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EDITORIALS |
From the Departments of General Surgery (DHR, AMK), and of Obstetrics and Gynecology (IG, DP), Medical School of University of Ioannina, 451 10 Ioannina, Greece.
Correspondence: Address correspondence to: Dimitrios H. Roukos, MD, P.O. Box 105 Neochoropoulo, Ioannina 455 00, Greece; Fax: 30-6510-70800; E-mail: droukos{at}cc.uoi.gr
Despite advances in the genetics of familial breast and ovarian cancer, the clinical management of women with established mutations in BRCA1 or BRCA2 genes remains controversial. For women who decide for prophylactic surgery and not for a conservative approach, it is highly debated whether they are benefited more by a prophylactic mastectomy rather than a prophylactic oophorectomy. Although BRCA mutation carriers are at a substantially higher risk for developing breast cancer rather than ovarian cancer, medical decision-making is a major challenge. Penetrance estimates of breast and ovarian cancer considerably vary and substantially differ between BRCA1 and BRCA2 mutation carriers. This variation is important in decision-making. Here we balance risks and benefits of these two surgical procedures regarding cancer risk estimates, effectiveness, morbidity, and quality of life.
Since the first description of breast cancer susceptibility in women carrying mutations in BRCA1 or BRCA2 genes 8 years ago, important advances have been made in cancer genetics and several clinical studies with surgical or conservative preventive approaches have been published. But the clinical management of these women has not yet been established. Surgical prophylaxis in BRCA mutation carriers seems to offer higher protection against cancer than conservative approach, but it is associated with a series of limitations and risks.1 Clinicians are increasingly being asked to involve patients in decisions that ‘have no clear best choice,‘ and in which the medical science is imperfect, leaving many questions unanswered. Approximately 50% of women with BRCA1 or BRCA2 mutations elect surgical prophylaxis after medical counselling. But it remains unclear whether prophylactic mastectomy or prophylactic oophorectomy is more beneficial.
BRCA1 and BRCA2 are tumor suppressor genes that play important roles in cellular functioning, such as DNA damage repair. Germ-line (inherited) mutations in these genes predispose to breast and ovarian cancer. Recent research on array-based methods has demonstrated differences in gene expression profiles between BRCA1- and BRCA2-associated tumors in both hereditary breast cancers2,3 and ovarian cancers.4 Thus, mutations inBRCA1 and BRCA2 genes lead to breast or ovarian cancer through different pathways. This subclassification of breast and ovarian cancer according to their gene expression patterns may clinically have prognostic and therapeutic value.5 Indeed, penetrance, the probability that cancer will in fact develop in a woman with these genetic abnormalities, differs substantially between BRCA1 and BRCA2 mutation carriers and this is important for treatment decision-making.
For BRCA1 mutation carriers, penetrance estimates range from a 45% to 85% lifetime risk of breast cancer and from a 16% to 63% lifetime risk of ovarian cancer.6–14 For BRCA2 mutations, penetrance is estimated to range between a 26% and 85% risk of breast cancer and from a 10% to 20% risk of ovarian cancer,7–11,13,15 and one study12 found no statistically significant evidence of an increased risk. The data indicate a rather lower risk of ovarian cancer among BRCA2 mutation carriers and this seems important in clinical decision. However, all estimates generated wide confidence intervals, indicating considerable uncertainty about the absolute magnitude of risk in an individual woman carrying the mutation. Familial cancer, rather than sporadic cancer, tends to occur at a younger age, but the increased risk in carriers of these mutations is life long, and in some carriers bilateral breast cancer or both breast and ovarian cancer develop.
The effectiveness of the surgical procedure used to reduce the risk of breast cancer and/or ovarian cancer and to improve overall survival is also an important parameter in decision-making between prophylactic bilateral mastectomy and prophylactic bilateral salpingo-oophorectomy in a woman with BRCA1 or BRCA2 mutation. There is no randomized or prospective comparative study between these two surgical procedures, and the data available emerge from retrospective or prospective studies between prophylactic surgery and surveillance.
Prophylactic bilateral mastectomy in women with family history of breast cancer has been demonstrated effective in reducing significantly the risks of both breast cancer and death in a previous retrospective study with 14 years follow-up.16 Based on these results, Meijers-Heijboer et al.17 conducted a prospective study of 139 women with BRCA1 or BRCA2 mutations. After a mean follow-up of 3 years, breast cancer was developed in 8 of 63 women who had elected surveillance but in none of the 76 carriers of such mutations who had undergone prophylactic surgery.17
However, several experts recommend and many women elect to undergo prophylactic bilateral salpingo-oophorectomy rather than prophylactic bilateral mastectomy, although the risk of ovarian cancer is substantially lower than the risk of breast cancer. What are the reasons for this selection?
Prophylactic oophorectomy has reduced the risks of both ovarian cancer and breast cancer in earlier, small studies.18–20 Consistent with these observations in BRCA1 or BRCA2 mutations are the results of a recent large, multicenter retrospective analysis of 551 women with a mean follow-up of 9 years.21 In a prospective study, Kauff et al.22 report the results of 170 carriers of BRCA mutations with a mean follow-up of 2 years. Ovarian cancer or a papillary serous carcinoma of the peritoneum developed in 5 of 72 women who elected intensive surveillance (6.9%). Of the 98 women who underwent prophylactic salpingo-oophorectomy, 3 had early-stage tumors that were diagnosed at the time of surgery (3.1%), and primary peritoneal cancer developed in 1 patient during follow-up (1.0%). The latter type of tumor is believed to derive from remnants of the mullerian duct in the mesothelial lining of the peritoneum, whose presence is associated with a persistent risk of cancer after oophorectomy. Among women who had not undergone prophylactic bilateral mastectomy, breast cancer was developed in 8 of the 62 women in the surveillance group (12.9%) and in 3 of the 69 women in the oophorectomy group (4.3%).
All of these studies provide evidence that oophorectomy can decrease not only the risk of ovarian cancer but also that of breast cancer by approximately 50%.18–22
Although there is no comparative data, surgical complications seem to be lower after laparoscopic salpingo-oophorectomy (4%)22 rather than after bilateral mastectomy with reconstruction (30%).23 Furthermore, laparoscopic oophorectomy, as a highly patient-friendly procedure, offers the well-known advantages of a minimally invasive treatment.
Prophylactic bilateral mastectomy may have a negative effect on self-esteem, sexual relationships, and satisfaction with body appearance.24 Salpingo-oophorectomy, besides these psychosocial and sexual effects, may have additional adverse effects on cardiovascular disease and osteoporosis and may produce more physical symptoms than those who underwent screening.25
Another important criterion for decision-making is whether early detection of cancer can be predicted more accurately in the breast or ovary because the earlier the disease is detected the higher the cure rates. Several experts recommend prophylactic oophorectomy because after that surveillance and screening technology are able to detect breast cancer at an early stage. However, the available data in BRCA mutations indicate the failure of early diagnosis for both breast17 and ovarian cancer.22 Whether magnetic resonance imaging screening in carriers of BRCA mutations adds to the efficacy of mammographic screening for early breast cancer detection26 and whether positron emission tomography adds to the efficacy of ovarian ultrasonography and CA-125-based screening for early-stage ovarian cancer are unknown. At the present time and until data from magnetic resonance imaging and positron emission tomography are available, earlier diagnosis rates seem to be higher for breast rather than for ovarian cancer.
For complete protection of women with BRCA mutations against cancer in both breasts and ovaries prophylactic bilateral mastectomy and salpingo-oophorectomy have been suggested.1 But the short- and long-term effects of this aggressive radical approach on morbidity, body image, sexuality, and quality of life have been studied insufficiently.
Previous and recent studies of penetrance estimates indicate that a woman’s risk with BRCA1 or BRCA2 mutations varies considerably depending on population ascertainment; risk is very high in multiple-cases families and much lower in population-based studies. Therefore, not only penetrance estimates but also family history should be considered for decision-making between the two surgical procedures.
For BRCA2 mutation carriers with a moderate lifetime risk of ovarian cancer ranging from 0% to 20%,7–13,15 the decision in favor of prophylactic mastectomy, particularly if a strong ovarian cancer family history is not the case, is easier than in women with BRCA1 mutation. Indeed, women with BRCA1 mutation do not only have a high risk for breast cancer but also a substantial ovarian cancer lifetime risk of approximately 40% (range, 16% to 63%).6–14 Thus, many oncologists recommend prophylactic oophorectomy after completion of childbearing for risk-reducing ovarian and breast cancer as well as because of lower side-effects profile of oophorectomy rather than mastectomy. The delay of oophorectomy timing after childbearing is not likely associated with increased risk of ovarian cancer because the average age at diagnosis is approximately 50 years.14,21
In summary, science-based medical decision-making between prophylactic bilateral mastectomy and oophorectomy is now not feasible for women with BRCA mutations who choose to undergo surgical intervention. Extensive and detailed consideration of a series of parameters, including penetrance, family history, effectiveness, morbidity, and quality of life in each individual woman should be considered. For carriers of BRCA2 mutation without a strong family history of ovarian cancer prophylactic mastectomy is preferable because the risk of ovarian cancer is substantially lower than that of breast cancer. However, decision-making for carriers of BRCA1 mutation is highly complicated and remains particularly personal after extensive counseling.
Received for publication October 9, 2002. Accepted for publication October 16, 2002.
REFERENCES
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