risk group, BSPO showed the largest gain in QALE for all other ages. In the medium-risk group, BSPO also led to larger QALE gains than PMOS. For the age groups 50 and 60 years, PMOS led to QALE losses.

Sensitivity Analyses
As illustrated in Table 2, gains in LE and QALE are sensitive to age, age of performing prophylactic oophorectomy, and risk level. To study the stability of the results, sensitivity analyses were performed for cohorts of 30-year-old BRCA1 mutation carriers in both risk groups assuming that oophorectomy is delayed to age 35 years.

LE. No thresholds were found for any of the parameters, neither in the high- nor medium-risk group, indicating that there is no change in preferred strategy within the range of values studied. For the high-risk group, Table 3 lists the effect on LE for each strategy when a range of different values is used for the six most important parameters. The same six parameters were also found to be most important for the medium-risk group (results not tabulated).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
The present decision analysis is the first to explore the effects of the recently reported interaction between oophorectomy and breast cancer risk on LE and QALE in BRCA1 mutation carriers.^11,12 Furthermore, it is the first analysis that incorporates utilities for prophylactic surgery assessed in proven BRCA1/2 mutation carriers. The results point towards a more prominent role of oophorectomy alone as a prophylactic strategy.

Previous decision analyses found that prophylactic mastectomy alone results in a larger gain in LE than prophylactic oophorectomy alone in both high- and medium-risk groups.^20-22,24 A previous study reported smaller gains for 30-year-old mutation carriers from a comparable high-risk group for all strategies;²² prophylactic mastectomy alone yielded 2.8 years compared with 4.9 years found in our analysis; prophylactic oophorectomy alone (at age 30) yielded 2.6 years compared with 9.5 years found in our analysis; and the combination of both types of surgery yielded 6.0 years compared with the 11.7 years reported here. For 30-year-old mutation carriers in the medium-risk group, we found gains comparable with those previously reported.^20,21,24 For prophylactic oophorectomy alone however, we found larger gains.

Our larger gains after prophylactic oophorectomy are a result of including the interaction between oophorectomy and breast cancer risk. Removal of ovarian tissue reduces estradiol levels, inducing menopause. As a result, both breast and ovarian cancer risk may be lowered.⁵⁴ By assuming no effect of oophorectomy on breast cancer risk, previous studies may have overestimated the additional effect of prophylactic mastectomy and underestimated the effect of prophylactic oophorectomy.^20,22-24 Tengs et al²¹ assumed that oophorectomy reduces breast cancer risk by as much as 9% to 25% based on expert opinion. We, however, assumed a greater reduction in breast cancer risk after oophorectomy, especially when oophorectomy is performed before age 40, based on estimates from Eisen et al.¹² These estimates by age category on breast cancer risk reduction associated with oophorectomy in BRCA1/2 mutation carriers are based on a follow-up study of Rebbeck et al.¹¹ Their findings are in agreement with a report showing that oophorectomy reduces the risk of contralateral breast cancer in BRCA1/2 mutation carriers.⁵⁵ Oophorectomy also reduces breast cancer risk in premenopausal women unselected for breast cancer risk.^13-15 Although further studies are needed to confirm the efficacy of prophylactic oophorectomy in reducing breast cancer risk, the potential implications for BRCA1 mutation carriers are important.

We did not evaluate the protective effect of tamoxifen on breast cancer risk in our decision model because mixed results were reported.^56-58 None of these studies have specifically evaluated women with a BRCA1 mutation. Two recent studies evaluating the effect of tamoxifen in reducing breast cancer risk and contralateral breast cancer risk in BRCA1 mutation carriers also found mixed results.^55,59 Even if tamoxifen effectively reduces breast cancer risk in BRCA1 mutation carriers, oophorectomy may be a more attractive option because it combines a reduction in breast cancer risk with a sharp reduction of the increased ovarian cancer risk.

A second reason for our different results lies in the expected risk reduction for ovarian cancer after oophorectomy. Most decision analyses used a 45% to 50% risk reduction of ovarian cancer after prophylactic oophorectomy, as reported by Struewing et al.^20,22-24,60 Tengs et al²¹ assumed a risk reduction of 77% to 81% based on expert opinion. In the general population, however, primary peritoneal cancer occurs in only approximately 5% of all ovarian cancers.⁶¹ This agrees with the result of Piver et al,³¹ who found that approximately 2% of women with a family history of ovarian cancer who underwent oophorectomy developed primary peritoneal cancer. Because it is very unlikely that all women in this study had a genetic predisposition to develop ovarian cancer, 2% is probably an underestimation of the true risk in carriers of a BRCA1 mutation. We, therefore, assumed that 5% of all ovarian cancers would present as primary peritoneal cancer, which cannot be prevented by oophorectomy. This concurs with a risk reduction after oophorectomy of 95%, much larger than used previously. Our estimate agrees with the estimate of Weber et al⁶² obtained in BRCA1/2 mutation carriers.

A further reason for our different results is that we included the effect of oophorectomy on breast cancer recurrence. The observed risk reduction in a meta-analysis of sporadic breast cancer was 26% among women aged under 50 years.³³ We assumed a risk reduction of 13% in our analysis, based on the observation that the incidence of estrogen receptor–positive tumors in BRCA1 mutation carriers is about half of that seen in sporadic cases.^36,37

For the long-term prognosis of breast cancer, we used the most recent SEER data.⁴⁷ The SEER data represent the long-term breast cancer survival of a large population, unselected for screening behavior and family history. It is not clear whether these survival data can be safely extrapolated towards an optimally screened population of relatively young BRCA1-positive breast cancer patients. Up to now, there are several studies that confirm that breast cancer in BRCA1 mutation carriers show more unfavorable tumor characteristics than sporadic tumors. However, survival was not found to be worse in BRCA1-related breast cancers.^36,63

The efficacy of screening in BRCA1/2 mutation carriers is uncertain. Although screening works for women in the general population aged 50 years and over⁶⁴ and seems to benefit younger women with a family history of breast cancer,⁶⁵ it remains unclear whether this is also true for BRCA1 mutation carriers, and published studies show contradictory results. A recent study observed a lower sensitivity for screening and a relatively unfavorable tumor stage at diagnosis in BRCA1 mutation carriers compared with an age-matched average-risk population,⁶⁶ whereas another study suggests that screening by annual magnetic resonance imaging (MRI) might indeed improve survival.⁶⁷ The favorable effect of screening by MRI in this group of women seems to be confirmed by the study of Warner et al,⁶⁸ who reported the detection of all six invasive cancers that developed in a high-risk population by MRI at a size of less than 1 cm. Ultrasound, conventional mammography, and palpation could detect only three, two, and two of the six cancers, respectively. Larger studies are needed to assess the effect of screening and tumor characteristics on survival in BRCA1 mutation carriers. We chose to model the survival of breast cancer detected during screening in BRCA1 mutation carriers by using the survival of women with sporadic breast cancer.

In our analysis, we incorporated utilities of prophylactic surgery assessed in 23 proven carriers of a BRCA1/2 mutation 2 months after receiving the test result. These utilities were considerably higher than those used in previous decision analyses of prophylactic surgery and screening. For example, Grann et al^22,53 reported utilities of 0.67 to 0.86 in various groups of substitute subjects for prophylactic mastectomy and oophorectomy combined, whereas we found a utility of 0.92 in our group of mutation carriers. For the other surgery options, our utilities are also considerably higher than those used in previous decision analyses. These higher utilities favor surgical strategies. Our utility for breast cancer was obtained from symptomatic carriers valuing their actual health; the utility given to breast cancer by presymptomatic carriers is probably lower, which can lead to a change in preferred strategy as was shown in the sensitivity analyses.

We conclude that prophylactic oophorectomy alone below age 40 should be seriously considered. The negative effects of oophorectomy on quality of life may be mitigated by hormone replacement therapy whereas prophylactic mastectomy is an irreversible procedure with adverse psychologic and social outcomes in some women.^19,69 BRCA1 mutation carriers who have completed their childbearing before age 40 may, therefore, reasonably consider prophylactic oophorectomy for risk reduction of both breast and ovarian cancer. We believe that the potential implications of our results, pointing to a more prominent role for prophylactic oophorectomy, should be considered in the counseling process.

	ACKNOWLEDGMENTS

 
Supported by a grant no. 98-1585 from the Dutch Cancer Society, Amsterdam, the Netherlands.

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Submitted May 8, 2001; accepted January 10, 2002.

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