|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology
Prophylactic Oophorectomy in BRCA1 and BRCA2 Mutation CarriersFrom the Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA. Address reprint requests to Timothy R. Rebbeck, PhD, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, 904 Blockley Hall, 423 Guardian Dr, Philadelphia, PA 19104; email trebbeck{at}cceb.med.upenn.edu
The availability of genetic testing for inherited mutations in the BRCA1 and BRCA2 genes provides potentially valuable information to women at elevated risk of breast or ovarian cancer. Unfortunately, women who have inherited a mutation in BRCA1 or BRCA2 have relatively few clinical management options available to reduce their risk of developing breast or ovarian cancer. Because most options for ovarian cancer prevention are not highly efficacious, many high-risk women consider the option of bilateral prophylactic oophorectomy (BPO), in the hope that removal of healthy ovarian tissue will reduce their risk of developing invasive malignancy. It is clear that BPO cannot completely prevent the subsequent development of ovarian cancers because reports have been made of patients who have developed cancers of epithelial ovarian origin subsequent to surgery. However, a number of studies have suggested that BPO may reduce the risk of subsequent breast or ovarian cancers in women. In general, these studies have been conducted in women who represent a heterogeneous group with respect to breast/ovarian cancer risk. Only one study of BPO has been undertaken in women whose elevated cancer risk has been based on knowledge of inherited mutations. This study indicated that a 50% to 70% breast cancer risk reduction could be achieved in women with BRCA1 mutations who underwent BPO. However, substantial additional information is required to provide clinically useful information about cancer prevention to women who carry mutations in BRCA1 or BRCA2.
INHERITANCE OF A germline mutation in the BRCA1 or BRCA2 (BRCA1/2) genes confers breast and ovarian cancer risk that is many times higher than that in the general population (Fig 1). 1–3 Breast and ovarian cancer risk in BRCA1/2 mutation carriers estimated from high-risk pedigrees used for linkage analysis (Fig 1) suggested a lifetime breast cancer risk of 80% to 90%.1 However, these families were highly selected for the existence of multiple cancers occurring at an early age and may not represent all high-risk breast cancer families in the general population. Population-based studies suggest that BRCA1/2 mutation cancer risks may be substantially lower than those originally reported. For example, Struewing et al4 have reported that cancer risk may be no higher than 60% in population-based samples of Ashkenazi Jewish women who carry one of the commonly occurring mutations in BRCA1/2 (ie, 185delAG, 5382insC, or 6174delT). Lifetime breast cancer risk associated with BRCA2 in hereditary family (not population-based) samples seems to be similar to that of BRCA1, although the mean age of onset is shifted to a somewhat later age in the BRCA2 mutation carriers (Fig 1). That is, although lifetime (total) risk may be similar, the age-specific penetrances of BRCA1 and BRCA2 may differ.
Because women who carry BRCA1/2 mutations are at increased cancer risk, they often are motivated to identify clinical options for cancer risk reduction. These options include increased surveillance, chemoprevention, and prophylactic surgery. With regard to breast cancer, recommendations for enhanced levels of screening using clinically established techniques have been made by many groups5 and generally include breast screening beginning at an earlier age as well as more frequent exams (eg, mammography and clinical breast exam every 6 months). However, concerns about intensive screening include potentially limited ability to detect cancers by mammography in younger women who have increased breast density. Other screening methods, such as breast imaging by magnetic resonance imaging and digital mammography, are being tested but are not widely available outside of research protocols. With regard to ovarian cancer screening, clinical recommendations are more limited. Neither vaginal ultrasound nor CA-125 measurement has been shown to reduce morbidity or mortality from ovarian cancer, and the efficacy of these approaches has not been reported in women with BRCA1/2 mutations. Thus, these women are often advised to undergo bilateral prophylactic oophorectomy (BPO) when childbearing is complete. Unfortunately, concerns about estrogen replacement therapy in women with BRCA1/2 mutations complicate this decision further. Schrag et al6 and Grann et al7 have suggested that additional gain of lifespan may be achieved in BRCA1/2 carriers who undergo BPO (eg, 0.3 to 1.7 years).6 However, these analyses made numerous assumptions that cannot yet be verified in BRCA1/2 mutation carriers, and some important competing factors (use of hormone replacement therapy [HRT], use of CA-125, or other screening tools) were not completely considered in these analyses. Hormonally based chemoprevention strategies in BRCA1/2 mutation carriers hold great promise for cancer risk reduction. Oral contraceptive use has been suggested as a means of reducing ovarian cancer risk among high-risk women.8,9 Early indications of a protective effect of tamoxifen may benefit women who are at increased breast cancer risk.10 However, not all studies have demonstrated a protective effect of tamoxifen,11,12 and none of these studies have specifically evaluated women who carry BRCA1/2 mutations. Until it is firmly established that tamoxifen or other chemopreventive agents are effective in breast cancer risk reduction in high-risk women, prophylactic surgery may remain an important clinical option.
Screening and early detection of ovarian cancers is substantially more difficult than for breast cancer. The majority of tumors are diagnosed at stage III and IV disease, and mortality from these higher stage cancers is high. In addition, intra-abdominal (peritoneal) carcinomatosis (histopathologically consistent with ovarian cancer in origin) does occur in women who have undergone BPO. Although the origins of these cancers are poorly understood, it is hypothesized that either (1) clinically undetectable ovarian cancer cells remain in the peritoneum after the removal of ovaries and/or (2) a field defect is present in the peritoneum as the epithelial covering of the ovary (ie, the origin of the epithelial ovarian cancer is in fact the peritoneal reflection onto the ovaries). Thus, BPO will at best reduce the risk of ovarian cancers and cannot be viewed as a strategy that confers complete ovarian cancer prevention. Removal of healthy ovarian tissue presumably reduces risk of ovarian cancer because less susceptible tissue is available to become cancerous. Removal of ovarian tissue also reduces serum estradiol levels, inducing menopause. As a result, both breast and ovarian risk may be lowered.13 Two studies to date have estimated risk reduction subsequent to oophorectomy in women who may be at elevated ovarian cancer risk because of family history. Struewing et al14 suggest that oophorectomy in high-risk women may confer ovarian cancer risk reduction of approximately 50%, but the residual ovarian cancer risk in postoophorectomy subjects is still substantially higher than that in the general population. This lifetime risk could be as high as 30% in some BRCA1/2 mutation carriers. However, that study had too few patient-years of follow-up to reach a statistically significant conclusion. Piver et al15 also described six cases of postoophorectomy intra-abdominal carcinomatosis, but these subjects were drawn from a registry sample that was not limited to subjects whose risk may approach that of a BRCA1/2 mutation carrier (ie, the subjects included some with only a single relative with ovarian cancer). Risks of morbidity and mortality exist from BPO and may vary depending on the type of procedure (eg, laparotomy v laparoscopy). However, the relative risks of one surgical type or another are unlikely to be related to mutation status. However, decisions about BPO may be complicated by the knowledge that there may be health consequences after surgery. Most importantly, women with BPO undergo immediate surgical menopause after BPO, with all of its associated sequelae. Because it may affect risk of breast cancer, concerns have arisen about HRT after BPO and hysterectomy to diminish these symptoms and address the increased risk of osteoporosis and cardiovascular disease. The extent to which the benefits of BPO outweigh these risks is not known. It may well be that estrogen replacement in premenopausal women given until the time at which natural menopause would have occurred may not increase breast cancer risk beyond a woman’s baseline risk. The availability of newer synthetic hormone replacement compounds such as raloxifene, which may confer cardiovascular and osteoporosis protection with no associated increase in breast cancer risk, are options that must also be considered. Ovarian cancers in BRCA1/2 mutation carriers have been reported in very young women, although the median age of BRCA1/2-associated ovarian tumors is approximately 50 years. Thus, ovarian tumors tend to arise later than breast tumors in BRCA1/2 mutation carriers, and the timing of BPO may be affected by events such as reproduction. For example, some clinicians suggest that BPO may be appropriate in very high–risk women after childbearing is complete. Using a decision analysis approach, Schrag et al6 have suggested that a delay of BPO for 10 years in a 30-year-old woman may not result in a substantial change in life expectancy. However, these analyses made numerous assumptions that cannot yet be verified in BRCA1/2 mutation carriers, and some important competing factors (use of other screening methods or hormone replacements) were not completely considered in these analyses.
Decreased exposure to ovarian steroid hormones is thought to affect a woman’s risk of developing breast cancer. To address this hypothesis, we have evaluated the effect of BPO on breast cancer risk reduction in 122 BRCA1 mutation carriers.16 We compared two groups of women, those who had undergone BPO and a matched set of women who did not undergo this surgery but who were born at approximately the same time and were ascertained at the same study site as the BPO subjects. Subjects were selected from a larger cohort of BRCA1 mutation carriers from five participating locations (Creighton University, The Dana-Farber Cancer Institute, The Fox Chase Cancer Center, The University of Pennsylvania, and The University of Utah). BPO was defined as prophylactic if the surgery was not performed to treat ovarian or related peritoneal cancers. Women with unilateral oophorectomies were excluded from analysis. Forty-three BPO subjects were included who had no history of breast or ovarian cancer before or at the time of their surgery and no history of prophylactic mastectomy before or at the time of their BPO. Controls were selected from women ascertained at the same five study locations. Potential control women were selected if they had a confirmed BRCA1 mutation, had both ovaries at the time of the surgical subject’s BPO, were born before 1970, were born within 5 years of a BPO surgical subject (to control for potential cohort effects), and were ascertained at the same study location. Among these potential control subjects, 79 controls were selected who were alive at the time of the BPO subject’s surgery, had no history of oophorectomy, no history of breast or ovarian cancer, and no history of prophylactic mastectomy at or before the time of the matched surgical subject’s BPO. Women who had BRCA2 mutation were excluded. Surgical subjects were observed for an average of 9.6 years after BPO (range, < 1 to 36 years), and controls were observed for an average of 8.1 years (range, < 1 to 43 years) after BPO in the matched surgical subject. There was no difference in length of follow-up in the two groups. Figure 2 presents the cumulative incidence of breast cancer in women with and without BPO. BPO significantly reduced the risk of developing breast cancer in the whole sample (hazard ratio [HR] = 0.53; 95% confidence interval [CI], 0.33 to 0.84). When six BPO subjects who had surgery after 50 years of age and their matched controls were removed from the sample, we estimated that the HR = 0.57 (95% CI, 0.36 to 0.92). Because many women elect to undergo BPO after childbearing, we also evaluated the effect of BPO among parous women. In this group, reduction in breast cancer risk by BPO was of similar magnitude to that estimated in the whole sample (HR = 0.49; 95% CI, 0.30 to 0.79). Subjects who were observed at least 10 years after surgery and were parous (HR = 0.35; 95% CI, 0.13 to 0.95) or had BPO before age 50 (HR = 0.34; 95% CI, 0.12 to 0.96) also experienced a substantial reduction in breast cancer risk. These results imply that risk reduction is greatest when a sufficient amount of time has elapsed after surgery.
The effect of HRT on breast cancer risk after BPO has not been well studied. Rebbeck et al16 reported that ever/never HRT use was not a significant independent predictor of breast cancer outcome in a multivariate Cox model that included BPO, and exclusion of women who had HRT exposure after BPO did not significantly affect the risk reduction conferred by BPO. However, this was a small sample, and additional information is required to guide women and their clinicians about the use of HRT after BPO. In conclusion, relatively little data exist that can help guide women who have inherited BRCA1/2 mutations about the use of BPO to reduce breast or ovarian cancer risk. Additional information about the magnitude of risk reduction, the magnitude of mortality reduction, proper timing of surgery, and use of HRT are required. It is likely, based on preliminary reports, that BPO will be of benefit to women in breast and ovarian cancer risk reduction. Recent recommendations by Eisen et al13 include the use of BPO in postmenopausal women with a hereditary susceptibility to ovarian cancer. For premenopausal women, the use of BPO should be weighed against age-related ovarian cancer risk, childbearing, and risk of complications that may arise as a result of surgically induced menopause. In the absence of strong data to guide a decision, HRT use may be recommended after BPO until age 50. Until less surgically invasive options become available, including improved screening and chemoprevention regimens, the use of BPO as a mean of reducing breast and/or ovarian cancer risk by women who have inherited a BRCA1/2 mutation is likely to be of value.
1. Easton DF, Bishop DT, Ford D, et al: Genetic linkage analysis in familial breast and ovarian cancer: Results from 214 families. Am J Hum Genet 52: 678-701, 1993[Medline] 2. Ford D, Easton DF, Stratton M, et al: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in BC families: The BC Linkage Consortium. Am J Hum Genet 62: 676-89, 1998[Medline] 3. Ford D, Easton DF, Bishop DT, et al: Risks of cancer in BRCA1-mutation carriers: Breast Cancer Linkage Consortium. Lancet 343: 692-695, 1994[Medline]
4.
Struewing JP, Hartge P, Wacholder S, et al: The risk of cancer associated with specific variants of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336: 1401-1408, 1997 5. Burke W, Daly M, Garber J, et al: Recommendations for follow-up care of individuals with an inherited predisposition to cancer. JAMA 277: 997-1003, 1998[Abstract]
6.
Schrag D, Kuntz KM, Garber JE, et al: Decision analysis: Effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. N Engl J Med 336: 1465-1471, 1997 7. Grann VR, Panageas KS, Whang W, et al: Decision analysis of prophylactic mastectomy and oophorectomy in BRCA1-positive or BRCA2-positive patients. J Clin Oncol 16: 979-985, 1998[Abstract]
8.
Narod SA, Risch H, Moslehi R, et al: Oral contraceptive use reduces the risk of hereditary ovarian cancer. N Engl J Med 339: 424-428, 1998
9.
Ursin G, Henderson BE, Haile RW, et al: Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 57: 3678-3681, 1997
10.
Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371-1388, 1998 11. Powles T, Eeles R, Ashley S: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 352: 98-101, 1998[Medline] 12. Veronesi U, Maisonneuve P, Costa A, et al: Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomized women. Lancet 352: 93-97, 1998[Medline]
13.
Eisen A, Rebbeck TR, Wood WC, et al: Prophylactic surgery in women with a hereditary predisposition to breast and ovarian cancer. J Clin Oncol 18: 1980-1995, 2000 14. Struewing JP, Watson P, Easton DF, et al: Prophylactic oophorectomy in inherited breast/ovarian cancer families. J Nat Cancer Inst Monogr 17: 33-36, 1995 15. Piver MS, Jishi MF, Tsukada Y, et al: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer: A report of the Gilda Radner Family Ovarian Cancer Registry. Cancer 71: 2751-2755, 1993[Medline]
16.
Rebbeck TR, Levin AM, Eisen A, et al: Reduction in breast cancer risk following bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Insti 91: 1475-1479, 1999 This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
BRCA1- AND BRCA2-ASSOCIATED...
