Challenges in Surgical Preventive Decision for BRCA1/BRCA2-Mutation Carriers

Dimitrios H. Roukos, MD, Niki J. Agnantis, MD, Evangelos Paraskevaidis, MD and Angelos M. Kappas, MD
From the Departments of Surgery (DHR, AMK), Pathology (NJA), and Obstetrics & Gynecology (EP), Ioannina University School of Medicine, 45110 Ioannina, Greece, droukos@cc.uoi.gr

Despite advances in 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 substantially higher risk for developing breast cancer rather than ovarian cancer, a 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 cancers[2,3] and ovarian cancers.[4] Thus, mutations in BRCA1 and BRCA2 genes lead to breast or ovarian cancer through different pathways. This subclassification of breast and ovarian cancer according 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 this genetic abnormalities- differs substantially between BRCA1 and BRCA2 mutation carriers and this is important for treatment decision-making.

For BRCA1-mutations carriers, penetrance estimates range from 45% to 85% lifetime risk of breast cancer and from 16% to 63% lifetime risk of ovarian cancer.[6-14] For BRCA2 mutations, penetrance is estimated to range between 26% to 85% risk of breast cancer and from 10% to 20% risk of ovarian cancer[7-11,13,15] and one study[12] 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. But all these estimates generated wide confidence intervals, indicating considerable uncertainty about the absolute magnitude of risk in an individual woman carrying the mutation. Familial cancer tends to occur at a younger age than sporadic cancer, but the increased risk in carriers of these mutations is lifelong, and in some carriers bilateral breast cancer or both breast and ovarian cancer develop.

The effectiveness of 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 to reduce 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 at 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. Which 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] reports the results of 170 carriers of BRCA mutations with a mean follow-up of two years. Ovarian cancer or a papillary serous carcinoma of the peritoneum developed in 5 of 72 women who elected intensive surveillance (6.9 percent). Of the 98 women who underwent prophylactic salpingo-oophorectomy, 3 had early-stage tumors that were diagnosed at the time of surgery (3.1 percent), and primary peritoneal cancer developed in 1 patient during follow-up (1.0 percent). The latter type of tumor is believed that derives 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 percent) and 3 of the 69 women in the oophorectomy group (4.3 percent).

All 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 in the ovary, since 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 early stage. However, the available data in BRCA mutations indicate the failure of early diagnosis for both breast[17] and ovarian cancer.[22] Whether in carriers of BRCA mutations magnetic resonance imaging (MRI) screening adds to the efficacy of mammographic screening for early breast cancer detection[26] and whether positron emission tomography (PET) adds to the efficacy of ovarian ultrasonography and CA-125-based screening for early-stage ovarian cancer is now unknown. At the present time and until data with MRI and PET will be available, earlier diagnosis rates seem to be higher for breast rather than for ovarian cancer.

For a complete protection of women with BRCA mutations against cancer in both breasts and ovaries prophylactic bilateral mastectomy and salpingo-oophorectomy has 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 depended on population ascertainment; very high in multiple-cases families 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 better side-effects profile. The delay of oophorectomy timing after childbearing does not likely associated with increased risk of ovarian cancer because the average age at diagnosis is about 50 years.[14, 21]

The high side-effects profile of risk-reducing surgery justifies the high proportion, approximately 50%, of BRCA1/BRCA2 carriers who currently choose surveillance. Indeed, advances in imaging technology including MRI and PET may allow an early detection of breast lesions in women with inherited susceptibility. A close surveillance therefore, probably each 6 months to avoid intervals cancer, is recommended for these women. The addition of chemoprevention may delay the early-onset disease. The selective estrogen receptor modulators tamoxifen or raloxifen, which have been proven effective in the prevention of specific subgroup of women with sporadic breast cancer,[27-28] provide promises for effective prevention. Because the utility of combination of close surveillance and chemoprevention is unclear, we recommend that these women should participate in clinical trials for the assessment of effectiveness of this nonsurgical preventive intervention.

In summary, a 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. Decision-making is complex, sophisticated and needs interpretation of a multivariate analysis by a multidisciplinary team of surgeons, oncologists and geneticists. For carriers of BRCA2 mutation, especially if there exists no strong history of ovarian cancer, because of a moderate risk of ovarian cancer, decision is easier and prophylactic mastectomy is preferable. However, for BRCA1-mutation carriers decision is highly complicated and remains particularly personal after extensive counselling.

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